ECMO is becoming widely used as a life saving measure for critically ill patients. However, there is limited data on pharmacokinetics and dosing of beta-lactam antibiotics in ECMO. In this study, we evaluated the serum concentrations of cefepime in patients on ECMO to determine the impact of ECMO circuitry and to guide therapeutic dosing. Methods: Patients 19 years or older admitted to the ICU, treated with ECMO and beta-lactam antibiotics for presumed or docu-mented infection, were enrolled. Three blood samples (peak, midpoint, trough) were obtained before ECMO (pre-ECMO) and during ECMO (intra-ECMO) at steady state. Results: Eight pa-tients met inclusion criteria; six received cefepime. All patients were male. Average ±SD age was 45.8±14.7. Four patients received ECMO for severe SARS-CoV-2 infection, and one each for Pneumocystis pneumonia and influenza A infection. Mean ±SD APACHE II and SOFA scores prior to ECMO were 24.6±7.1 and 11.0±3.9, respectively. All but one received venovenous (VV) ECMO. Cefepime 1 gram every 6 hours intravenously over 2 minutes was administered to all patients before and during ECMO. Cefepime concentrations were fit to a one-compartment model and area under the serum-concentration time curve averaged ± SE 204.6 ± 51.2 pre-ECMO and 344.7 ± 51.5 mg*h/L intra-ECMO, p>0.05. No patients displayed signs of cefepime neurotoxi-city. Patients received ECMO for 43.1± 30 days. All patients expired. Cefepime dosed at 1 gram every 6 hours intravenously appears to achieve therapeutic levels for critically ill patients on ECMO.

To analyze the effects of CYP3A5 polymorphism on liver function after LT and to characterize the pharmacokinetics of tacrolimus after conversion from a twice-daily regimen to a once-daily extended-release formulation. A prospective open-label study included 60 stable liver transplant recipients who underwent 1:1 conversion from twice-daily tacrolimus to once-daily tacrolimus. All participants were genotyped for CYP3A5 polymorphism. The study was registered at ClinicalTrials.gov (NCT 02882113). Twenty-eight patients were enrolled in the CYP3A5 expressor group and 32 in the non-expressor group. Although there was no statistical difference, incidence of liver dysfunction was higher in the expressor group than in the non-expressor group when converted to once-daily extended-release tacrolimus (P=0.088). No biopsy-proven acute rejection, graft failure, and mortality were observed in either group. The decrease in dose-adjusted trough level (- 42.9% vs. - 26.1%) and dose/kg-adjusted trough level of tacrolimus (- 40.0% vs. - 23.7%) was significantly greater in the expressor group than in the non-expressors after the conversion. The absorption of the tacrolimus in the non-expressor group was slower than in the expressors. In line with this observation, the AUC for once-daily tacrolimus correlated with Cmin in the non-expressors and Cmax in the expressors. Determination of CYP3A5 genotype in liver transplant recipients might be helpful in prediction of tacrolimus pharmacokinetics after conversion from a twice-daily regimen to a once-daily formulation.

Invasive aspergillosis (IA) is an opportunistic infection affecting immunocompromised patients. Current clinical guidelines support the use of voriconazole for the treatment of IA, although this treatment is not free of interactions in this group of patients who are often treated with polytherapy; in these cases, isavuconazole may be a safe alternative with a lower risk of interactions. The oral route is commonly preferred to the parenteral route, but in patients who do not have access to the enteral route, the use of isavuconazole is limited to the parenteral route only, since the technical information sheet does not recommend the handling of tablets for enteral administration, stating that the capsules should not be chewed, crushed, dissolved or opened. This paper presents the case of a patient with diffuse large B-cell lymphoma with confirmed AI on treatment with isavuconazole by enteral tube. It is detailed here that isavuconazole concentrations are maintained when administered by enteral tube, as measured by therapeutic pharmacokinetic monitoring of its plasma concentrations. Administering isavuconazole by enteral tube was found to be a safe practice with monitoring of its plasma concentrations.

Extracorporeal membrane oxygenation (ECMO) is increasingly used in intensive care units; however, ECMO can modify drug pharmacokinetics (PK), leading to underexposure and associated treatment failure. The aim of the present study was to determine the effect of ECMO on the PK of dexmedetomidine (DEX). In vivo rat models were developed, both of which involved a bolus injection of DEX and concentration monitoring. In the in vivo model experiment, rats which underwent ECMO were compared with a control group. PK analysis of in vivo data (noncompartmental analysis and nonlinear mixed-effects modelling) was carried out to determine the effect of ECMO. In vivo PK exploration showed that ECMO induced a decrease in DEX clearance. Because the effect of ECMO on the PK of DEX is not clinically significant, normal DEX dosing for critically ill patients should be effective for patients undergoing ECMO.

The body of evidence available in paediatrics population is limited for making clinical decisions regarding pharmacotherapy optimization of tacrolimus. The objective of this study was to estimate the frequency of CYP3A5 genetic polymorphisms and their relationship with tacrolimus requirements in paediatric population. This was a longitudinal cohort study, with two-year follow-up of 77 patients under 18 who had liver transplant over the period 2009-2012 at the Paediatric Hospital J. P Garrahan. Tacrolimus levels from day 5 to 2-year post-transplant were obtained from hospital records of routine therapeutic drug monitoring. The genotyping of CYP3A5 (CYP3A5*1/*3 or *3/*3) were performed in liver biopsies of both the donor and the recipient. Recipients frequency of CYP3A5 *1 expression was 37.1% and 32.2% for Donors. Patient who received an organ expresser showed lower Co/dose especially after 90 days post-surgery. The role of each polymorphism is different according to days after transplantation proceeds and it must be taken into account to optimize the benefits of TAC therapy during the post-transplant induction and maintenance phase.

Background: Tilmicosin, a macrolide antibiotic, has the potential to treat bacterial respiratory infections in donkeys. However, the pharmacokinetics of tilmicosin in donkeys have not been reported. Objectives: The aim of this study was to investigate the pharmacokinetics of tilmicosin in donkey plasma, urine and feces after a single intragastric administration to determine the suitability of tilmicosin for donkeys. Animals: A total of 4 healthy fattening male donkeys were selected with body weights of 148, 140, 145, and 135 kg, with an average body weight of 142.00 ± 4.95 kg. Methods: The donkeys were administered intragastrically a single dose of 10 mg·kg-1 BW tilmicosin. Blood, urine and fecal samples were collected. The concentrations of tilmicosin in plasma, urine, and feces were determined using high-performance liquid chromatography-tandem masss pectrometry. Results: After a single intragastric administration of 10 mg·kg-1 body weight, tilmicosin in donkey plasma reached a maximum concentration of 11.23 ± 5.97 mg·L-1 at 0.81 ± 0.11 h, with a mean residence time of 8.05 ± 2.44 h, a Cl/F of 0.48±0.22 L·kg-1·h-1, and a Vd/F of 9.28 ± 4.10 L·kg-1. The percentage of tilmicosin excreted through the urine of donkeys is (2.47±0.43)%, and the percentage excreted through the feces is (66.43±8.65)%. Conclusions: A single intragastric administration of 10 mg·kg-1 BW of tilmicosin to donkeys was rapidly absorbed and was able to achieve plasma concentrations of against pathogenic bacteria.

Overactive bladder (OAB) is characterized by urinary urgency and increased urinary frequency, and can impact quality of life significantly. Tamsulosin and mirabegron combination therapy has been studied as a safe and effective treatment option for patients with OAB. This study evaluated the effects of combining these two drugs on their pharmacokinetics and safety profiles in healthy Korean males. In this open-label, fixed-sequence, 3-period, drug-drug interaction phase 1 study, a total of 36 male participants were administered multiple doses of tamsulosin alone (0.2 mg once daily), mirabegron alone (50 mg once daily), and a combination of both drugs. The results showed that the combination of tamsulosin and mirabegron increased tamsulosin exposure in the plasma by approximately 40%. In contrast, the maximum plasma concentration of mirabegron reduced by approximately 17%, when administered along with tamsulosin. No clinically significant changes in safety profiles, vital signs, or clinical laboratory test results were observed in this study. In conclusion, there were no clinically relevant drug-drug interactions between tamsulosin and mirabegron in terms of pharmacokinetics, safety, and tolerability, suggesting that their combination therapy could be a promising treatment option for patients with OAB.

Fexuprazan is a potassium-competitive acid blocker approved for treating gastric acid-related diseases. Herein, we evaluated the pharmacokinetics (PKs) of single-dose and multiple-dose oral administration of fexuprazan 10 mg tablets in healthy subjects (Part 1) and investigated the bioequivalence between fexuprazan 10 mg and 40 mg tablets (Part 2). Part 1 comprised a single- and multiple-dose, 1-sequence, and 2-period design, and Part 2 comprised a single-dose, 2×2 crossover design. Eight and 23 subjects completed Parts 1 and 2, respectively. In Part 1, multiple doses accumulated twice as much as single doses. In Part 2, the geometric mean ratios [90% confidence intervals] for maximum plasma concentration (Cmax) and area under the concentration–time curve from zero to the time of the last quantifiable concentration (AUClast) of four fexuprazan 10 mg tablets to those of one fexuprazan 40 mg tablet were 1.0290 (0.9352–1.1321) and 1.0290 (0.9476–1.1174), respectively, which met bioequivalence criteria. Overall, favorable PK was observed after single and multiple administrations of one fexuprazan 10 mg tablet, and four fexuprazan 10 mg tablets were pharmacokinetically equivalent to one fexuprazan 40 mg tablet.

Ecdysterone is a phytosteroid widely discussed for its various pharmacological, growth-promoting and anabolic effects mediated by activation of estrogen receptor beta (ERbeta). Performance-enhancement in sports was demonstrated recently, and ecdysterone was consequently included in the Monitoring Program to detect potential patterns of misuse in sport. Only few studies on the pharmacokinetics of ecdysterone in humans have been reported so far. In this study, post-administration urines in twelve volunteers (single dose of 50 mg of ecdysterone) were analyzed using dilute-and-inject liquid chromatography-tandem mass spectrometry. Identification and quantitation of ecdysterone and of two metabolites, 14-deoxy ecdysterone and 14-deoxy poststerone was achieved. Ecdysterone was the most abundant analyte present in post-administration urines, detected for more than 2 days with a maximum concentration (Cmax) in the 2.8-8.5 h urines (Cmax = 4.4-30.0 µg/mL). The metabolites 14-deoxy ecdysterone and 14-deoxy poststerone were detected later reaching the maximum concentrations at 8.5-39.5 h (Cmax = 0.1-6.0 µg/mL) and 23.3-41.3 h (Cmax = 0.1-1.5 µg/mL), respectively. Cumulative urinary excretion yielded average values of 18%, 2.3% and 1.5% for ecdysterone, 14-deoxy ecdysterone and 14-deoxy poststerone, respectively. Ecdysterone and 14-deoxy ecdysterone were excreted following first order kinetics with half-lives calculated with three hours, while pharmacokinetics of 14-deoxy poststerone needs further evaluation.

Ceftiofur (CEF) sodium is a third-generation broad-spectrum cephalosporin commonly used in an extra-label manner in dogs for the treatment of respiratory and urinary system infections. To contribute to the literature supporting CEF use in companion animals, we have developed a compartmental, nonlinear mixed-effects (NLME) model of CEF pharmacokinetics in dogs (PK). We then used the mathematical model to predict (via Monte Carlo simulation) the duration of time for which plasma concentrations of CEF and its pharmacologically active metabolites remained above minimum inhibitory concentrations (respiratory tractEscherichia coli spp). Twelve healthy beagle dogs were administered either 2.2 mg/kg ceftiofur-sodium (CEF-Na) intravenously (I.V) or 2.2 mg/kg CEF-Na subcutaneously (S.C). Plasma samples were collected over a period of 72 hours post-administration. To produce a measurement of total CEF, both CEF and CEF metabolites were derivatized into desfuroylceftiofur acetamide (DCA) before analysis by UPLC-MS/MS. No adverse effects were reported after I.V or S.C dosing. The NLME PK models were parameterized using the stochastic approximation expectation maximization algorithm as implemented in Monolix 2018R2. A two-compartment mamillary model with first-order elimination and first-order S.C absorption best described the available kinetic data. Final parameter estimates indicate that CEF has a low systemic clearance (0.25 L/h/kg) associated with a low global extraction ratio E = 0.02) and a moderate volume of distribution (2.97 L/kg) in dogs. The absolute bioavailability after S.C administration was high (93.7%). Gender was determined to be a significant covariate in explaining the variability of S.C absorption. Our simulations predicted that a dose of 2.2 mg/kg CEF-Na S.C would produce median plasma concentrations of CEF of at least 0.5 µg/mL (MIC₅₀) for approximately 30 hours.

Background: pathophysiological changes like low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80-125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80-125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40-50%, a dose reduction of 15% is warranted in neonates, infants and children, 25% in adolescents and adults. Conclusions: PBPK driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, proportionally greater in adults. Consequently, age group specific dose reductions for propofol are required in LCO conditions.

Exogenous melatonin, a nutraceutical for maintaining a healthy sleep-wake cycle and managing sleep disorders, requires large, repeated doses due to low bioavailability and short half-life. This necessitates the development of a sustained-release formulation with a longer half-life and sustained plasma concentration. Therefore, exogenous novel 5 mg sustained-release melatonin capsules (Melatonin-SR, test product) were formulated. This open-label cross-over study compared the pharmacokinetics (maximum concentration [Cmax], time to reach Cmax [Tmax], area under the curve [AUC] and elimination half-life [t1/2]) and safety of Melatonin-SR with 5 mg immediate-release melatonin capsules (Melatonin-IR, reference product) after single-dose oral administration in healthy fasting adults. Sixteen participants (aged 18-45 years) were randomized (1:1) to receive either Melatonin-SR or Melatonin-IR in two periods with a 7-day washout period. Melatonin-SR reported lower Cmax (11446.87 pg/mL) compared to Melatonin-IR (22786.30 pg/mL). The mean Tmax of Melatonin-SR and Melatonin-IR was 1.26 h and 0.87 h, respectively. The mean t1/2 of Melatonin-SR (5.10 h) was prolonged by five-fold compared to Melatonin-IR (1.01 h). One adverse event (vomiting) was reported following administration of the Melatonin-IR. Melatonin-SR resulted in higher and sustained plasma melatonin concentrations for an extended period and was well-tolerated. Hence, Melatonin-SR may be a promising nutraceutical for maintaining healthy sleep.

Objective: Infliximab (IFX) concentrations are a predictive factor (PF) of pharmacokinetic (PK) origin in the treatment of Crohn’s disease (CD). We evaluated clearance, another PF of PK origin, either alone or in combination with concentrations. Methods: PF of PK origin were evaluated from two cohorts, the first received standard dosing (n=37), and the second was designed to proactively target therapeutic IFX concentrations (n=108). Concentrations were measured using homogenous mobility shift assay. Clearance was estimated using nonlinear mixed effects methods with Bayesian priors. C-reactive protein based clinical remission (<3mg/L in the absence of symptoms) was used for the disease control outcome. Longitudinal changes in disease control due to factors including time, IFX concentration, and clearance were analyzed using repeated event analysis. Change in objective function value (∆OFV) was calculated to compare concentration and clearance. Results: Lower baseline clearance and proactive dosing associated with enhanced disease control during induction (p<0.01). Higher IFX concentrations and lower Clearance measured at the second, third and fourth infusion yielded improved disease control during maintenance (p<0.032). During maintenance, the association with disease control was better with clearance than with concentrations (∆OFV= -19.2; p<0.001), and the combination of both further minimized OFV (p<0.001) with markedly improved clinical yield in the presence of both PF of PK origin. Conclusion: PF of PK origin and lower clearance during induction and maintenance yielded enhanced disease control in pediatric CD treated with IFX. The combination of IFX concentration and clearance are better predictors of therapeutic outcome compared to either one alone.

Malnutrition in children is a global health problem, particularly in developing countries. The effects of an insufficient supply of nutrients on body composition and physiological functions may have implications for drug disposition and ultimately affect the clinical outcome in this vulnerable population. Physiologically based pharmacokinetic (PBPK) modeling can be used to predict the effect of malnutrition as it links physiological changes to pharmacokinetic (PK) consequences. However, the absence of detailed information on body composition and the limited availability of controlled clinical trials in malnourished children complicates the establishment and evaluation of a generic PBPK model in this population. In this manuscript we describe the creation of physiologically-based bridge to a malnourished pediatric population, by combining information on a) the differences in body composition between healthy and malnourished adults and b) the differences in physiology between healthy adults and children. Model performance was confirmed using clinical reference data. This study presents a physiologically-based translational framework for prediction of drug disposition in malnourished children. The model is readily applicable for dose recommendation strategies to address the urgent medicinal needs of this vulnerable population.

A sensitive and robust liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of nimbolide in mouse serum. Exemestane was used as the internal standard (IS). Here, we employed acetonitrile-based protein precipitation (PPT) for serum sample preparation, and performed chromatographic separation using an ODS Hypersil C18 column (100×2.1 mm, 5µm) with gradient elution (0.1% formic acid in water vs 100% acetonitrile). The run time was 6 min. Instrumental analysis was performed by electrospray ionization tandem mass spectrometry (ESI-MS/MS) in the multiple-reaction monitoring (MRM) under positive mode. A good linear calibration was achieved in the 5–1000 ng/ml range. The intra- and inter-day precisions for nimbolide were ≤ 12.6% and ≤ 13.9 % respectively. Intra-day accuracy ranged from 96.9% – 109.3% while inter-day accuracy ranged from 94.3% – 110.2%. The matrix effect of nimbolide, detected but consistent at low and high concentrations, do not affect linearity of standard curve. In conclusion, we have developed and validated a sensitive analytical method for determination of a novel natural compound nimbolide in mouse serum and it has been successfully applied to our preclinical study in investigating the pharmacokinetic properties of nimbolide, which could greatly facilitate the preclinical development of the promising lead compound for anticancer therapy.

The objective of this work is to evaluate the potential effect of cardiac stress exercise on the accumulation of [¹²³I]IAZA, a radiopharmaceutical used to image focal tissue hypoxia, in otherwise normal myocardium in healthy volunteers, and to determine the impact of exercise on [¹²³I]IAZA pharmacokinetics. The underlying goal is to establish a rational basis and a baseline for studies of focal myocardial hypoxia in cardiac patients using [¹²³I]IAZA. Three healthy male volunteers ran the ‘Bruce’ treadmill protocol, a clinically-accepted protocol designed to expose myocardial ischemia in patients. The ‘Bruce’ criterion heart rate is 85% of [220 – age]. Approximately one minute before reaching this level, [¹²³I]IAZA (5.0 mCi/0.85 mg) was administered as a slow (1–3 min) single intravenous (i.v.) injection via an indwelling venous catheter. The volunteer continued running for an additional 1 min before being transferred to a gamma camera. Serum samples were collected from the arm contralateral to the administration site at pre-determined intervals from 1 min to 45 h post injection and were analyzed by radio HPLC. Pharmacokinetic (PK) parameters were derived for [¹²³I]IAZA and total radioactivity (total[¹²³I]) using compartmental and noncompartmental analyses. Whole-body planar scintigraphic images were acquired from 0.75 to 24 h after dosing. PK data and scintigraphic images were compared to previously published [¹²³I]IAZA data from healthy volunteers rest. Following exercise stress, both [¹²³I]IAZA and total[¹²³I] exhibited bi-exponential decline profiles, with rapid distribution phases [half-lives (t_1/2α) of 1.2 and 1.4 min, respectively], followed by slower elimination phases [t_1/2β of 195 and 290 min, respectively]. Total body clearance (CL_TB) and the steady state volume of distribution (V_ss) were 0.647 L/kg and 185 mL/min, respectively, for [¹²³I]IAZA and 0.785 L/kg and 135 mL/min, respectively, for total[¹²³I]. The t_1/2β, CL_TB and V_ss values were comparable to those reported previously for rested volunteers. The t_1/2α was approximately 4-fold shorter for [¹²³I]IAZA and approximately 3-fold shorter for total[¹²³I] under exercise relative to rested subjects. The heart region was visualized in early whole body scintigraphic images, but later images showed no accumulated radioactivity in this region, and no differences from images reported for rested volunteers were apparent. Minimal uptake of radiotracer in myocardium and skeletal muscle was consistent with uptake in non-stressed myocardium. Whole-body scintigrams for [¹²³I]IAZA in exercise-stressed healthy volunteers were indistinguishable from images of non-exercised volunteers. There was no evidence of hypoxia-dependent binding in exercised but otherwise healthy myocardium, supporting the conclusion that exercise stress at Bruce protocol intensity does not induce measurable myocardial hypoxia. Effects of exercise on PK parameters were minimal; specifically, the t_1/2α was shortened, reflecting increased cardiac output associated with exercise. It is concluded that because [¹²³I]IAZA was not metabolically bound in exercise-stressed myocardium, a stress test will not create elevated myocardial background that would mask regions of myocardial perfusion deficiency. [¹²³I]IAZA would therefore be suitable for the detection of viable, hypoxic myocardium in patients undergoing stress-test-based diagnosis.

A rapid and simple high-performance liquid chromatography (HPLC) method using extraction with zinc sulfate has been developed for the determination of Casiopeina III-ia (Cas III-ia) and validated over the linear range 10-120 g/mL in 200 L of rabbit blood. Previously we have reported a HPLC method to quantify CasIII-ia in plasma, but in distribution studies in total blood [20], the Cas III-ia concentrations were higher in total blood that in plasma [19]. The analysis was performed on a Symmetry C (18) (5 microm) column. The mobile phase was Methanol-sodium phosphate buffer (pH 6.5; 0.01 M) (40:60 v/v) was kept at a flow-rate of 0.8 ml/min. The analyses were performed at room temperature. The column effluent was monitored at 262 nm. Acetaminophen was used as internal standard. The results showed that the assay is sensitive at 10 g/mL. Maximum intra-day coefficient of variation was 5.10%. The average recovery obtained in blood was 94.51%. The applicability of this method for distribution in vitro and pharmacokinetic studies in rabbits was demonstrated. Conclusions: the present assay is rapid, simple, precise, and accurate. The pharmacokinetic study was carried out in rabbits and the following pharmacokinetic parameters were obtained: (kel) = 0.0150 min-1, half-life time (T1/2) = 53.92 min, apparent volume of distribution (Vd) = 202.81 mL, clearance (Cl) = 2.08 mL /mi and area under the curve (AUC)=23163.85 µg/mL.min. Contributing to the preclinical characterization of the Cas III-ia.

A Tamoxifen (TAM) response varies significantly among individuals due to genetic variations in cytochrome P450 2D6 (CYP2D6), as well as other TAM pharmacokinetic and/or pharmacodynamic proteins. In this study, 40 ER+ breast cancer patients who received at least 6 months of TAM treatment were prospectively recruited. The study aimed to evaluate, using HPLC-MS/MS, plasma concentrations of TAM and its metabolites, and to study the association with genetic polymorphisms (CYP2D6*4, CYP3A4*1B, CYP3A5*3, UGT2B7*2, UGT2B15*2, SULT1A1*2, and ESR1V364E) and adverse reactions. Bivariable linear regression analyses showed that CYP3A4*1/*1B is significantly associated with an increase of 4-hydroxyTAM plasmatic concentration, a decrease of endoxifen/4-hydroxyTAM ratio and the elimination of 17β estradiol. It was found that the CYP3A4*1/1B genotype alone could explain part of the variability in [4OHTAM], [endoxifen]/[4OHTAM], and 17β-estradiol plasma levels. Similarly, SULT1A1*1/*2 genotype affects the [endoxifen]/[4OHTAM] plasma ratio. Multivariable predictive models, incorporating both polymorphisms and non-genetic variables, are proposed to explain [NdesMeTAM]/[TAM], [4OHTAM]/[TAM], [endoxifen]/[NdesMeTAM], [endoxifen]/[4OHTAM], and 17β-estradiol plasma levels, as well as for predicting hot flashes and cramps. This preliminary study suggests that the genetic variants studied may influence the bioactivation and elimination of TAM, the clinically observed adverse reactions, and potentially the treatment efficacy.

Not occasional phamracokinetic variability and suboptimal exposure have been reported for micafungin in the intensive-care-unit (ICU) patients. This study aims to evaluate the quality of population pharmacokinetic models and provide rational using recommendation of this drug in clinical practice. Monte Carlo simulations were implemented to compare pharmakinetic parameters and probability of target attainment (PTA) towards various Candida species. Body weight, liver function, and SOFA score were the most frequent covariates in the final 16 included studies. micafungin clearance for ICU adults (SOFA≥10 or &lt;10) was 39%–52% and 43%–57% higher, respectively, than non-ICU adults. For Candida infections with MICs &lt;0.016 mg/L, the ICU group had lower proportions achieving PTA &gt; 90% compared to the non-ICU group (2/6 (33%) vs. 4/7 (57%)), and for non-ICU and ICU adults, micafungin dosages of 100 and 150 mg were recommended, respectively. While for C. tropicalis and C. glabrata, 200 and 250 mg were recommended respectively. However, for C. krusei and C. parapsilosis, it failed to reach assumed PTA at MICs of 0.125-0.25 mg/L and 0.125-2 mg/L, respectively. Adjusting micafungin dosage in ICU patients may be necessary. Both ICU and non-ICU adults should modify their dosage regimens based on the Candida species and their respective MICs.

Demethyleneberberine is an active component extracted from the Chinese herbal drug Cortex Phellodendri. It is also a metabolite of the berberine in animals and humans. However, the pharmacokinetics, tissue distribution and excretion of demethyleneberberine have not been reported. The present study aimed to investigate the pharmacokinetic parameters of demethyleneberberine by developing a method of high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The detection was performed by using positive ion electrospray ionization in multiple reaction monitoring mode. The MS/MS ion transitions were monitored at m/z 324.4→308.3 for demethyleneberberine and 465.5→350.3 for IS. After oral administration of demethyleneberberine in rats and mice, the pharmacokinetics, tissue distribution, and excretion of desmethylberberine in rats and mice were comparatively studied for the first time. The plasma concentration of desmethylberberine reached its peak within 5 min after oral administration in both rats and mice. The bioavailability of rats and mice was comparable, ranging from 4.47% to 5.94%, higher than that of berberine. The total excretion of desmethylberberine in urine, feces and bile is 7.28~9.77%. These findings provide valuable insights into the pharmacological and clinical research on desmethylberberine.

Febuxostat (FBX), a selective xanthine oxidase inhibitor, belongs to BCS class II showing low solubility and high permeability with a moderate F value (&lt; 49%). Recently, FBX/L-pyroglutamic acid cocrystal (FBX-PG) was developed with improving 4-fold increase of the FBX solubility. Nevertheless, in vivo pharmacokinetic property of FBX-PG has not been evaluated yet. Therefore, the pharmacokinetic feasibility of FBX in FBX and FBX-PG-treated rats and mice was compared in this study. The results showed that the F values of FBX were 210% and 159% in FBX-PG rats and mice, respectively. The 2.10-fold greater AUC of FBX was due to the increased absorption (i.e., 2.60-fold higher Cmax,1 at 15 min) and entero-hepatic circulation of FBX (i.e., 1.68-fold higher Cmax,2 at 600 min) in FBX-PG rats compared to the FBX rats. The 1.59-fold greater AUC of FBX was due to a 1.65-fold higher Cmax,1 at 5 min, and 1.15-fold higher Cmax,2 at 720 min of FBX in FBX-PG mice than those in FBX mice. FBX was highly distributed in the liver, stomach, small intestine, and lungs in both groups of mice, and the FBX distributions to the liver and lungs were increased in FBX-PG mice compared to FBX mice. The results suggest the FBX-PG has a suitable pharmacokinetic profile of FBX for improving its oral F value.

The pharmacokinetics of salicylic acid (SA) in sheep was evaluated following intravenous (IV) and oral administration of sodium salicylate (sodium salt of salicylic acid) at different doses. Six healthy sheep were administered sodium salicylate (SS) IV at doses of 10, 50, 100 and 200 mg/kg body weight and another six sheep were drenched with 100 and 200 mg/kg of SS orally. Both studies were randomised crossover trials. A one-week washout period between each treatment was allowed in both studies. Blood samples were collected at 0, 15, 30 minutes and 1, 2, 4 and 6 hours after IV and oral SS administrations. Plasma SA concentrations were determined using high performance liquid chromatography with diode array detection method. Pharmacokinetic variables were calculated in a non-compartmental model. The elimination half-life (T_{1/2 el}) of SA after IV administration of 200 mg/kg SS was 1.16 ± 0.32 hours. Mean bioavailability of SA was 64%, and mean T_{1/2 el} was 1.90 ± 0.35 hours, after 200 mg/kg of oral SS. The minimum plasma SA concentration (16.8 µg/mL) required to produce analgesia in humans was achieved after IV administration of 100 and 200 mg/kg SS in sheep for about 0.17 hour in this study. Experiments on pharmacokinetic-pharmacodynamics modelling are required to determine the actual effective plasma concentration range of SA in sheep.

Anticonvulsant drugs are widely used in the management of epilepsy and other neurological disorders. However, their concomitant use with other medications can lead to significant drug interactions, impacting both efficacy and safety. This article aims to provide a comprehensive overview of common anticonvulsant interactions with other frequently used drugs. It discusses the mechanisms of these interactions, their clinical implications, and strategies for managing them. The article also highlights the importance of monitoring and patient education in minimizing adverse outcomes.

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for the efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1 and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7, with half maximal inhibitory concentration (IC50) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10−5 nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via sequestration of bio-relevant metal ions (i.e. Fe3+ and Cu2+), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of HL has a significantly longer half-life t1/2 of 21.61 ± 9.4 h, nearly doubled as compared to that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration.

The supramolecular based macrocyclic amphiphiles have attracted great attention in the field of drug delivery due to their unique self-assembling nature. Therefore, these macrocycles are used as nanocarriers for the delivery of poor water soluble drugs, and also for those which have lower permeability, and cannot cross the barrier to reach the desired site. Herein, we design and synthesized a new supramolecular amphiphilic macrocycle to overcome these problems. The macrocycle was synthesized in two steps. In first step 4-hydroxybenzaldehyde was treated with 1-bromotetradecane to obtain a derivatized product which was then treated with resorcinol to cyclize and get calix(4)resorcinarene based supramolecular amphiphilic macrocycle. The synthesized macrocycle and intermediate products were characterized by Mass spectrometry, IR and 1H-NMR spectroscopic techniques. The amphiphile was screened for biocompatibility studies, vesicles formation, and then Amphotericin-B was loaded in the supramolecular amphiphile based vesicles and was characterized for shape, size, homogeneity, surface charge, drug entrapment, in-vitro release profile and stability through atomic force microscopy (AFM), Zetasizer, HPLC and FT-IR. Amp-B loaded macrocycle based vesicles were investigated for in-vivo bioavailability in rabbits. The synthesized macrocycle was nontoxic in cancer cells, hemo-compatible and safe in mice. The drug-loaded macrocycle based vesicles appeared spherical, nano-ranged, and homogeneous in size with negative surface charge and were able to load an increased amount of drug. The vesicles are stable upon storage and when incubated with gastric simulated fluid. Amp-B increased oral bioavailability was achieved when delivered in synthesized macrocycle based vesicles. These results point out that the synthesized supramolecular amphiphile is an efficient nanocarrier to enhance the oral bioavailability of lipophilic drugs

Rapid in vitro assessment of antimicrobial drug efficacy under clinically relevant pharmacokinetic conditions is an essential element of both drug development and clinical use. Here we present an overview of a novel integrated methodology for rapid assessment of such efficacy, particularly against emergence of resistant bacterial strains, as jointly researched by the authors in recent years. This methodology enables rapid in vitro assessment of antimicrobial efficacy of a single or multiple drugs in combination, following clinically relevant pharmacokinetics. The proposed methodology entails (a) automated collection of longitudinal time-kill data in an optical-density instrument; (b) processing of collected time-kill data with the aid of a mathematical model to de-termine optimal dosing regimens under clinically relevant pharmacokinetics for a single or mul-tiple drugs; and (c) in vitro validation of promising dosing regimens in a hollow fiber system. Proof-of-concept of this methodology through a number of in vitro studies is discussed. Future directions for refinement of optimal data collection and processing are discussed.

Galangin(Gal) is a natural active flavonoid compound separated from the roots and rhizomes of Alpinia ofcinarum Hance. Modern pharmacological studies have shown that Gal has a variety of biological activities such as anti-tumor, anti-fungal, anti-bacterial, anti-inflammatory, anti-ischemic stroke, suppressing vitiligo and Alzheimer’s disease, etc. The purpose of this research was to prepare a galangin self-microemulsion drug delivery system (Gal-SMEDDS) and compare its anti-oxidant activity and pharmacokinetics with free Gal.The average particle size of the prepared Gal-SMEDDS was approximately 21.33 nm, the polydispersity index was 0.096, the zeta potential was -4.09 mV, and the entrapment efficiency was 96.74%. Compared with free Gal, the release of Gal-SMEDDS was improved in vitro release experiment. Cell experiments showed that Gal had obvious anti-oxidation effect, and the effect of Gal-SMEDDS was better than that of free Gal. In vivo pharmacokinetic experiments showed that the pharmacokinetic parameters of Gal-SMEDDS were better than that of free Gal, which indicated that the self-microemulsion drug delivery system(SMEDDS) effectively increases the oral bioavailability of Gal and alters its pharmacokinetic parameters, such that it may be effective in the treatment of anti-oxidant.

A novel, rapid and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the evaluation of OTS167 pharmacokinetics in mouse serum. SN-38 was optimized to be selected as the internal standard. Chromatographic separation was performed on a BDS Hypersil C18 column (100 x 2.1 mm, 5 µm) using gradient elution with mobile phase solvent A as water containing 0.1% formic acid and solvent B as acetonitrile containing 0.1% formic acid. The analysis was carried out using multiple reaction monitoring (MRM) with a triple-quadrupole mass spectrometer operated in the positive electrospray ionization mode. Mass transitions of 487.2 > 348.0 and 393.2 > 349.2 were monitored for OTS167 and SN-38 respectively. The standard calibration curve demonstrated high linearity at a range of 5-1000 ng/mL, with a coefficient of determination (r2) ≥ 0.996. The accuracy for OTS167 ranged from 92.3% to 102.2% and the precision was ≤ 12.7%. Recovery was consistent at about 83% to 89%. No significant matrix effect was observed. This method was successfully applied to monitor the pharmacokinetic profiles in mice over 24 h after ingestion of 5 mg/kg of OTS167. Maximum serum concentrations (3197 ng/mL) of OTS167 was observed at 1.67 hour after OTS167 ingestion via garage at 5 mg/kg and area under the curve (AUC) was 28579 h*ng/mL, suggesting that OTS167 can be quickly absorbed after oral administration.

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of fenretinide, a synthetic retinoid chemically related to all-trans-retinoic acid, after administration of a novel oral nanoformulation of fenretinide, called bionanofenretinide (BNF). BNF was developed to overcome the major limitation of fenretinide: its poor aqueous solubility and bioavailability due to its hydrophobic nature. The method proved to be reproducible, precise, and highly accurate for the measurement of the drug and the mains metabolites. The lower limit of quantification resulted 1 ng/mL. The curve range of 1-500 ng/mL and 50-2000 ng/mL, for plasma and tumor homogenate respectively, was appropriate for the analysis, as demonstrated by the accuracy between 96.8% and 102.4% for plasma and 96.6-102.3% for tumor. The inter-days precision and accuracy determined on quality controls at 3 different levels were in ranges of 6.9%-7.5% and 99.3-101.0% and 0.96-1.91% and 102.3-105.8% for plasma and tumour, respectively.

Flomoxef (FMX) may be a potential alternative to carbapenems for dogs infected with Enterobacterales producing extended-spectrum β-lactamase (ESBL-E). However, the appropriate dosage of FMX in dogs with ESBL-E infections has yet to be established. This study was carried out to establish appropriate treatment regimens for FMX against ESBL-E infections in dogs by a pharmacokinetics–pharmacodynamics (PK–PD) approach. Five dogs received an intravenous bolus dose of FMX (40 mg/kg). Serum FMX concentrations were evaluated using high-performance liquid chromatography-tandem mass spectrometry, and PK indices were determined based on non-compartmental model. The cumulative fraction of response (CFR) was calculated based on the distribution of minimum inhibitory concentrations among wild-type ESBL-E from companion animals. As the results, the dosage regimens of 40 mg/kg q8h and q6h were estimated to achieve a CFR of &gt;90% for wild-type isolates of ESBL-producing Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis for dogs. In contrast, all regimens exhibited a CFR of &lt;80% for ESBL-producing Enterobacter cloacae. Our results indicated that dosage regimens of 40 mg/kg FMX q8h and q6h can be a non-carbapenem treatment for dogs infected with ESBL-producing isolates of Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, but not for those infected with ESBL-producing Enterobacter cloacae.

Hepatic carboxylesterase 1(CES1) metabolizes many prodrugs into active ingredients or direct-acting drugs into inactive metabolites. We aim to develop a semi-physiologically based pharmacokinetic model(Semi-PBPK model) to simultaneously predict pharmacokinetics of CES1 substrates and their active metabolites in liver cirrhosis(LC) patients. Six prodrugs(enalapril, benazepril, cilazapril, temocapril, perindopril and oseltamivir) and three direct-acting drugs (flumazenil, pethidine and remimazolam) were selected. The parameters including organ blood flows, plasma binding protein concentrations, functional liver volume, hepatic enzymatic activity, glomerular filtration rate(GFR) and gastrointestinal transit rate were introduced into the simulation. Pharmacokinetic profiles of these drugs and their active metabolites were simulated in 100 virtual subjects. The developed semi-PBPK model, following validation in healthy subjects, was extrapolated to LC patients. Most of the observations are within the 5% and 95% quantile of simulations from 100 virtual patients. The estimated AUC and Cmax are within 0.5-2-fold of observation. The sensitivity analysis showed that the decreased plasma exposure of active metabolite due to the decreased CES1 was partly attenuated by the decreased GFR. Conclusion: The developed PBPK model has successfully predicted pharmacokinetics of CES1 substrates and their metabolites in healthy subjects and LC patients, which assists in tailoring dosages of CES1 substrates in LC patients.

Puerarin (PUE) is a compound isolated from the roots of Pueraria lobata. We studied the pharmacokinetics and tissue distribution kinetics of PUE in Sprague-Dawley rats following intraperitoneal administration of three concentrations. Indirect competitive ELISA based on an anti-PUE monoclonal antibody was used to determine the concentration of PUE in the blood, heart, liver, spleen, lung, kidney, hippocampus, cerebral cortex, and striatum. The plasma and tissue distribution kinetic characteristics following a single injection of PUE (20, 40, and 80 mg/kg) were calculated using a non-compartment model. In the high-dose (80 mg/kg) and medium-dose (40 mg/kg) groups, the kinetic profile of PUE in blood and kidney samples showed two absorption peaks, while that of the other tissues showed only one peak. In the low-dose (20 mg/kg) group, there was only one peak, irrespective of the sample type. Pharmacokinetic parameters such as the area under the curve, C_max, and T_max varied according to the administered dose. AUC and C_max values increased dose-dependently. PUE was widely distributed in areas of the brain such as the hippocampus, cerebral cortex, and striatum, providing a foundation for guiding the use of PUE in the treatment of cerebral ischaemic stroke and neurodegenerative diseases.

Curcumin, extracted from the Curcuma longa rhizome, has gained substantial attention for its anti-inflammatory, antioxidant, and neuroprotective properties. Despite these potential benefits, its low bioavailability limits its usage and potential in clinical settings. To overcome these limitations, novel formulations have been developed using liposomal, nanoparticular and micellization technologies to improve bioavailability. The current randomized, double-blind, crossover, pharmacokinetic study compared AQUATURM^®, a novel, patented water-soluble formulation, to another commercially available and widely used curcumin supplement in 12 human subjects over a 12-hour period separated by a 7-day washout period. Plasma samples were analyzed by tandem mass spectrometry detection (UPLC-MS/MS). The area under the plasma concentration-time curve indicated that the bioavailability of AQUATURM^® was over 7-fold greater than that of the other curcumin supplement, reaching concentrations up to 20 ng/mL for up to 12-hours. This study demonstrates AQUATURM^®’s superior bioavailability to that of another, conventional, widely used curcumin supplement.

LR004 is a novel chimeric (human/mouse) monoclonal antibody developed for the treatment of advanced colorectal carcinoma with detectable epidermal growth factor receptor (EGFR) expression. We aimed to investigate the preclinical pharmacokinetics (PK) and in vivo biodistribution of LR004. The PK profiles of LR004 were initially established in rhesus monkeys. Subsequently, 125I radionuclide-labeled LR004 was developed and its binding activity to the EGFR antigen were evaluated. Furthermore, the biodistribution, autoradiography, and NanoSPECT/CT of 125I-LR004 in xenograft mice bearing A431 tumors were examined. The PK data revealed a prolonged half-life and nonlinear PK characteristics of LR004 within the dose range of 6–54 mg/kg. The radiochemical purity of 125I-LR004 was approximately 98.54%, and iodination of LR004 did not affect its specific binding activity to the EGFR antigen. In a classical biodistribution study, 125I-LR004 exhibited higher uptake in highly perfused organs than in poorly perfused organs. Prolonged retention properties of 125I-LR004 in tumors were observed at 4 and 10 days. Autoradiography and NanoSPECT/CT confirmed the significant accumulation and sustained retention of 125I-LR004 at the tumor site in xenograft mice. These findings demonstrated the adequate tumor targeting capabilities of 125I-LR004 in EGFR-positive tumors, which may improve dosing strategies and future drug development.

Molecules sourced from marine environments hold immense promise for the development of novel therapeutic drugs, owing to their distinctive chemical compositions and valuable medicinal attributes. Notably, Talarolide A and Talaropeptides A-D have gained recent attention as potential candidates for pharmaceutical applications. This study aims to explore the chemical reactivity of Talarolide A and Talaropeptides A-D through the application of molecular modeling and computational chemistry techniques, specifically employing Conceptual Density Functional Theory (CDFT). By investigating their chemical behaviors, the study seeks to contribute to the understanding of the potential pharmacological uses of these marine-derived compounds. The investigation involves the utilization of molecular modeling and computational chemistry tools, with a specific focus on Conceptual DFT. These techniques are applied to examine the chemical reactivity of Talarolide A and Talaropeptides A-D, shedding light on their potential for interacting with various biological targets. The research reveals insights into the chemical reactivity of Talarolide A and Talaropeptides A-D, uncovering active reaction sites and potential biological targets. Talarolide A demonstrates robust anti-inflammatory properties and antitumor activity against diverse cancer cell lines, while Talaropeptide A displays antimicrobial efficacy against both bacteria and fungi. The study underscores the significance of comprehending the chemical reactivity of natural marine products for advancing pharmaceutical development. By employing computational tools such as Conceptual DFT, this research uncovers crucial information about the active sites and potential targets of Talarolide A and Talaropeptides A-D. The findings contribute to the broader understanding of marine-derived peptides and their prospects as pharmaceutical agents, though further investigations are necessary to fully elucidate their pharmacological attributes.

A newly UHPLC-MS/MS method development and validation for S-Allyl Cysteine was used to evaluate the comparative pharmacokinetic parameters. SC PLGA NPs were developed by the emulsion solvent evaporation method. SC PLGA NPs showed their drug loading and encapsulation efficiency i.e. 5.13±0.10% and 82.36±4.01%, respectively. SC PLGA NPs showed a spherical morphology on an average size (134.8±4.61nm), PDI: 0.277±0.004, and −25.3±1.03mV zeta-potential is suitable for oral delivery. Development and validation of the UHPLC-MS/MS bioanalytical method were performed successfully for PK-parameters examinations with 1.219-minutes RT, MS (162.00/73.10), and a total run-time was 2.0-minutes. 1.0–1000.0ng/mL was a linear-range with inter & intra-day accuracy (92.55–99.40%) followed by precision (1.88–4.23%). SC PLGA NPs oral bioavailability was significantly higher (**p<0.01) as compared to SC-S treated groups (iv & oral). We found that the antimicrobial activity of SC PLGA NPs was more effective than pure S-Allyl-L-Cysteine with significant results (p<0.01) as compared to SC-S. SC PLGA NPs showed fitted physicochemical and enhanced antimicrobial properties which can be helpful for oral administration. On the basis of our observations, SC PLGA NPs suggested the highest potential for the improvement of oral bioavailability with a sustained and controlled release of S-Allyl-L-Cysteine delivery.

This paper presents a compartmental model aimed at investigating the pharmacokinetics of medical THC after oral administration. The model was developed to be multi-compartmental, describing the kinetics of THC and its metabolites in bodily tissues. Utilizing the law of mass action, the model was converted into ordinary differential equations (ODEs), illustrating the rate of concentration changes of THC and its metabolites in each compartment. Subsequently, we applied the nonstandard finite difference (NSFD) method to construct numerical solution schemes. These schemes were implemented in the MATLAB program, along with estimated pharmacokinetic rate constants. The results of the investigation demonstrate that the simulation curves depicting the plasma concentration-time profiles of THC and THC-OH closely resemble the actual data samples, indicating that this model accurately describes the pharmacokinetics of medical THC and its metabolites. Moreover, the model exhibits predictive capabilities regarding the pharmacokinetics of THC and its metabolites in various tissues. Consequently, the model serves as a valuable tool for enhancing our understanding of the pharmacokinetics of THC and its metabolites and for guiding adjustments to dosage and administration durations for oral medical THC products.

This study was to designed to develop sorafenib-loaded polymeric nanoparticles, surface-modified with pluronic F-127 for the effective treatment of hepatocellular (HCC) and renal cell carcinomas (RCC). Poly lactic coglycolic acid (PLGA) was used to encapsulate different concentrations of sorafenib by a simple modified solvent evaporation method applying pluronic F-127 as a surfactant and coating agent. The preformulation and characterization studies were conducted to evaluate the incompatibilities among sorafenib, PLGA and pluronic F-127, and physicochemical properties of the formulations, respectively. The sizes of the coated and plain PLGA nanoparticles were ~140 ± 14.7 nm and ~ 120 ± 10.1 nm, respectively. It has been confirmed from the in vitro release studies that PLGA sustained the release of sorafenib, avoiding the initial burst release, while the in vivo studies demonstared that surface-modified nanoparticles have greater affinity in the target aorgans than plain PLGA nanoparticles and free drug keeping the dose constant (20 mg/kg body weight). The delivery of sorafenib-loaded polymeric PLGA nanoparticles into the target tissues and their pharmacokinetic parameters have been improved significantly compared to the reported formulations.

Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small cell lung cancer (NSCLC) and EGFR-activating mutations. Proton pump inhibitors decreased dacomitinib exposure. This anal-ysis summarizes the effect of H2RA on dacomitinib exposure. A within-patient comparison of steady-state trough concentrations (Ctrough,ss) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RA was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption PBPK model was constructed and verified using clinical PK data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib PK. The adjusted geometric mean of dacomitinib Ctrough,ss of dacomitinib parent, metabolite and active moiety following co-administration with H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without H2RA (P>0.05). The PBPK modeling showed negligible change in dacomitinib Cmax and AUC over 0-24 hours after H2RA administra-tion, when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.

Demonstrating biosimilarity entails comprehensive analytical evaluations, clinical pharmacolo-gy profiling, and efficacy testing for at least one medical indication in patients. These require-ments are stipulated by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The costliest element—efficacy testing—can be waived if other compliance benchmarks are satisfied, including comparing functional pharmacodynamic (PD) biomarkers, even when they do not di-rectly correlate with clinical outcomes. Most biological drugs, such as monoclonal antibodies (mAbs), lack identifiable PD biomarkers. The FDA has employed various 'omics' technologies to identify potential PD biomarkers, including proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. Although these efforts provide a robust scientific basis for estab-lishing biosimilarity, they are neither practical nor necessarily superior to existing functional biomarkers, such as receptor binding and mode-of-action outcomes. As we report for the first time, these functional biomarkers can effectively serve as PD indicators for all FDA-licensed bio-logical drugs. We recommend that the FDA consider officially listing these functional biomarkers to expedite and reduce the cost of biosimilar development, thereby increasing the accessibility of biological drugs. PD surrogates, like the receptor binding and pharmacokinetic profiles, are more robust and offer a rational solution to finding PD markers to compare for establishing biosimi-larity.

Inflammation can regulate hepatic drug metabolism enzymes and transporters. The impact of inflammation on renal drug transporters remains to be elucidated. We aimed to quantify the effect of inflammation (caused by acute pyelonephritis) on the in vivo activity of renal OAT1/3, using the probe drug furosemide. Pregnant women (2nd or 3rd trimester) received a single oral dose of furosemide 40 mg during acute pyelonephritis (Phase 1; n = 7) and after its resolution (Phase 2; n = 7; by treatment with intravenous cefuroxime 750 mg TID for 3-7 days), separated by 10 to 14 days. IL-6, IFN-γ, TNF-α, MCP-1, and C-reactive protein plasma concentrations were higher in Phase I vs Phase II. The pregnant women had a lower geometric mean [CV%] furosemide CLsecretion (3.9 [43.4] vs 6.7 [43.8] L/h) and formation clearance to the glucuronide (1.1 [85.9] vs 2.3 [64.1] L/h) in Phase 1 vs. Phase 2. Inflammation reduced the in vivo activity of renal OAT1/3 (mediating furosemide CLsecretion) and UGT1A9/1A1 (mediating the formation of furosemide glucuronide) by approximately 40% and 54%, respectively, presumably by elevating plasma cytokine concentrations. The dosing regimens of narrow therapeutic window OAT drug substrates may need to be adjusted during inflammatory conditions.

Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It has been early on recognized that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical composition has recently been used as a means to enhance their targeting or absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.

Because of the need to replace the current clinical artemisinins in artemisinin combination therapies, we are evaluating fitness of amino-artemisinins for this purpose. These include the thiomorpholine derivative artemiside obtained in one scalable synthetic step from dihydroartemisinin (DHA) and the derived sulfone artemisone. We have recently shown that artemiside undergoes facile metabolism via the sulfoxide artemisox into artemisone and thence into the unsaturated metabolite M1; DHA is not a metabolite. Artemisox and M1 are now found to be approximately equipotent with artemiside and artemisone in vitro against asexual P. falciparum (Pf) blood stage parasites (IC50 1.5 – 2.6 nM). Against Pf NF54 blood stage gametocytes, artemisox is potently active (IC50 18.9 nM early-stage, 2.7 nM late-stage). Comparative drug metabolism and pharmacokinetic (DMPK) properties were assessed via po and iv administration of artemiside, artemisox and artemisone in a murine model. Following oral administration, the composite Cmax value of artemiside plus its metabolites artemisox and artemisone formed in vivo is some 2.6-fold higher than that attained following administration of artemisone alone. Given that efficacy of short half-life rapidly-acting antimalarial drugs such as the artemisinins is associated with Cmax, it is apparent that artemiside will be more active than artemisone in vivo, due to additive effects of the metabolites. As is evident from earlier data, artemiside indeed possesses appreciably greater efficacy in vivo against murine malaria. Overall, the higher exposure levels of active drug following administration of artemiside coupled with its synthetic accessibility indicate it is much the preferred drug for incorporation into rational new artemisinin combination therapies.

Interferon alpha (IFNα) is a protein drug used to treat viral infections and cancer diseases. Due to its poor stability in the gastrointestinal tract, only parenteral administration ensures bioavailability, which is associated with severe side effects. We hypothesized that the nanoencapsulation of IFNα within nanoparticles of the mucoadhesive polysaccharide chitosan would improve the oral bioavailability of this drug. In this work, we produced IFNα-loaded chitosan nanoparticles by the ionotropic gelation method. Their size, size distribution and concentration were characterized by dynamic light scattering and nanoparticle tracking analysis. After confirming their good cell compatibility in Caco-2 and WISH cells, the permeability of unmodified and PEGylated nanoparticles was measured in monoculture (Caco-2) and co-culture (Caco-2/HT29-MTX) cell monolayers. Results indicated that the nanoparticles cross the intestinal epithelium mainly by the paracellular route. Finally, the oral pharmacokinetics in BalbC mice of nanoencapsulated IFNα revealed that it was absorbed reaching an area-under-the-curve of 56.9 pg.h/mL.

Zingiber officinale rhizome is widely cultivated in the central region of Sudan (Gezira) and data on the biological properties of this variety grown in the Sudan climate is scarce. The study aims to comprehensively analyze the antibacterial, antioxidant, phytochemical, and GC-MS properties of Zingiber officinale (Ginger rhizome) to explore its potential applications. The in vitro antibacterial assessment of the aqueous extract of the Sudanese ginger revealed moderate activity against Staphylococcus aureus, Salmonella typhi, Pseudomonas aeruginosa, Escherichia coli , and Klebsiella pneumonia, as resulted from the disc-diffusion which ranged between 12.87±0.11 mm to 14.5±0.12 mm at 30 µg/disc. The minimum inhibition concentration ranged between 6.25 to 25 µg/ml, the MBC were between 25 and 50 µg/ml, and the MBC/MIC exhibited its bactericidal effect against all tested bacteria. The phytochemical screening revealed the presence of various chemical constituents such as saponins, flavonoids, glycosides, alkaloids, steroids, terpenoids, and absence of tannins in the Sudanese ginger rhizome. Furthermore, the GC-MS study of ginger rhizome identified 22 chemical compounds with retention times ranging from 7.564 to 17.023 minutes. The identification of 22 chemical compounds through GC-MS analysis further underscores the prospect of harnessing ginger rhizome for the development of novel medications. The computational analyses showed that ginger compounds bind the 1JIJ and 2QZW with high binding affinities, which reach –9.5 kcal/mol. Ginger compounds also established promising molecular interactions with some key residues, that satisfactorily explain the in vitro results and support the pharmacokinetic and experimental findings. This study lays the groundwork for future research and pharmaceutical exploration aimed at harnessing the beneficial properties of ginger rhizome for medicinal and therapeutic purposes, particularly its antimicrobial potential.

Background: in this paper, a new physical penetration technology for transdermal administration with traditional Chinese medicine (TCM) characteristics - Fu’s cupping therapy (FCT) - was established and studied by in-vitro and in-vivo experiments; the penetration effect and mechanism of FCT physical penetration technology (FCT-PPT) was preliminarily discussed. Method: Indomethacin (IM) as a model drug，by transdermal in vitro tests the establishment of the high，medium and low reference were finished as the chemical permeation system；chemical penetration enhancers and iontophoresis as a reference，the percutaneous penetration effect of FCT for IM patch was evaluated with 7 species diffusion kinetics model and in vitro drug distribution；naproxen as an internal standard，using UPLC-MS/MS technology，the IM quantitative analysis method in vivo was established，and pharmacokinetic parameters (AUC0-t，AUC0-∞，AUMC0-t，AUMC0-∞, Cmax and MRT) as indicators were used evaluate to FCT penetration role in vivo；in the same time，the group used 3K factorial design to study joint synergistic penetration effect on FCT and chemical penetration enhancers (CPEs)；by SEM and TEM，the skin micro and ultrastructural changes of the stratum corneum (SC) surface were observed, to explore pay tank penetration mechanism. Results: In vitro and in-vivo skin permeation experiments revealed that both the total cumulative percutaneous amount and in-vivo percutaneous absorption amount (AUC and AUMC) of indomethacin that permeated SD mouse skin using FCT techniques were greater than the amount observed using CPE and iontophoresis: Firstly, in contrast to the control group, the indomethacin percutaneous rate (PR) of the FCT lower group (FCTL) was 35.52%, and the enhancement ratio (ER) at 9h was 1.76X, which was roughly equivalent to the penetration enhancing effect of the CPEs and iontophoresis; secondly, the indomethacin PR of the FCT middle (FCTM) group and the FCT high intensity group (FCTH) were respectively 47.36% and 54.58%, ER at 9h were separately 3.58X and 8.39X; thirdly, pharmacokinetic studies showed that in-vivo indomethacin percutaneous absorption of the FCTs was higher than that of the control group, that of the FCTM group was slightly higher than that of the CPEs group, and that of the FCTM group was significantly higher than that of the others. Meanwhile, the variance analysis indicated that the combination of the FCT penetration enhancement method and the CPE method had beneficial effects in penetration enhancing of the skin: the significance level of the CPE method was 0.0004, which was apparently lower than the 0.001, meaning the difference was markedly significant; the significance level of the FCT was under 0.0001, its difference markedly significant; and the significance level of factor interaction A×B was lower than 0.0001, indicating that its difference of the synergism was markedly significant. Moreover, SEM and TEM images showed that the SC surfaces of SD rats treaded with FCT-PPT was damaged, and hard to observe the complete surface structure with its SC pores growing bigger and its special “brick structure” becoming looser, indicating that it broke the barrier function of skin, which revealed potentially a major route of skin penetration. Conclusion: FCT, as percutaneous penetration new technologies, has penetration effects significantly, with Chinese characteristics and highly clinical value, worth promoting development.

Evaluation of drug permeability using cell monolayers is an important in vitro assay in the process of drug development, to identify compounds with favourable pharmacokinetics that may proceed to in vivo studies. When allowed to differentiate on permeable filters for at least 21 days, monolayers of Caco-2 cells develop morphological and functional properties similar to those of the intestinal epithelium. Permeability through Caco-2 monolayers is thus particularly relevant to assess drug absorption after oral administration. The major drawback of this assay is its very low throughput, with the cell monolayers being used in a single permeability assay. We have previously proposed a protocol to allow the re-use of the Caco-2 monolayer on additional permeability assays during the stable period and shown that cell monolayer integrity is maintained. In this work we evaluate the effect of re-use on the permeability of several reference compounds that permeate through passive pathways and show that the cell monolayers can be re-used twice in additional permeability assays. Preliminary results were also obtained regarding active transport pathways, and a new methodology is proposed to quantify the contribution from passive and active transport. This is a major step towards the full validation of the re-use methodology proposed, which at least triplicates the throughput of this important in vitro assay.

Several studies have shown that antibiotics, analgesic – sedative, and antiseizure medications are among the most commonly used medications in preterm and sick neonates. These infants are at high risk of developing nosocomial infections, central nervous system complications, and are exposed to numerous painful/stressful procedures. These severe, potentially life-threatening complications may have serious short- and long-term consequences and should be prevented and/or promptly treated. Previous studies and reviews have revealed significant variability in medications used in neonatal intensive care units (NICUs) worldwide, especially concerning the indications and dosages of first-line medications. This variability indicates the lack of adequate studies regarding the effectiveness and safety of these medications in neonates, especially the preterm ones. Important obstacles contributing to inadequate studies in preterm infants include difficulties in obtaining parental consent, physicians’ unwillingness to recruit preterm infants, the lack of license for use in neonates, and other scientific and ethical concerns. This review is an update on the use of antimicrobials – antifungals, analgesics – sedatives, and antiseizure medications used in neonates, focusing on existing evidence or knowledge gaps regarding their pharmacokinetics, indications, safety, dosage regimen (dose, dosing interval, route of administration), and evidence-based guidelines for the optimal use in neonates.

The aim of the study is to develop a population pharmacokinetic (PopPK) model and to investigate the influence of CYP3A5/CYP3A4 and ABCB1 single nucleotide polymorphisms (SNPs) on the Tacrolimus PK parameters after LCP-Tac formulation in stable adult renal transplant patients. The model was developed using NONMEM v7.5, from full PK profiles from a clinical study (n=30) and trough concentrations (C0) from patient follow-up (n=68). The PK profile of the LCP-Tac formulation was best described by a two-compartment model with linear elimination, parameterised in elimination (CL/F) and distributional (CLD/F) clearances and central compartment (Vc/F) and peripheral compartment (Vp/F) distribution volumes. A time lagged first order absorption process was characterized using transit compartment models. According to the structural part of the base model, the LCP-Tac showed an absorption profile characterized by 2 transit compartments and a mean transit time of 3.02 hours. Inter-individual variability was associated with CL/F, Vc/F and Vp/F. Adding inter-occasion variability (IOV) on CL/F caused a statistically significant reduction in the model minimum objective function MOFV (p<0.001). Genetic polymorphism of CYP3A5 and cluster of CYP3A4/A5 SNPs statistically significantly influenced Tac CL/F. In conclusion a PopPK model was successfully developed for LCP-Tac formulation in stable renal transplant patients. CYP3A4/A5 SNPs as a combined cluster including three different phenotypes (high, intermediate, and poor metabolizers) was the most powerful covariate to describe part of inter-individual variability associated with apparent elimination clearance. Incorporating this covariate in the initial dose calculation and during the therapeutic drug monitoring (TDM) would probably optimize Tac exposure attainments.

Kisspeptin (KISS1) and its cognate receptor (KISS1R) are implicated in the progression of various cancers. However, a theranostic radiopharmaceutical targeting the KISS1 receptor (KISS1R) has yet to be explored. A gallium-68 labelled kisspeptin-10 (KP10) has potential as a pan-tumor radiopharmaceutical for the detection of cancers. Furthermore, a lutetium-177 labelled KP10 could find therapeutic application in treating oncological diseases. We attached DOTA to the NH2-terminus of KP10 as we posited that this modification would not impair biological activity and showed that receptor stimulation of inositol phosphate accumulation in HEK293 transfected with the KISS1R gene was similar for KP10 and DOTA-KP10. We describe optimization of radiolabeling with gallium-68 and lutetium-177 and stability in serum, plasma, and whole blood. Pharmacokinetics was established with µPET/CT and ex vivo measurements. Dynamic studies with µPET/CT demonstrated that background clearance for the radiopharmaceutical was rapid with a blood half-life of 18 ± 3 minutes. DOTA-KP10 demonstrated preserved functionality at KISS1R and good blood clearance. These promising results advocate the further development of KP10 structures which have high binding affinity along with proteolytic resistance.

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory activity towards dimethylarginine dimethylaminohydrolase 1 (DDAH1) and vasculogenic mimicry, and its active metabolite L-257 in a xenograft model of triple negative breast cancer (TNBC). The method proved to be reproducible, precise, and highly accurate for the measurement of both compounds in plasma and tumour tissue following acute and chronic (five days) intraperitoneal administration of ZST316 (30mg/Kg daily) in six-week-old SCID mice inoculated with MDA-MB-231 TNBC cells. ZST316 was detected in tumour tissue and plasma after 1 hour (6.47 and 9.01M, respectively) and 24 hours (0.13 and 0.16M, respectively) following acute administration, without accumulation during chronic treatment. Similarly, the metabolite L-257 was found in tumour tissue and plasma after 1 hour (15.06 and 8.72M, respectively) and 24 hours (0.17 and 0.17M, respectively) following acute administration of ZST316, without accumulation during chronic treatment. The half-live after acute and chronic treatment ranged between 4.4-7.1hrs (plasma) and 4.5-5.0hrs (tumour) for ZST316, and 4.2-5.3hrs (plasma) and 3.6-4.9hrs (tumour) for L-257. The results of our study demonstrate the a) capacity to accurately measure ZST316 and L-257 concentrations in plasma and tumour tissue in mice using the newly developed HPLC-MS/MS method, b) rapid conversion of ZST316 into L-257, c) good intra-tumour penetration of both compounds, and d) lack of accumulation of both ZST316 and L-257 in plasma and tumour tissue during chronic administration. The new HPLC-MS/MS method is useful to investigate the in vivo effects of ZST316 and L-257 on vasculogenic mimicry, tumour mass, and metastatic burden in xenograft models of TNBC.

The pharmacokinetic profile of fat-soluble vitamins A, E, K1, and D3 co-administered with liquid paraffin or water in an experimental rat model was investigated. Animals received a solution of the four vitamins orally through a probe, followed 10 minutes later by the administration of either the liquid paraffin product dissolved in water (Emuliquen Simple®) or water (control). Vitamin formulations were 20, 50, 0.30 and 0.10 mg/kg for vitamins A, E, K1, and D3, respectively. Blood samples were collected before dosing and at 0.17, 1, 2, 4, 8, and 24 hours post-dosing. Vitamin concentrations were quantified by liquid chromatography coupled with mass spectrometry. No relevant differences in the absorption of vitamins in terms of AUC0-last (area under the curve up to the last measurable concentration) or Cmax in the absence or presence of co-administration of the liquid paraffin product were observed. The difference of these parameters between the treatment groups for all vitamins was in the range of bioequivalence (≤ 20%). The liquid paraffin-based laxative product did not interfere with the absorption of vitamins A, E, K1, and D3 that are ingested in the diet, which is clinically relevant due to the high prevalence of functional constipation in children and adults.

Tandem mass spectrometry (TMS) has emerged as a critical analytical tool in pharmaceutical sciences, playing a pivotal role in ensuring the rational use of medications. This article explores the applications of TMS across various stages of drug development, quality assurance, and patient care, highlighting its precision and reliability in advancing therapeutic efficacy. TMS facilitates the accurate identification and quantification of drug compounds, ensuring that pharmaceutical products meet high standards of purity and potency. By detecting even trace levels of impurities or contaminants, TMS strengthens the quality control processes critical to patient safety. In the realm of pharmacokinetics and pharmacodynamics, TMS enables detailed monitoring of drug absorption, distribution, metabolism, and excretion (ADME), allowing for a better understanding of drug behavior in the human body. It is also instrumental in therapeutic drug monitoring (TDM), ensuring that medication levels remain within therapeutic windows, thus optimizing dosing regimens and minimizing adverse effects. Additionally, TMS supports personalized medicine approaches by assessing drug interactions and tailoring treatments to individual patients. Through its application in drug discovery, development, and therapeutic monitoring, TMS serves as an indispensable tool for fostering rational medication use, contributing to more effective, safe, and personalized pharmaceutical care.