European Journal of Drug Metabolism and Pharmacokinetics最新文献

Background and objectives: With diabetes prevalence rising and original formulations unable to meet demand, establishing generic equivalence is crucial for treatment accessibility. This study evaluated the bioequivalence of generic metformin hydrochloride (0.25 g) versus the reference drug in Chinese volunteers under fasting and fed conditions.

Methods: In this randomized, open-label, two-period crossover trial, 26 healthy volunteers per group received single doses under fasting and fed conditions. Plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, pharmacokinetic metrics were calculated using the WinNonlin 6.3 software, and bioequivalence was evaluated using SAS 9.4.

Results: Under fasting conditions, the geometric mean ratios (GMRs) between the test and reference groups were 103.12% (C_max), 103.65% (AUC_0-t), and 103.31% (AUC_0-∞), with 90% CIs of 92.64-114.78%, 96.04-111.85%, and 96.00-111.17%, respectively. Fed conditions yielded GMRs of 93.98% (C_max), 97.34% (AUC_0-t), and 96.97% (AUC_0-∞), with 90% CIs of 89.42-98.78%, 92.72-102.18%, and 92.40-101.78%, respectively. All these parameters met bioequivalence criteria (80-125%). Median T_max was delayed under fed conditions (2.125 h vs. 4.000 h), with consistent food effects (reduced C_max and AUC) and safety profiles between formulations.

Conclusion: These results demonstrate that the generic metformin formulation is bioequivalent to the innovative product and well tolerated in Chinese healthy volunteers under both fasting and fed conditions.

Background/objectives: Tacrolimus (TAC, FK-506) is a calcineurin inhibitor commonly used to prevent organ rejection in transplant patients. It has a narrow therapeutic index and nephrotoxic effects, characterized by interindividual dose variability. TAC is metabolized by the CYP450 (CYP3A5, CYP3A4) enzyme system and transported by P-glycoprotein (ABCB1). Additionally, the CYP2C8 enzyme has been suggested to play a protective role against both graft rejection and drug-induced toxicity. Genetic polymorphisms in these pathways may influence the risk of tacrolimus-related nephrotoxicity. This retrospective cohort study was conducted to evaluate the association between CYP3A5, ABCB1, and CYP2C8 gene polymorphisms and renal function in kidney transplant recipients METHODS: This study investigated the impact of CYP3A5, ABCB1 and CYP2C8 polymorphisms on blood TAC level and kidney function in renal transplant patients. Genotyping was conducted to determine allele frequencies for CYP3A5 (6986A>G), ABCB1 (13435C>T), and CYP2C8 (A1196G) polymorphisms. Renal function was assessed by measuring serum creatinine, estimated glomerular filtration rate (eGFR), and protein/creatinine ratios at 3, 6, and 12 months post-transplantation.

Result: At 12 months post-transplant, the median serum creatinine level was significantly higher in patients with CYP2C8 (*1/*3 and *3/*3) genotypes compared to those with the CYP2C8*1/*1 genotype (p = 0.021). Additionally, the increase in creatinine from the 3rd to the 12th month was significantly greater in the CYP2C8 (*1/*3 and *3/*3) group (p = 0.036). No significant differences were observed in TAC dosage, blood concentration, or renal function between ABCB1 genotype groups. Although daily TAC doses differed significantly between CYP3A5 genotypes, renal function did not significantly vary.

Conclusion: In light of these data, CYP2C8 gene polymorphism has been associated with an increase in serum creatinine, one of the key markers of renal function. ABCB1 gene polymorphism showed no association while CYP3A5 gene polymorphism influenced TAC dose; however, further studies with larger cohorts are required to clarify these associations.

Background: Ticagrelor is an oral P2Y₁₂ receptor antagonist used mostly in combination with aspirin, in patients with acute coronary syndromes (ACS). Ticagrelor is discontinued 3-5 days before major procedures. Due to its reversible effect, discontinuation is likely to increase the risk of thrombosis. While the effect of dose interruptions on the risk of thrombosis has not been directly studied, pharmacokinetic/pharmacodynamic (PK/PD) simulations provide useful insights.

Objectives: The objective of the current study was to simulate the impact of therapy interruption on the PK/PD of ticagrelor.

Methods: The oral absorption of ticagrelor was described by a transit compartment model, and population PK/PD parameters were obtained from published literature. The PD of ticagrelor was described using a sigmoidal direct-response I_max model. A population PK/PD model describing the relationship between ticagrelor dose, plasma concentrations, and P2Y₁₂ reaction units (PRU) was used to perform simulations using Simulx (Lixoft, France). Simulated patients (n = 1000) received a loading dose of 180 mg followed by a maintenance dose of 90 mg twice daily orally for 15-days. Doses were stopped on day 8 for 0-5 days and resumed with or without a loading dose.

Results: During uninterrupted ticagrelor use, median PRUs ranged between ~ 13 to ~ 40, with > 70% below low platelet reactivity (LPR). The % of PRUs below high platelet reactivity (HPR) drops to ~ 47%, ~ 11%, ~ 2% and 0% upon dose interruption of 1, 2, 3, and 5 days, respectively. Within 2 h of dose resumption with either the loading or the maintenance dose, > 94% of PRUs were below LPR.

Conclusion: Our results suggest the need for individualizing duration of dose interruption prior to surgery and its resumption afterwards.

Background and objective: In a recent simulation-based study, we found that sample size had minimal influence on the external evaluation of population pharmacokinetic (PK) models. However, the applicability of these findings to clinical data remains unexplored. This study aims to validate our previous simulation-based results using real-world clinical data.

Methods: Data from a prospective clinical study in the > 75-year-old population admitted to the McGill University Health Center (MUHC) receiving piperacillin/tazobactam were collected. A virtual population of 1000 patients representative of the characteristics of MUHC patients was also simulated. A population PK model was externally evaluated both using the small clinical dataset and a larger simulated dataset. The predictive performance of the model was assessed using bias, imprecision, goodness-of-fit plots (GOF), and prediction-corrected visual predictive checks (pcVPC). The distribution of prediction errors between the clinical and simulated datasets was compared using the Wilcoxon rank-sum test.

Results: Data from 13 patients undergoing piperacillin/tazobactam therapy were collected. The Ishihara et al. model showed low bias (2.4% population, 0.5% individual) and imprecision (23.8% and 3.2%) and was therefore chosen for Monte Carlo simulation of the virtual population. The Hemmersbach-Miller et al. model showed bias values of - 37.8% (population) and - 21.4% (individual), with imprecision values of 43.2% (population) and 31.3% (individual) for the clinical dataset. For the simulated population, bias values were - 28.4% (population) and - 13.9% (individual), with imprecision values of 40.2% (population) and 18.1% (individual). No significant difference was observed between the prediction error distributions of the clinical and simulated datasets. Both GOF plots and pcVPCs showed similar model misspecification across the clinical and simulated datasets.

Conclusions: This study confirms that small clinical datasets may be used to externally evaluate population PK models.

Background and objectives: Iclepertin, a selective glycine transporter-1 inhibitor, was investigated as a potential treatment for cognitive impairment associated with schizophrenia. The objective of this trial was to determine the effect of food on the pharmacokinetics of iclepertin 10 mg.

Methods: This Phase I, open-label, 2-period cross-over trial randomised (1:1) healthy volunteers to 2 treatment sequences (fasted-fed or fed-fasted) to receive a single oral dose of iclepertin 10 mg once daily in either the fasted or fed state followed by cross-over to the other state. Primary endpoints included maximum measured concentration in plasma (C_max) and area under the concentration-time curve over the time interval from 0 to the last quantifiable data point (AUC_0-tz). The secondary endpoint was area under the concentration-time curve over the time interval from 0 extrapolated to infinity (AUC_0-inf). Relative bioavailability was estimated by calculating an adjusted geometric mean (gMean) fed/fasted ratio using analysis of variance. Safety was assessed.

Results: Of 16 participants enrolled [mean (SD) age: 37.1 (10.1) years], 15 were included in the analysis. The C_max, AUC_0-tz and AUC_0-inf of iclepertin were higher in the fed versus fasted state; adjusted gMean ratios (90% confidence intervals) were 118.33% (110.01, 127.28), 114.61% (110.13, 119.27) and 114.38% (110.11, 118.80), respectively. Iclepertin 10 mg was well tolerated.

Conclusion: Iclepertin exposure was higher in fed versus fasted conditions, but the increase was minor, suggesting food has no meaningful effect on the pharmacokinetics of iclepertin 10 mg.

Study registration: ClinicalTrials.gov (NCT05347004; registered: 20 April 2022).

Background and objective: Current immunosuppressive treatment to prevent graft rejection in organ transplant recipients commonly includes mycophenolate mofetil (MMF) and a calcineurin inhibitor. After absorption, MMF is activated to mycophenolate (MPA) by the carboxylesterase (CES) enzymes, which is considered to occur rapidly and completely. Recent research utilizing pharmacometabolomics (PMx), however, identified an unknown/unreported MMF glucuronide metabolite in several kidney transplant recipients (KTR). This finding indicates incomplete MMF prodrug activation by CES, thereby suggesting enzyme saturation and/or inhibition, which warrants further study. In this work, we aimed to identify clinical factors that could (partially) explain incomplete MMF activation as observed in KTR.

Methods: We analyzed untargeted urinary PMx data to determine MMF prodrug activation in 321 KTR from the TransplantLines Biobank and Cohort Study (NCT03272841) and 403 KTR from the TransplantLines Food and Nutrition Biobank and Cohort Study (NCT02811835). Beta regression was used to associate incomplete MMF activation with clinical parameters. Subsequently, in vitro experiments using human S9 liver extracts were performed to compare the influence of potential CES inhibitors on MMF activation.

Results: Beta regression linked an impaired MMF activation with increasing MMF dose and kidney function as well as with cyclosporine (CsA) use. Regarding the latter, in vitro experiments revealed a decreased MMF activation caused by the pharmaceutical excipient Kolliphor^® EL, which is present in CsA capsules, rather than by CsA itself.

Conclusion: Substantially reduced MMF prodrug activation was observed in large numbers of KTR, indicating relevant attenuation of the MMF-converting CES enzymes, which may be due to enzyme saturation and inhibition. However, there may be other factors affecting MMF activation, which require elucidation to improve immunosuppression therapy.

Background and objective: In Japan, the "Guideline for Bioequivalence (BE) Studies of Generic Products for Topical Use" was issued in 2003 to present the basic principles for BE evaluation methods for generic topical dermatological drug products. However, a detailed analysis of trends in BE evaluation methods in Japan has not yet been reported. In addition, a detailed comparison of the BE evaluation methods used at the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (US FDA), and the European Medicines Agency (EMA) has also not been performed.

Methods: We surveyed BE evaluation methods for generic topical dermatological drug products in Japan based on the PMDA website from 2000 to 2023. We also compiled the latest guideline information for the PMDA, US FDA, and EMA.

Results: Before the guideline was issued from 2000 to 2003, most generic topical dermatological drug products were evaluated using pharmacological tests in animals. After the guideline was issued in 2003, dermato-pharmacokinetic studies have become the main method for BE evaluation other than antiseptics in Japan. The greatest difference between the US FDA and EMA versus current Japanese regulations was the introduction of a biowaiver approach based on Q1/Q2 and Q3 similarities and in vitro test equivalence.

Conclusion: This finding confirmed that the publication of the guideline significantly influenced the BE evaluation methods for topical dermatological drug products in Japan. Furthermore, Japan may consider a biowaiver approach based on Q1/Q2 and Q3 similarity and in vitro test equivalence.

Background and objective: Antihistamines are an essential treatment option for cough and upper respiratory symptoms. Bilastine is a 2nd-generation antihistamine which is approved as a 20 mg once daily dose. The objective of the current study is to compare the oral bioavailability of bilastine administered thrice daily as a triple combination syrup of test product bilastine + dextromethorphan hydrobromide + phenylephrine hydrochloride (3.3 mg + 10 mg + 5 mg)/5 mL and a reference product of single-dose administration of 2.5 mg/mL (bilastine 2.5 mg) in healthy, adult, male human subjects under fed condition.

Methods: This was an open-label, balanced, randomized, two-treatment, two-period, cross-over comparative bioavailability study. Patients were administered 10 mL of three 8-hourly doses of the triple combination test product and once daily dose of the reference product (syrup containing bilastine 2.5 mg). A 7-day washout period was implemented between doses. Blood samples were collected to assess the oral bioavailability of the test and reference products. Each subject received both treatments, serving as their own control, eliminating the need for a separate control group. Blood samples were collected pre-dose and at various intervals post-dose to determine plasma concentrations of bilastine using LC-MS/MS (Liquid Chromatography-Mass Spectrometry/Mass Spectrometry. Primary pharmacokinetic parameters were analyzed for bioequivalence using SAS version 9.4.

Results: A total of 34 subjects out of 36 enrolled, successfully completed the study, and were analyzed. The geometric mean ratios of test versus reference product for the areas under the curve (AUC_0-t and AUC_0-∞ ) were 88.42% (84.15-92.91%) and 98.06% (93.63-102.69%), respectively, which are within the bioequivalence acceptance limits of 80.00-125.00%.

Conclusion: Our study concluded that the test product, bilastine + dextromethorphan hydrobromide + phenylephrine hydrochloride syrup (3.3 mg + 10 mg + 5 mg)/5 mL, and the reference product, bilastine solution 2.5 mg/mL, are bioequivalent with respect to the extent of absorption and were well tolerated.