European Journal of Drug Metabolism and Pharmacokinetics最新文献

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: 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 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.

Vadadustat is an innovative drug that inhibits prolyl hydroxylase and has been approved for the treatment of anemia in patients with chronic kidney disease. Its pharmacokinetics are linear, i.e., vadadustat's absorption, distribution, and elimination are predictable. Vadadustat is well absorbed from the gastrointestinal tract, with over 99% of the drug bound to plasma proteins. The majority of the drug is conjugated with glucuronic acid in the liver, and these conjugates are primarily excreted through urine, with a smaller portion eliminated through stool. Only 1% of the unchanged drug is found in the urine, while 9% appears in the stool. In clinical trials, vadadustat demonstrated clear effectiveness compared with placebo, significantly increasing hemoglobin levels in patients with anemia due to chronic kidney disease, with an average increase of 1.43 ± 0.05 g/dL after 6 months of treatment. However, its effectiveness is somewhat lower than that of erythropoietin. The rates and severity of adverse events with vadadustat and erythropoietin are similar. Given that vadadustat is taken orally and has a beneficial efficacy and safety profile, it represents a meaningful addition to the standard treatment for anemia associated with renal failure, working alongside erythropoietin.

Background and objective: Intraperitoneal lidocaine is an emerging strategy for analgesia following abdominal surgery but its pharmacokinetics are poorly quantified. We aimed to develop a pharmacokinetic model for unbound and total lidocaine by intraperitoneal and intravenous routes.

Methods: Unbound and total lidocaine concentrations, and pain scores (visual analogue score 0-10) were from a published randomized control trial of adults (n = 56) undergoing laparoscopic colon resection. Participants received intravenous or intraperitoneal lidocaine (2 mg/kg bolus then 1.5 mg/kg/h infusion) for 72 h postoperatively. Data were pooled with literature-derived alpha-1-acid glycoprotein concentrations (AAG) to support total lidocaine modelling. Unbound kinetics were described using compartmental models with first order absorption between intraperitoneal and plasma compartments. A turnover model described AAG kinetics with constant binding to lidocaine. An inhibitory pharmacodynamic model was explored to link concentration to pain scores.

Results: Maximum lidocaine concentrations after intraperitoneal administration were means (range) of 3.0 (0.4-4.5) mg/L total and 0.6 (0.1-0.9) mg/L unbound. Intraperitoneal absorption was incomplete (bioavailability = 0.66, 95% confidence interval (CI) 0.6-0.76) with a half-time of 0.5 (0.4-0.8) h. A two-compartment model with first order elimination fit best, with unbound clearance 121 (108-136) L/h/70 kg. The binding constant to AAG (K_D) was 2.98 (2.69-3.35) µmol/L. A pharmacodynamic model with C₅₀ of 0.21 mg/L and maximal reduction (E_max) of 6 units captured pain scores and was used to simulate dosing strategies.

Conclusions: A third of the intraperitoneal dose did not reach the central compartment and absorption took ~2 h. Simulations show that 2 mg/kg/h intraperitoneal infusion achieves a 5-point pain score reduction within ~36 min.

Background and objective: Sepsis-induced pathophysiological changes may lead to pharmacokinetic variability which alters antibiotic concentrations at the host infection site. This poses a challenge in clinical practice, as sufficient antibiotic concentrations in tissue are necessary to effectively eradicate bacterial pathogens. In this exploratory study, we aimed to evaluate the potential of routinely used laboratory biomarkers to predict subcutaneous and muscle tissue penetration of moxifloxacin in septic patients.

Methods: We retrospectively analyzed data from 10 septic patients included in a pharmacokinetic study, in which moxifloxacin concentrations in subcutaneous adipose and muscle tissues were measured with microdialysis. We correlated the tissue-to-plasma ratio and protein binding with various clinical biomarkers.

Results: Our results revealed significant correlations for CRP, LDH, BUN, GPT, and total protein with moxifloxacin subcutaneous penetration, and BUN, GOT, and GPT with muscle penetration. Notably, all biomarkers except CRP correlated negatively with tissue penetration. Moreover, we found a positive correlation between moxifloxacin protein binding and total plasma proteins and albumin.

Conclusion: Biomarker tissue correlations suggest that the penetration of moxifloxacin into tissues is a complex process influenced by factors like inflammation, tissue integrity, liver function, protein levels, and renal function. Understanding these interactions might help optimize antibiotic dosing strategies.

Background and objectives: The HIV infection in malnourished conditions raises the concerns with antiretroviral medications, which may worsen the already compromised physiological state. The alteration in the plasma protein binding in malnourished HIV patients exacerbates the unbound fraction of antiretroviral medications, resulting in alterations in the therapeutic effectiveness and toxicity. Thus, the present study investigates the effects of protein deficiency and protein-energy malnutrition on the pharmacokinetics of the antiretroviral efavirenz.

Method: Malnutrition was induced in this study through a modified diet containing only 2% protein. The experiment involved 16 Wistar rats, divided into two groups of 8. The control group was provided with a standard pellet diet (AIN 93G) that contained 19% protein, while the second group was subjected to the low-protein (2%) diet for 90 days. Rats were fed ad libitum with their respective diets during this period. On the 90th day, efavirenz (200 mg/kg, p.o.) was administered, and pharmacokinetic parameters were assessed using HPLC analysis.

Results: The findings indicate that the protein-deficient diet successfully created a model of malnutrition, evidenced by a significant reduction in body weight (26%), hemoglobin levels (33%), total protein (27%), and blood albumin (41%) compared to the control group on a standard diet. The pharmacokinetic analysis of efavirenz in the protein-deficient rats revealed an increase in half-life (T_½) by 51.27%, maximum concentration (C_max) by 31.57%, and area under the curve (AUC 0-∞) by 51.40%, alongside a decrease in total body clearance (45.81%) and volume of distribution (12.1%) relative to the pharmacokinetic profile observed in rats on the standard AIN 93G diet.

Conclusion: These findings indicate that the pharmacokinetic profile of efavirenz is significantly altered under protein-deficient conditions. Therefore, it is recommended that further pharmacokinetic studies be conducted in patients with protein deficiency to determine if standard dosing of efavirenz should be adjusted based on the individual's nutritional status.