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The aim of the study was to investigate if there is a clinically relevant drug interaction between metformin and codeine. Volunteers were randomized to receive on four separate occasions: (A) orally administered metformin (1 g), (B) intravenously administered metformin (0.5 g), (C) five doses of tablet codeine 25 mg; the last dose was administered together with oral metformin (1 g), and (D) five doses of tablet codeine 25 mg; the last dose was administered together with metformin (0.5 g) intravenously. Blood samples were drawn for 24 h after administration of metformin, and for 6 h after administration of codeine and analyzed using liquid chromatography and tandem mass spectrometry. Healthy volunteers genotyped as CYP2D6 normal metabolizers (*1/*1) without known reduced function variants in the OCT1 gene (rs12208357, rs34130495, rs34059508, and rs72552763) were invited. The median absorption fraction of metformin was 0.31 and was not influenced by codeine intake. The median time to maximum concentration (Tmax) after oral intake of metformin was 2 h without, and 3 h with codeine (p = 0.06). The geometric mean ratios of the areas under the plasma concentration time‐curve (AUCs) for morphine and its metabolites M3G and M6G for oral intake of metformin‐to‐no metformin were 1.21, 1.31, and 1.27, respectively, and for i.v. metformin‐to‐no metformin 1.28, 1.34, and 1.30, respectively. Concomitant oral and i.v. metformin increased the plasma levels of morphine, M3G and M6G. These small pharmacokinetic changes may well contribute to an increased risk of early discontinuation of metformin. Hence, a clinically relevant drug‐drug interaction between metformin and codeine seems plausible.

Polymorphism of the CYP2D6 gene leads to substantial interindividual variability in CYP2D6 enzyme activity. Despite improvements in prediction of CYP2D6 activity based on genotype information, large interindividual variability within CYP2D6 genotypes remains and ethnicity could be a contributing factor. The aim of this study was to investigate interethnic differences in CYP2D6 activity using clinical datasets of three CYP2D6 substrates: (i) brexpiprazole (N = 476), (ii) tedatioxetine (N = 500), and (iii) vortioxetine (N = 1073). The CYP2D6 activity of all individuals in the dataset was estimated through population pharmacokinetic analyses as previously reported. Individuals were assigned a CYP2D6 phenotype and CYP2D6 genotype group based on their CYP2D6 genotype and interethnic differences were investigated within each group. Among individuals categorized as CYP2D6 normal metabolizers, African Americans had a lower CYP2D6 activity compared to Asians (p < 0.01) and in the tedatioxetine and vortioxetine analyses also compared to Whites (p < 0.01). Among CYP2D6 intermediate metabolizers, interethnic differences were also observed, but the findings were not consistent across the substrates. Asian carriers of CYP2D6 decreased function alleles tended to exhibit higher CYP2D6 activity compared to Whites and African Americans. The observed interethnic differences within the CYP2D6 phenotype and genotype groups appeared to be driven by differences in CYP2D6 allele frequencies across ethnicities rather than interethnic differences in enzyme activity for individuals carrying identical CYP2D6 genotypes.

Diverse representation in clinical trials is crucial to understand the efficacy and safety of drugs in minority groups. This review aims to (1) describe research participants' sex, racial, and ethnic diversity in clinical drug trials and (2) describe the sex distribution of researchers conducting the research. We reviewed all clinical drug trials published in the journals “Clinical Pharmacology and Therapeutics” and “Clinical and Translational Science” in 2000–2001 and 2020–2021 and analyzed the research participants' and researchers' demographics. We compared the race of the research participants with the concurrent race diversity of the reference population in the countries where the research was conducted. We identified 281 articles with 17,639 research participants. Approximately one‐third of the research participants were women in both 2000–2001 and 2020–2021. The representation from racial minorities of Black and Asian people increased from 2000–2001 to 2020–2021, but Asian and Native American people are still under‐represented in clinical drug trials today. The proportion of female authors increased, but female authors still made up less than 40% of the total number of authors in 2020–2021. In conclusion, men are still over‐represented in clinical pharmacology research, and some races are still vastly under‐represented. Furthermore, although the proportion of female authors increased with time, they are still under‐represented as first and last authors.

Pharmacokinetics is the cornerstone of understanding drug absorption, distribution, metabolism, and elimination. It is also the key to describing variability in drug response caused by drug‐drug interactions (DDIs), pharmacogenetics, impaired kidney and liver function, etc. This tutorial aims to provide a guideline and step‐by‐step tutorial on essential considerations when designing clinical pharmacokinetic studies and reporting results. This includes a comprehensive guide on how to conduct the statistical analysis and a complete code for the statistical software R. As an example, we created a mock dataset simulating a clinical pharmacokinetic DDI study with 12 subjects who were administered 2 mg oral midazolam with and without an inducer of cytochrome P450 3A. We provide a step‐by‐step guide to the statistical analysis of this clinical pharmacokinetic study, including sample size/power calculation, descriptive statistics, noncompartmental analyses, and hypothesis testing. The different analyses and parameters are described in detail, and we provide a complete R code ready to use in supplementary files. Finally, we discuss important considerations when designing and reporting clinical pharmacokinetic studies. The scope of this tutorial is not limited to DDI studies, and with minor adjustments, it applies to all types of clinical pharmacokinetic studies. This work was done by early career researchers for early career researchers. We hope this tutorial may help early career researchers when getting started on their own pharmacokinetic studies. We encourage you to use this as an inspiration and starting point and continuously evolve your statistical skills.

The cytochrome P450 (CYP) 2D6 enzyme exhibits large interindividual differences in metabolic activity. Patients are commonly assigned a CYP2D6 phenotype based on their CYP2D6 genotype, but there is a lack of consensus on how to translate genotypes into phenotypes, causing inconsistency in genotype‐based dose recommendations. The aim of this study was to quantify and compare the impact of different CYP2D6 genotypes and alleles on CYP2D6 metabolism using a large clinical data set. A population pharmacokinetic (popPK) model of tedatioxetine and its CYP2D6‐dependent metabolite was developed based on pharmacokinetic data from 578 subjects. The CYP2D6‐mediated metabolism was quantified for each subject based on estimates from the final popPK model, and CYP2D6 activity scores were calculated for each allele using multiple linear regression. The activity scores estimated for the decreased function alleles were 0.46 (CYP2D6*9), 0.34 (CYP2D6*10), 0.01 (CYP2D6*17), 0.65 (CYP2D6*29), and 0.21 (CYP2D6*41). The CYP2D6*17 and CYP2D6*41 alleles were thus associated with the lowest CYP2D6 activity, although only the difference to the CYP2D6*9 allele was shown to be statistically significant (p = 0.02 and p = 0.05, respectively). The study provides new in vivo evidence of the enzyme function of different CYP2D6 genotypes and alleles. Our findings suggest that the activity score assigned to CYP2D6*41 should be revisited, whereas CYP2D6*17 appears to exhibit substrate‐specific behavior. Further studies are needed to confirm the findings and to improve the understanding of CYP2D6 genotype–phenotype relationships across substrates.

Purpose The aim of the study was to determine the steady-state pharmacokinetics of metformin in healthy volunteers with different numbers of reduced-function alleles in the organic cation transporter 1 gene ( OCT1) . Methods The study was conducted as part of a randomized cross-over trial. Thirty-four healthy volunteers with known OCT1 genotypes (12 with two wild-type alleles, 13 with one and 9 with two reduced-function alleles) were included. In one of the study periods, they were titrated to steady-state with 1 g metformin twice daily. Results Neither AUC 0-12 , C max nor Cl renal were statistically significantly affected by the number of reduced-function alleles (0, 1 or 2) in OCT1 : (AUC 0-12 : 0, 1, 2: 14, 13 and 14 h ng/L ( P = 0.61)); ( C max : 0, 1, 2: 2192, 1934 and 2233 ng/mL, ( P  = 0.26)) and (Cl renal : 0, 1, 2: 31, 28 and 30 L/h ( P  = 0.57)) Conclusions In a cohort of healthy volunteers, we found no impact of different OCT1 genotypes on metformin steady-state pharmacokinetics.

Background This study aims to assess the migraine-inducing effects of sildenafil in men with migraine without aura. While sildenafil has been shown to provoke migraine in women, its effect on men remains unknown. Methods The trial will enroll 12 men and 15 women, all diagnosed with migraine without aura. The men will participate in a randomized, placebo-controlled crossover trial and the women in an open-label study. Participants will be monitored for migraine attacks and associated symptoms for 12 h post-administration. The primary endpoints include the incidence of migraine attacks in sildenafil-treated men compared to placebo and between sildenafil-treated men and women. Secondary endpoints are headache incidence, heart rate, mean arterial pressure, and adverse events. Conclusion The findings will contribute to a better understanding of sex-related differences in migraine mechanisms, potentially leading to more tailored treatment approaches. Trial registration: The trial is registered in the Clinical Trial Information System (CTIS) of the European Union under the number 2024-512014-17-02.

Metformin is the world’s most commonly used oral glucose-lowering drug for type 2 diabetes, and this is mainly because it protects against diabetes-related mortality and all-cause mortality. Although it is an old drug, its mechanism of action has not yet been clarified and its pharmacokinetic pathway is still not fully understood. There is considerable inter-individual variability in the response to metformin, and this has led to many drug–drug interaction (DDI) studies of metformin. In this review, we describe both in vitro and human interaction studies of metformin both as a victim and as a perpetrator. We also clarify the importance of including pharmacodynamic end points in DDI studies of metformin and taking pharmacogenetic variation into account when performing these studies to avoid hidden pitfalls in the interpretation of DDIs with metformin. This evaluation of the literature has revealed holes in our knowledge and given clues as to where future DDI studies should be focused and performed.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially serious adverse effect of a wide range of chemotherapeutics. The lack of understanding of the molecular mechanisms underlying CIPN limits the efficacy of chemotherapy and development of therapeutics for treatment and prevention of CIPN. Human induced pluripotent stem cells (iPSCs) have become an important tool to generate the cell types associated with CIPN symptoms in cancer patients. We reviewed the literature for iPSC-derived models that assessed neurotoxicity among chemotherapeutics associated with CIPN. Furthermore, we discuss the gaps in our current knowledge and provide guidance for selecting clinically relevant concentrations of chemotherapy for in vitro studies. Studies in iPSC-derived neurons revealed differential sensitivity towards mechanistically diverse chemotherapeutics associated with CIPN. Additionally, the sensitivity to chemotherapy was determined by donor background and whether the neurons had a central or peripheral nervous system identity. We propose to utilize clinically relevant concentrations that reflect the free, unbound fraction of chemotherapeutics in plasma in future studies. In conclusion, iPSC-derived sensory neurons are a valuable model to assess CIPN; however, studies in Schwann cells and motor neurons are warranted. The inclusion of multiple iPSC donors and concentrations of chemotherapy known to be achievable in patients can potentially improve translational success.

BackgroundInflammation suppresses cytochrome P450 (CYP) enzyme activity, and single-dose interleukin 6 receptor antagonists (anti-IL-6R) reverse this effect. Here, we assess the impact of continuous anti-IL-6R therapy in patients with rheumatoid arthritis.MethodsIn a clinical pharmacokinetic trial, the Basel cocktail was administered before and after 3 and 12 weeks of anti-IL-6R therapy to assess CYP enzyme activity (registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021). In a retrospective study, the 4β-hydroxycholesterol/cholesterol ratio was measured as a biomarker for CYP3A4 activity before and after 3 and 6 months of anti-IL-6R therapy. The control group was patients initiating a tumor necrosis factor alfa (TNF-α) inhibitor.ResultsIn the clinical pharmacokinetic trial (n = 3), midazolam metabolic ratio (CYP3A4) was inconclusive due to the limited sample size. Midazolam AUC and Cmax indicate a weak impact on CYP3A4 activity after 3 weeks of anti-IL-6R therapy compared to baseline (AUC geometric mean ratio (GMR): 0.80, 95% CI: 0.64–0.99 and Cmax GMR: 0.58, 95% CI: 0.37–0.91), which returns to baseline levels after 12 weeks of therapy (AUC GMR 1.02, 95% CI: 0.72–1.46 and Cmax GMR 1.03, 95% CI 0.72–1.47). No effect on the 4β-hydroxycholesterol/cholesterol ratio was observed in the retrospective study.ConclusionBased on sparse data from three patients, continuous anti-IL-6R therapy seems to cause an acute but transient increase in CYP3A4 activity in rheumatoid arthritis patients, which may be due to a normalization of the inflammation-suppressed CYP activity. Further studies are warranted to understand the mechanism behind this putative transient effect.Trial registration Registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021.