Clinical Pharmacology & Therapeutics最新文献

Grapefruit juice is a well-established inhibitor of cytochrome P450 (CYP) 3A4, but its effects on other CYP enzymes or organic anion transporting polypeptides (OATPs) are not fully characterized in humans. Recently, lingonberry powder was shown to induce murine CYP enzymes. We investigated the effects of lingonberry powder and grapefruit juice on seven CYP enzymes and two OATPs. Eleven healthy volunteers received three pretreatments three times per day: water for 1 day (control), lingonberry powder for 9 days, and grapefruit juice for 3 days. CYP index drugs (caffeine/CYP1A2, bupropion/CYP2B6, repaglinide/CYP2C8, flurbiprofen/CYP2C9, omeprazole/CYP2C19, dextromethorphan/CYP2D6, midazolam/CYP3A4, and simvastatin/CYP3A4) were administered orally on the study day of each pretreatment (day 1, 10, and 3, respectively). Venous blood samples were collected until 23 hours postdose. The concentrations of index drugs, their metabolites and endogenous OATP1B1 and OATP1B3 biomarkers glycochenodeoxycholate 3-O-glucuronide (GCDCA-3G) and glycochenodeoxycholate 3-sulfate (GCDCA-3S), respectively, were quantified. Grapefruit juice expectedly increased the AUC_0-23h values of the CYP3A4 index drugs midazolam and simvastatin (P < 0.01). Additionally, grapefruit juice decreased the hydroxybupropion/bupropion (CYP2B6), 4'-hydroxyflurbiprofen/flurbiprofen (CYP2C9), 5'-hydroxyomeprazole/omeprazole (CYP2C19), and 1'-hydroxymidazolam/midazolam AUC_0-23h ratios to 0.57-fold (90% confidence interval: 0.45-0.74), 0.78-fold (0.69-0.87), 0.43-fold (0.36-0.52), and 0.72-fold (0.63-0.84) of control, respectively (P < 0.01). Lingonberry pretreatment did not change any CYP indices. GCDCA-3G and GCDCA-3S concentrations were unaffected by grapefruit juice or lingonberry pretreatment. Collectively, our findings indicate that in addition to inhibiting CYP3A4, repeated grapefruit juice intake causes clinically relevant inhibition of CYP2B6, CYP2C9, and CYP2C19, revealing previously underappreciated interaction risks. Conversely, lingonberry powder is unlikely to induce CYP enzymes in humans.

The pharmacokinetics (PK) of monoclonal antibodies (mAbs) during pregnancy remains poorly characterized, despite active inflammatory bowel diseases (IBD) being the greatest risk factor for adverse pregnancy outcomes. To quantify pregnancy-induced changes, vedolizumab concentrations from 39 pregnant patients on various dosing regimens were analyzed using a sequential albumin-trend/PK modeling approach, extending a published vedolizumab non-pregnancy model. Albumin trends were first characterized using a polynomial mixed-effect model. Then, individual changes in albumin from their pre-pregnancy concentrations, implemented as time-varying patient-influential factor (covariate) in the PK model, served as potential biomarker of pregnancy-induced plasma volume expansion. The modeling framework allowed model-informed imputation of missing covariate data, extraction of hemodilution effect, and estimation of pre-pregnancy PK parameters. Due to albumin change, the central volume of distribution increased 52.4%, consistent with known gestational plasma volume expansion, while clearance increased to 38.6%. An additional third-trimester effect of gestational age, potentially reflecting transplacental transfer, increased clearance by an additional 33.3 percentage points. These changes led to a 49.5% decline in vedolizumab trough concentrations (C_min) by late pregnancy. To maintain efficacious pre-pregnancy exposure (dependent on the individual dosing interval), dosing intervals were gradually shortened for approximately one-third (e.g., to up to 5.6 weeks for pre-pregnancy 8-week regimens). Optimized dosing times were summarized in an easy-to-use nomogram-like plot. This work provides the first population PK model of vedolizumab in pregnancy. By integrating physiologically motivated pregnancy effects, it advanced quantitative understanding of mAbs PK in pregnancy with potential application to other biologics and provides optimized dosing strategies to mitigate risks of adverse pregnancy outcomes.

As antiretroviral therapy (ART) prolongs lifespans, people with HIV (PWH) face a new syndemic: Cardiovascular-Kidney-Metabolic (CKM) syndrome. Yet CKM in PWH is poorly characterized. Inflammation, complex pharmacokinetic (PK) alterations, ART-associated metabolic effects, and gut dysbiosis amplify risk. Managing CKM increases medication burden, thereby heightening the risk of drug-drug interactions and adverse drug effects. Therefore, CKM in PWH represents an emerging clinical pharmacology priority. We outline gaps and challenges and call for CKM research in PWH.

Cisplatin is a chemotherapy drug that causes permanent hearing loss by damaging a critical tissue lining the inner ear, called the stria vascularis (SV). Currently, the molecular mechanisms of SV damage are largely unknown and the incidence of ototoxicity in patients cannot be reliably predicted. Growing evidence suggests certain genetic variants expressed in the SV are significant risk factors for ototoxicity, which may be leveraged to better understand cisplatin-induced hearing loss. Also highlighted are innovative developments in integrating genomic and transcriptomic data through multi-omic approaches that may be translated to improve future genetic testing and otoprotectant development.

The European Medicines Regulatory Network plays a critical role in safeguarding public health through the assessment and supervision of human medicines. However, rapid scientific and technological advancements have exposed capability deficits across the network, threatening timely and effective regulatory decision-making. To identify the most critical learning needs within the European Medicines Regulatory Network-specifically those related to capability gaps-the EU4Health Joint Action, IncreaseNET, conducted a learning needs analysis. This study presents a learning needs analysis conducted via two complementary approaches: stakeholder collaboration with European Medicines Agency expert committees and a network-wide survey of National Competent Authorities. The analysis identified six priority subject areas requiring urgent capability development: Advanced Therapy Medicinal Products, Biologically Active Substances, Clinical Trials, Modeling and Simulation, Pharmacokinetics, and Statistics. Additional training needs-such as Environmental Risk Assessment and Radiopharmaceuticals-were highlighted through the National Competent Authority survey. Key barriers to capability development include uneven distribution of expertise, limited time for training due to high workloads, and recruitment challenges. The study also revealed methodological variation in how learning needs analyses are conducted across the European Medicines Regulatory Network, underscoring the need for a standardized yet context-sensitive framework. IncreaseNET will pilot innovative training development strategies, including the use of pedagogical specialists, formalized training processes, and targeted expert recruitment initiatives. These efforts aim to build a more agile, capable, and resilient regulatory workforce across Europe.

Li, F., Sun, Q., Du, S., Florian, J., Wang, Y., Huang, S.M., Zineh, I. & Wang, Y.-M.C. Model-based approach to selecting pegfilgrastim dose for pharmacokinetic and pharmacodynamic similarity studies in biosimilar development. Clin. Pharmacol. Ther. 113: 62–70 (2023). https://doi.org/10.1002/cpt.2722

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Despite widespread rhFSH use in infertile women undergoing ART, real-world comparative data on its effectiveness and safety across different rhFSH types remain limited. Using the HIRA claims database, we included 10,684 women aged 20–39 with infertility (2016–2021) who used only rhFSH in their first in vitro fertilization–embryo transfer (IVF-ET). Outcome variables comprised effectiveness (≥ 11 oocytes retrieved, pregnancy rates and live birth rate) and safety (ectopic pregnancy, miscarriage, preterm birth and ovarian hyperstimulation syndrome [OHSS]) in the whole cohort, further categorized into follitropin and other rhFSH. Baseline characteristics were described, and relative risks (RR) with 95% confidence intervals (CI) were estimated using a generalized linear model, adjusting for age and imbalanced variables. Of 10,684 patients prescribed rhFSH, 7.1% were aged 20–29, 41.6% were 30–34, and 51.3% were 35–39. ICSI was utilized in 57.7% of cycles, and 76.8% used the GnRH antagonist protocol. The live birth rate was 38.8%, and the OHSS rate was 5.9%. Comparing baseline characteristics of the follitropin (n = 2,594) and other rhFSH group (n = 8,090), ICSI (62.2% vs. 56.3%) and GnRH antagonist protocol (81.3% vs. 75.3%) were more common in the follitropin group. Women who received follitropin were more likely to have ≥ 11 oocytes retrieved (adjusted RR, 1.09; 95% CI: 1.02–1.16) and less likely to have OHSS (adjusted RR, 0.73; 95% CI: 0.60–0.90). These findings provide real-world evidence supporting rhFSH effectiveness and safety in fresh IVF cycles, with follitropin potentially offering advantages in oocyte retrieval and reduced OHSS rates.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has formally updated the SLCO1B1 allele functionality table based on new evidence. Notably, the alleles studied (SLCO1B1 *9, *31, *41) are enriched in the genomes of patients historically excluded from pharmacogenomics research. This perspective illustrates how new evidence can advance clinical pharmacogenetics implementation guidelines incorporation in real time through collaboration with CPIC. Together, we can accelerate the translation of pharmacogenetics into a tool that truly improves health outcomes for everyone.

Methadone is a utilitarian opioid with growing use for anesthesia and postoperative pain. Methadone pharmacokinetic models have evolved over time; however, there is no comprehensive population pharmacokinetic model. This investigation developed a population model for R(−)- and S(+)-enantiomers of methadone and the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) in plasma and urine, incorporating enantiomeric disposition, metabolism, genetics, renal elimination, and frequent and long-duration sampling, to adequately describe both distribution and elimination. In this secondary analysis of previously obtained data from 64 adults sampled for 96 hours, a compartmental model utilizing eight distinct measurement categories of drug and metabolite concentration that unified enantiomer kinetics was developed using nonlinear mixed effects techniques. Potential model covariates for weight, race, sex, CYP2B6 genetics, and CYP2C19 genetics were tested. The final unified three-compartment population model accounted for significant and systematic enantiomer-specific differences in volumes of distribution, intercompartmental and elimination clearances between R(−)- and S(+)-methadone, by estimating S(+)/R(−) ratios. The model incorporated weight and CYP2B6 genotype but not CYP2C19 genotype, sex or race as covariates. Intersubject variability was consistent with that of other intravenous opioids. S(+)/R(−) ratios were consistent with known enantiomeric differences in α₁-acid glycoprotein binding and in vitro biotransformation, and disposition was explainable by enantiomeric restrictive plasma protein binding effects on drug distribution, pharmacokinetic flow, and intrinsic hepatic clearance (CYP2B6-catalyzed metabolism). The population model may be applicable to pharmacokinetically guided intravenous methadone dosing and CYP2B6-mediated drug interactions in perioperative and critical care settings.

High-dose methotrexate for pediatric cancer treatment is frequently associated with mucositis, which can lead to delayed or discontinued treatment and impact survival. While individual genetic variants have been implicated, the cumulative impact of genetic variation within relevant biological pathways remains unexplored. We evaluated single nucleotide polymorphisms across 18 pathways previously identified as relevant to mucositis in 278 pediatric patients with acute lymphoblastic leukemia from six academic health centers across Canada. Pathway enrichment was assessed using the Joint Association of Genetic variants tool, and a predictive model was developed using XGBoost, a supervised machine learning algorithm based on gradient-boosted decision trees. Pathway enrichment identified significant associations in IL6 (P = 0.04) and WNT/β-catenin (P = 0.048) signaling pathways. The predictive model (area under the curve [AUC] = 0.76) highlighted single nucleotide polymorphisms associated with inflammation- and mucosa-related genes, including PRKCD, IL17B, MAST3, and CAPN9, with both risk and protective effects. Model performance dropped by 0.15 in AUC (from 0.76 to 0.61) after removing single nucleotide polymorphism features, underscoring their predictive value. This pathway-informed approach identifies genetic contributors to methotrexate-induced mucositis and supports polygenic risk prediction. Our findings provide a foundation for individualized toxicity risk profiling and suggest potential therapeutic targets to mitigate treatment-limiting mucositis in pediatric oncology.