Wiley-Online-Library: The Journal of Clinical Pharmacology: Table of Contents

Correction to “A Phase 1 Study Evaluating the Pharmacokinetics and Safety of Avacopan in Participants With End‐Stage Kidney Disease on Hemodialysis”

Fri, 05 Jun 2026 23:45:18 -0700

The Journal of Clinical Pharmacology, Volume 66, Issue 6, June 2026.

Street Pharmacology: The Mechanistic Basis of Clinical Pharmacology Underlying the Microdosing Method of Buprenorphine–Naloxone With a Focus on the Unhoused Population

Tue, 02 Jun 2026 05:45:39 -0700

Abstract

Expanded use of buprenorphine–naloxone use, particularly for marginalized communities, such as the unhoused, is an established priority. Unfortunately, due to fear of the precipitation of opioid withdrawal, this goal remains unmet. In response, microdosing methods during the initial week of treatment do not require opioid abstinence and do not precipitate withdrawal. This review establishes the scientific basis for microdosing that is centered on the pharmacodynamic principle of pseudo-irreversibility for a partial agonist, such as buprenorphine.

Ontology‐Enhanced Deep Learning for Mechanistic Prediction of Drug–Drug Interactions: A Clinically Interpretable Framework

Adeeb Noor — Mon, 01 Jun 2026 21:17:28 -0700

Abstract

Drug–drug interactions (DDIs) have critical impacts on patient safety and healthcare efficiency because of their significant contributions to adverse drug reactions. Accurately predicting DDIs and their biological mechanisms is therefore essential, yet remains challenging. This study aims to enhance prediction accuracy and mechanistic interpretability by leveraging biomedical ontologies. We developed ontology-based embeddings from SIDER, DrugBank, and Gene Ontology data to represent phenotypic, functional, and mechanistic drug characteristics, providing biologically enriched features for neural network-based prediction of DDIs. The proposed framework achieved robust performance, validated externally (receiver operating characteristic area under the curve values up to 0.94), and effectively predicted DDIs across 11 pharmacokinetic and pharmacodynamic mechanisms. These mechanism-specific predictions emphasize the biological and pharmacological relevance of putative DDIs, enhancing interpretability by identifying high-risk DDI mechanisms linked to known adverse reactions. Our approach, integrating ontology-based embeddings with deep learning, therefore not only significantly improves DDI prediction but also supports clinical decisions to mitigate adverse drug reactions risks, albeit indirectly.

Acetylation Variability in Elderly Tunisians: Implications for Isoniazid Dose Individualization

Mon, 01 Jun 2026 07:24:45 -0700

Abstract

The relationship between age and isoniazid acetylation phenotype remains insufficiently characterized, particularly in elderly populations, where pharmacokinetic variability and susceptibility to toxicity may be increased. This study aimed to characterize isoniazid acetylation phenotypes in elderly Tunisian patients using a phenotypic index and to assess its clinical implications. A retrospective study was conducted on 476 Tunisian tuberculosis patients treated with isoniazid between 2019 and 2024. Plasma concentrations at 3 h post-dose (C₃) were used to determine the acetylation index (I₃) and classify patients as rapid acetylators (RAs) or slow acetylators (SAs). Associations between acetylation phenotype, C_3, dose adjustments, adverse events, and clinical variables were assessed using non-parametric and categorical statistical tests. Slow acetylators represented 68.1% of the cohort and were associated with significantly higher isoniazid exposure and a greater proportion of supra-therapeutic concentrations. Overall, 66.0% of patients exhibited supra-therapeutic concentrations. Acetylator status significantly influenced dose adjustment requirements, with 89.2% of SAs requiring modification, mainly dose reductions. Adverse events occurred in 34.9% of patients and were significantly more frequent in SAs compared with RAs (44.1% vs 15.1%, p <.001). No significant association was observed between age and acetylation phenotype or plasma exposure, although age was associated with adverse events. Renal function showed no significant correlation with acetylation status or exposure. The high interindividual variability observed supports the use of phenotypic assessment (I₃) to guide individualized dosing, particularly in settings where NAT2 genotyping is not routinely available. Prospective studies integrating pharmacogenetic and pharmacokinetic approaches are warranted to refine precision therapy in this high-risk population.

The High Cost of Inexpensive Medicines

George Selali Blewusi, Ruohui Zheng, Lobna Gaayeb, Charles Flexner — Sun, 31 May 2026 23:05:45 -0700

The Journal of Clinical Pharmacology, Volume 66, Issue 6, June 2026.

A Phase 1 Study to Evaluate the Potential Drug–Drug Interaction Between Islatravir and Lenacapavir

Fri, 29 May 2026 08:49:42 -0700

Abstract

People with HIV-1 may find adhering to life-long daily oral antiretroviral therapy difficult, which can lead to treatment failure or drug resistance. Longer-acting treatments may improve adherence, treatment outcomes, and quality of life. Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor, plus lenacapavir (LEN), the first-in-class HIV-1 capsid inhibitor, are being evaluated as a weekly oral regimen for HIV-1. We investigated drug–drug interactions (DDI) between ISL and LEN by evaluating the pharmacokinetics and safety of a single-dose oral co-administration of 20 mg of ISL and 600 mg of LEN relative to single-agent administration in 55 adults without HIV. Co-administration showed similar pharmacokinetic profiles compared with single-agent administration; no clinically meaningful pharmacokinetic DDI was identified. The percent geometric least-squares mean (%GLSM) ratios for ISL exposure parameters were 88%–105%, and corresponding 90% confidence intervals (CIs) were within prespecified bounds (60%–167%). While there were no clinically significant differences in LEN exposure between ISL+LEN and LEN administration, the %GLSM ratios for LEN exposures were 80%–90%, with 90% CIs within 60%–167% except for maximum LEN concentration. High percentage coefficient of variation was observed for LEN pharmacokinetic parameters, resulting in relatively wide 90% CIs. ISL and LEN were generally well tolerated, with no serious or Grade 3 or 4 adverse events, deaths, or discontinuations of the study due to an adverse event. These results and positive initial findings from an ongoing Phase 2 study (NCT05052996) support further clinical development of ISL and LEN as a weekly combination oral treatment for HIV-1.

Partial Differential Equation (PDE)‐Based Spatial Pharmacometrics in NONMEM: Method of Lines (MOL) Implementation with AI‐Assisted Model Development

Yiming Cheng, Yan Li — Fri, 29 May 2026 03:28:10 -0700

Abstract

Spatial heterogeneity in drug distribution, particularly within solid tumors, compromises target engagement, yet is rarely represented in population pharmacokinetic analyses. Standard “well-stirred” models fail to capture intratumoral gradients. Reaction–diffusion partial differential equations (PDEs) mechanistically represent penetration and washout, but routine implementation in nonlinear mixed-effects modeling (NONMEM) is limited by operational complexity. Native numerical templates remain cumbersome, and manual method of lines (MOL) coding is labor-intensive and error-prone. This work presents a streamlined workflow to implement spatial PDEs in NONMEM using AI tools. We utilized AI-assisted code generation to systematically translate continuous spatial models into coupled ordinary differential equation systems directly executable in NONMEM, maintaining transparent $DES block implementations. We illustrate this approach with one-dimensional, spherical, and two-dimensional reaction–diffusion models, providing guidance for iterative refinement via prompt engineering. Although AI does not resolve numerical stiffness or identifiability limitations, it substantially reduces the engineering burden of large MOL systems. Coupled with disciplined verification, AI-assisted code generation makes PDE-based spatial pharmacometrics in NONMEM practical and maintainable, supporting wider adoption to interrogate target-site exposure and penetration-driven efficacy.

Population Pharmacokinetics of Oral Gecacitinib in Healthy Subjects and Patients with Autoimmune and Inflammatory Diseases

Fri, 29 May 2026 03:24:19 -0700

Abstract

Gecacitinib is a novel, broad-spectrum Janus kinase (JAK) inhibitor being developed for the treatment of myelofibrosis, severe alopecia areata, ankylosing spondylitis, and atopic dermatitis. This study aimed to develop population pharmacokinetic (PopPK) models for gecacitinib and its metabolites ZG0244 and ZG0245 to evaluate influential factors. Data from healthy subjects and patients across nine clinical trials were pooled. PopPK models were developed using NONMEM, and covariates of interest were tested. The PopPK structure for gecacitinib was a two-compartment model with first-order absorption and linear elimination. The metabolite ZG0244 was best described by a two-compartment model with Michaelis–Menten formation and linear elimination, while for metabolite ZG0245, it was a one-compartment model with Michaelis–Menten formation and linear elimination. Statistically significant factors affecting pharmacokinetic parameters included sex, age, indication, and co-administration with a strong CYP3A inducer or inhibitor. The effects of sex, age, and strong CYP3A inducer on exposure were limited, requiring no dose adjustment. A strong CYP3A inhibitor increased exposure by approximately 1.3-fold. The median time to reach 95% of steady-state concentration was approximately 3 days for gecacitinib and ZG0244, and approximately 7 days for ZG0245. This study developed population pharmacokinetic models for gecacitinib and its metabolites, and quantified the effects of covariates.

Hepatic CYP1A2 Activity in Adolescents with and without Obesity Assessed by the Urinary Paraxanthine‐to‐Caffeine Metabolic Ratio: A Pharmacokinetic Study

Fri, 29 May 2026 03:24:03 -0700

Abstract

Obesity-related metabolic and hepatic alterations may influence drug metabolism via cytochrome P450 enzymes. While adult studies suggest altered CYP1A2 activity in obesity, data in pediatric populations remain limited and inconclusive. The objective was to assess the in vivo CYP1A2 phenotype in adolescents aged 11-18 years with and without obesity, and to explore sex-based differences in enzyme activity within this age group. In this open-label pharmacokinetic study, which is a part of the CYTONOX study, 65 adolescents aged 11–18 years were included, comprising 30 individuals with obesity and 35 without obesity, recruited based on feasibility. The CYP1A2 phenotype was assessed using urinary paraxanthine/caffeine metabolic ratios following caffeine exposure. Hepatic fat content was measured via magnetic resonance spectroscopy. The study received approval from the Danish Health Authorities (EudraCT: 2014-004554-34) and the Regional Ethical Committee of Zealand (SJ-455). Despite metabolic differences and increased hepatic fat in the obese group, the CYP1A2 phenotype did not differ significantly between obese and non-obese adolescents (mean log10 urinary metabolic ratio: 0.82 vs 0.80; P = .93). No sex-based differences were observed. Obesity in adolescents does not appear to significantly impact CYP1A2 phenotype assessed by urinary metabolic ratio, in contrast to selected studies in adults. These findings suggest preserved CYP1A2 function during adolescence despite metabolic and hepatic changes. Further longitudinal studies are needed to elucidate the age-related progression of hepatic enzyme activity in context of obesity.

Response to Letter to the Editor from Madhuri Tribhuvan and Shashikant N. Phatke

Kevin. V. Tobin, Addison Leabo, J. Steven Leeder, Joga Gobburu, Allison Dunn — Fri, 29 May 2026 03:23:13 -0700

The Journal of Clinical Pharmacology, Volume 66, Issue 6, June 2026.

Comment on “Understanding Atomoxetine Exposure Variability in Children and Adolescents with ADHD through Population Pharmacokinetics”

Madhuri Tribhuvan, Shashikant N. Phatke — Fri, 29 May 2026 03:20:18 -0700

The Journal of Clinical Pharmacology, Volume 66, Issue 6, June 2026.

Evaluation of Vancomycin Dosing Practices in Critically Ill Patients Receiving Accelerated Venovenous Hemofiltration

Fri, 29 May 2026 03:20:13 -0700

Abstract

Accelerated venovenous hemofiltration (AVVH) is a hybrid renal replacement therapy (RRT) offering higher hemofiltration rates and improved hemodynamic stability, but can alter pharmacokinetics and pharmacodynamics of numerous antibiotics, creating uncertainty in efficacy and toxicity. The purpose of this study was to describe vancomycin dosing practices in patients receiving AVVH, with the potential to model vancomycin dosing and monitoring strategies. This was a single-center retrospective analysis of vancomycin dosing strategies utilized in critically ill adult patients receiving AVVH. Patients were included if they received vancomycin while undergoing AVVH and had a vancomycin concentration measured within the first 24 h of initiating concomitant vancomycin and AVVH. Major endpoint of this study was the incidence of in-range vancomycin concentrations (10–20 mcg/mL) in patients undergoing AVVH. There were 52 patients included in the analysis, with 79 unique AVVH sessions with an associated vancomycin concentration assessed. Median dose of vancomycin was 1250 mg (1000–1500), or 14.5 mg/kg (12.7–16.6), per AVVH session. Incidence of in-range vancomycin concentrations was 68.4%, with a median vancomycin concentration of 17.1 mcg/mL (14.0–21.5). Median duration of vancomycin therapy with concomitant AVVH was 2 days (1–7) and the median time from AVVH completion to vancomycin concentration obtainment was 2.8 h (0.3–5.7). The majority of vancomycin concentrations collected were in range, using a median vancomycin dose of 14.5 mg/kg and achieving a median vancomycin concentration of 17.6 mcg/mL. This suggests most patients achieved in-range concentrations, but additional prospective pharmacokinetic studies are needed to understand vancomycin exposure and dosing requirements in patients undergoing AVVH.

Population Pharmacokinetics and Exposure‐Response Analyses for Ubrogepant Efficacy and Safety in the Acute Treatment of Migraine: Analysis of Phase 1–3 Studies

Sven Stodtmann, Lucia Siovitz, Heiko Babel, Ramesh R. Boinpally — Fri, 29 May 2026 03:16:22 -0700

Abstract

A population pharmacokinetic (popPK) model was developed for ubrogepant using data from 10 Phase 1, 1 Phase 2, and 2 Phase 3 studies. The data were described by a 2-compartment model with linear elimination and transit compartment absorption. Formulation, food intake, race, gender, and hepatic impairment had a statistically significant impact on ubrogepant PK. Significant exposure-response relationships were found for 2 h pain relief and pain freedom, and 24 h sustained pain relief and sustained pain freedom. Ubrogepant significantly improved the symptoms of phonophobia and photophobia, and the most bothersome migraine symptom, with a modest trend with ubrogepant dose. A Phase 3 study evaluating ubrogepant use during the prodrome was incorporated into the popPK model, and the mean transit time and inter-individual variability were re-estimated. Exposure-response analysis across multiple endpoints in the prodrome study (including absence of moderate/severe headache within 24 or 48 h, absence of headache of any intensity within 24 h, and ability to function normally within 24 h) showed a treatment effect with improved outcomes after receiving ubrogepant.

Issue Information

Fri, 29 May 2026 03:14:47 -0700

The Journal of Clinical Pharmacology, Volume 66, Issue 6, June 2026.