The Journal of Clinical Pharmacology最新文献

BIIB107 is a recombinant, humanized monoclonal antibody targeting α4 integrin receptors, exhibiting a high binding affinity and strong receptor engagement potential in preclinical models, designed to prevent lymphocyte trafficking in multiple sclerosis (MS). This study aimed to characterize its pharmacokinetics (PK) and pharmacokinetic–pharmacodynamic (PK–PD) relationship using model-based approaches to inform dose optimization. A Phase 1 study (NCT04593121) was conducted in 76 healthy volunteers who received single ascending doses intravenously or subcutaneously (SC), along with multiple ascending doses SC. Population PK and PK–PD models were developed to quantify BIIB107 disposition and its effect on α4 integrin receptor saturation. A sigmoidal Emax model was used to characterize the concentration–effect relationship, and Monte Carlo simulations assessed dosing strategies for sustained α4 integrin engagement. BIIB107 exhibited nonlinear, target-mediated clearance, best described by a two-compartment model with first-order absorption and Michaelis–Menten elimination. Body weight was included in the model using allometric scaling on clearance and volume of distribution-related parameters. In a 70-kg subject, key PK parameters included clearance, 7.28 mL/h; central and peripheral compartment Vd, 3.01 and 1.18 L; terminal half-life 19.3 days; and SC bioavailability 73.8%. PK–PD analysis demonstrated dose-dependent α4 integrin saturation, with an EC50 of 0.376 µg/mL. Simulations showed that 450 mg SC every 8 weeks maintained sustained α4 integrin saturation ≥70%, the therapeutic threshold for efficacy, supporting this regimen for investigation in MS patients. These findings emphasize the value of model-informed drug development in optimizing therapeutic monoclonal antibody doses and support BIIB107's further clinical advancement.

Melatonin is increasingly used to treat sleep disturbances, yet its overall efficacy remains unclear due to variability in existing evidence. This scoping review aimed to synthesize systematic reviews with meta-analyses assessing the effects of exogenously administered melatonin on sleep quality in humans. Seven databases were searched from inception to July 9, 2025. Eligible studies were systematic reviews containing at least one meta-analysis evaluating melatonin's effects on any domain of sleep quality compared to any comparator. Fifty-seven systematic reviews were included, comprising 227 meta-analyses. Overlap in primary studies was low (corrected covered area = 2.5%), suggesting that reviews drew on largely distinct evidence bases. Methodological quality was variable: only 8.8% of reviews met all seven predefined criteria for rigor, including protocol pre-registration, dual screening, and bias assessments. Vote counting based on the direction of effect was used to summarize efficacy. Of the 215 meta-analyses comparing melatonin to an inactive comparator, 80.9% favored melatonin, 7.9% favored the comparator, and 11.2% reported unclear results. Sleep quality was assessed using heterogeneous definitions and tools, with few reviews evaluating overall sleep quality directly. Adverse events were commonly reported and generally mild, with headaches, gastrointestinal problems, and dizziness most frequently observed. However, inconsistent terminology and reporting limited synthesis. Despite heterogeneity in review methods and outcome definitions, the direction of evidence consistently favored melatonin over placebo. These findings support the feasibility of a future quantitative umbrella review to estimate pooled effects and guide clinical practice.

Telisotuzumab vedotin (Teliso-V; ABBV-399) is an antibody-drug conjugate (ADC) comprised of the c-Met targeting antibody telisotuzumab (ABT-700) conjugated to the potent cytotoxic monomethyl auristatin E (MMAE). Teliso-V has been evaluated for treating solid tumors and is approved for adults with locally-advanced or metastatic non-squamous non-small cell lung cancer with high c-Met protein overexpression (≥50% tumor cells with strong [+3] staining; determined by FDA-approved test), who have received prior systemic therapy. Here, physiologically-based pharmacokinetic (PBPK) modeling was utilized to evaluate Teliso-V drug-drug interaction (DDI) potential. A published PBPK-model for MMAE as the primary metabolite and a newly-developed telisotuzumab model from existing pre-clinical and clinical trial data were used to create a novel Teliso-V PBPK-model. Unconjugated MMAE release was modeled with drug-to-antibody ratio-specific deconjugation rates, with non-specific and catabolic clearance added to capture half-life and overall PK profile. The Teliso-V model was calibrated and validated using observed clinical trial data, requiring dose-normalized exposure %PEs ≤50%. CYP3A-mediated DDI simulations demonstrated that when Teliso-V was modeled as the victim, a 43% increase and 70% decrease in MMAE AUC were predicted with ketoconazole (strong CYP3A4-inhibitor) and rifampin (strong CYP3A4-inducer) coadministration, respectively. DDI magnitude was comparable to that observed between another approved ADC with the same MMAE payload (brentuximab vedotin) and ketoconazole and rifampin. The current PBPK simulations demonstrated a lack of perpetrator effect of Teliso-V on midazolam, a sensitive CYP3A substrate. The current analysis provides important information on Teliso-V DDI potential and further demonstrates the utility of PBPK models, particularly in oncology, where dedicated DDI studies are challenging.

Many patients with inflammatory bowel disease (IBD) do not adequately respond to infliximab, potentially due to individual differences in pharmacokinetics (PK). This study aimed to identify clinical and biochemical variables associated with infliximab PK. Adult IBD patients treated with infliximab and with registered infliximab trough levels between March 1, 2021 and November 22, 2023, were included. Univariable and multivariable linear mixed-effects models were used to evaluate associations between clinical and biochemical covariates and infliximab trough levels. A systematic literature review was conducted to contextualize findings. The study included 259 patients (CD: n = 202; UC: n = 47; IBD-unclassified: n = 10) with 560 infliximab trough levels available for analysis. Higher hemoglobin was associated with lower infliximab levels (IBD: β = 0.668, p = 0.036; UC: β = 1.639, p = 0.018), as were albumin (IBD: β = 0.214, p = 0.002; CD: β = 0.345, p < 0.001) and AST (CD: β = 0.040, p = 0.019). Inverse associations were also found for ALT (UC: β = −0.100, p = 0.016), ALP (CD: β = −0.029, p = 0.021; UC: β = −0.018, p = 0.037) and GGT (IBD: β = −0.015, p = 0.028; UC: β = −0.034, p < 0.001). Endoscopic inflammation was positively associated with infliximab levels in CD (β = 3.402, p = 0.035). Systemic steroid use was associated with lower infliximab levels in UC (β = −4.263, p = 0.013). In conclusion, this study identified several clinical and biochemical variables, including albumin, hemoglobin and GGT across all patients, albumin, AST and ALP in CD, and hemoglobin, ALT, ALP and GGT in UC, that were associated with infliximab trough levels. Given the correlative nature of this study, these results should be interpreted cautiously. These findings merit validation and could inform model-informed precision dosing strategies in IBD clinical care.

Ervogastat, a diacylglycerol-O-acyltransferase-2 inhibitor, and clesacostat, an acetyl-CoA carboxylase inhibitor, are in clinical development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Study 1 and Study 2 were open-label, Phase 1 trials that assessed the pharmacokinetics (PK) of a single dose of ervogastat (100 mg) and clesacostat (25 mg), respectively, in participants (n = 6/cohort) with mild, moderate, or severe hepatic impairment (HI) and compared to those without HI (reference). Plasma samples were analyzed for both total and unbound concentrations in Study 2 as clesacostat is highly protein bound. In Study 1, compared to participants without HI, ervogastat exposure (AUC_inf) was 56%, 65%, and 52% higher in participants with mild, moderate, and severe HI, respectively. However, when excluding PK data from a participant with unexplained low exposures in reference group, ervogastat exposures were similar between those with/without HI. In Study 2, total clesacostat exposure was 36%, 24%, and 19% higher for mild, moderate, and severe HI, respectively, as compared to reference group. Unbound clesacostat exposures were 70%, 83%, and 166% higher for mild, moderate, and severe HI cohorts, respectively, with clesacostat plasma protein binding shown to decrease with increasing HI severity. Ervogastat and clesacostat were well tolerated with no clinically significant laboratory abnormalities or changes in vital signs and/or electrocardiograms observed. Observed exposures in HI studies were consistent with simulated exposures in MASH population. Taking into consideration the safety margins at the highest doses evaluated in Phase 2, no dose adjustment of ervogastat or clesacostat is currently warranted for patients with hepatic impairment.

Lemborexant, a dual orexin receptor antagonist, is suitable for the long-term treatment of insomnia. It is primarily metabolized in the liver. The aim was to develop physiologically based pharmacokinetic (PBPK) models of lemborexant to provide dosing regimens for populations with hepatic impairment. The PBPK models of lemborexant were developed and validated using PK-Sim for healthy populations and populations with mild, moderate hepatic impairment, respectively. Then, the effect of severe hepatic impairment on lemborexant pharmacokinetics was investigated to determine dosing regimens. The developed model successfully described the pharmacokinetics of lemborexant in healthy and hepatic impairment populations. Mean plasma concentrations of lemborexant were higher in populations with hepatic impairment compared to those with normal hepatic function. The area under the plasma concentration-time curve at steady state (AUC_ss,24h) values in populations with mild, moderate, and severe hepatic impairment were 1.54-, 2.18-, and 2.08-fold higher, respectively, compared to those with normal hepatic function. Based on the changes in exposure, it is recommended that the maximum dose for populations with severe hepatic impairment should be limited to 5 mg once daily, which is similar to moderate hepatic impairment. The PBPK model can be used as a tool for dose adjustments in populations with hepatic impairment.

Levetiracetam (LEV) exhibits considerable interindividual pharmacokinetic variability; however, data in Thai populations remain limited. This study aimed to develop a population pharmacokinetic model of LEV, identify covariates affecting clearance, and inform individualized dosing strategies. A total of 374 LEV plasma concentrations from 264 Thai patients with epilepsy were analyzed using nonlinear mixed-effects modeling. The median age was 65.3 years (range 18.09-97.71). LEV pharmacokinetics was characterized by a one-compartment model with first-order elimination and proportional residual variability. The typical apparent clearance and volume of distribution were estimated at 2.61 L/h and 56.3 L, respectively. Clearance was significantly influenced by creatinine clearance (CrCL), estimated using the Cockcroft–Gault equation with adjusted body weight, and by phenytoin co-administration. Phenytoin increased clearance by 43.1%, while reduced CrCL was associated with lower clearance. Monte Carlo simulations demonstrated that both trough concentrations and the probability of achieving therapeutic targets (12-46 mg/L) declined with increasing CrCL, especially in patients receiving phenytoin. Standard 12-h dosing was generally sufficient for patients with impaired renal function who were not receiving phenytoin. In contrast, subtherapeutic exposure was more frequent in those with preserved or augmented renal function, particularly when phenytoin was co-administered. These findings support the use of higher or more frequent dosing in these subgroups. The final model provides a framework for individualized LEV dosing. Prospective studies are needed to validate these findings and guide their implementation in clinical practice.

Topiramate is increasingly used in the treatment of epilepsy during pregnancy. However, its plasma concentration evidently decreases during pregnancy, which may reduce its efficacy. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of topiramate to simulate maternal and fetal pharmacokinetic changes across different trimesters and to propose dose adjustments. We established a topiramate pregnancy PBPK model in PK-Sim and Mobi. The model was validated using clinically observed data and subsequently used to optimize the dosage during pregnancy. Simulation results showed that the mean steady-state trough plasma concentration of topiramate decreased by 9.4%, 32%, and 46% in the first, second, and third trimesters, respectively. Based on these findings, the dosage should remain unchanged during the first trimester of pregnancy. However, increasing the baseline dose of topiramate by at least 1.5- and 1.9-fold during the second and third trimesters, respectively, may help maintain effective plasma concentrations. This study provides reference information for topiramate dosage adjustment during pregnancy and helps improve its safety and efficacy in pregnant women and fetuses.

Valemetostat is a dual inhibitor of EZH2/1 approved in Japan for the treatment of relapsed/refractory (R/R) adult T–cell lymphoma/leukemia (ATLL) and R/R peripheral T–cell lymphoma (PTCL). It is administered orally once daily (QD) at 200 mg. Here, we present comprehensive population pharmacokinetic (PPK) and exposure–response (ER) analyses of valemetostat. The PPK model included data from six clinical trials in patients with non–Hodgkin lymphoma, including ATLL/PTCL, or healthy participants. ER efficacy analyses were based on data from one phase 2 clinical trial in patients with PTCL; ER safety analyses used data from three trials in patients with ATLL or PTCL. Valemetostat unbound average concentration up to event was used as the exposure metric. ER analyses included overall response rates for efficacy and six safety endpoints (any Grade ≥3 treatment–emergent adverse event [TEAE]; Grade ≥3 thrombocytopenia, anemia, and neutropenia; and dose reduction and interruption due to TEAEs). Valemetostat pharmacokinetics were well described by a three–compartment model, with a sequential linked zero–/first–order absorption, a saturable binding component in the central compartment, and linear elimination of unbound valemetostat from the central compartment. Alpha-1-acid glycoprotein was the only identified covariate significantly affecting total valemetostat exposure but had no impact on unbound exposure. The ER relationship on efficacy was not significant, and positive relationships were identified for multiple safety endpoints. Safety simulations across different doses suggested an acceptable safety profile for 200 mg QD. Overall, these analyses support the favorable benefit–risk profile of valemetostat at 200 mg QD in patients with R/R PTCL.

Garadacimab is a novel, fully human, anti-activated factor XII monoclonal antibody approved for long-term prophylaxis of patients with hereditary angioedema. This open-label, parallel-group, Phase 1, single-center, bridging study in healthy adults (18–55 years of age) characterized the pharmacokinetics and safety of a single 200 mg subcutaneous injection of garadacimab administered via autoinjector/pre-filled pen (AI/PFP) compared with the pre-filled syringe (PFS) used in previous studies. The aim of the study was to bridge the understanding of the PK and safety of garadacimab between PFS and AI/PFP modes of administration. Participants (N = 132) were stratified by body weight, randomized evenly in six groups by device (AI/PFP or PFS) and injection site (abdomen, thigh, or upper arm). The primary endpoint comprised pharmacokinetic parameter comparison between devices. Safety/tolerability were secondary endpoints. The geometric mean ratio (GMR) for C_max and AUC_0–inf comparing administration by PFS and AI/PFP was close to 1 with 90% confidence intervals within a range of 0.8–1.25, meeting bioequivalence criteria; GMR (90%) was 0.92 (0.81, 1.05) for C_max and 0.96 (0.87, 1.07) for AUC_0–inf. No participants in this study had anti-drug antibodies against garadacimab. Treatment-related emergent adverse events were reported in 9/66 (13.6%) participants in the PFS group and 11/66 (16.7%) participants in the AI/PFP group. Garadacimab 200 mg administered as a single subcutaneous dose via AI/PFP had a consistent safety and tolerability profile to that administered via PFS. These findings support administration of garadacimab via AI/PFP, providing at-home convenience for patients and physicians.