The Journal of Clinical Pharmacology最新文献

TV-44749 is a long-acting subcutaneous (SC) injectable olanzapine based on a novel copolymer drug delivery technology ensuring controlled olanzapine release over the dosing interval. TV-44749's formulation and SC route of administration aim to eliminate the causes of post-injection delirium/sedation syndrome (PDSS) that may occur with the intramuscular LAI olanzapine formulation. The main objective of this analysis was to utilize a population pharmacokinetic (PPK) modeling and simulation approach to select TV-44749 doses for a Phase 3 clinical trial that are comparable to the oral olanzapine approved doses and achieve dopamine D2 receptor occupancy (D2RO) within the therapeutic range. The PPK model was developed using data from a Phase 1 study in healthy participants and patients with schizophrenia or schizoaffective disorder. The Phase 1 study consisted of an oral olanzapine period followed by a washout and then single or multiple doses of TV-44749. The PK model was characterized by a double Weibull input function representing a two-phase drug release: an initial rapid release of a fraction of the dose, followed by a delayed and sustained release of a second fraction with two-compartment disposition model. The predicted steady-state pharmacokinetic parameters (C_max, C_avg, and C_trough) of once-monthly TV-44749 doses of 318, 425, and 531 mg were comparable to daily oral doses of 10, 15, and 20 mg, respectively. The exposure values resulted in simulated D2RO levels within the recommended range (60%–80%) and were therefore selected for the Phase 3 trial of TV-44749 (SOLARIS; NCT05693935).

Methadone is used in hospitalized children to treat pain and iatrogenic opiate withdrawal. Optimal pediatric dosing for both enteral and intravenous methadone is unknown. We conducted two prospective, multi-center, open-label studies to characterize the pharmacokinetics of methadone in the pediatric population. These studies were conducted at a total of 23 US children's hospitals. Ninety-nine children with a median (range) age of 2.3 (0–19.0) years and weight of 13.0 (0.72–159) kg were prescribed methadone per standard of care for treatment of pain or iatrogenic opiate withdrawal. Ninety-nine children received median (range) methadone doses of 0.11 (0.01–0.39) mg/kg intravenously and 0.10 (0.01–0.61) mg/kg enterally. Ten participants received only intravenous doses; 78 received only enteral doses; and 11 received intravenous and enteral doses. We analyzed 263 pharmacokinetic samples with a median (range) methadone plasma concentration of 42.2 (0.9–729.2) ng/mL. A one-compartment population pharmacokinetic model described the methadone data well. Median (range) empiric Bayesian estimates of clearance, volume of distribution, and half-life were 0.17 (0.009–1.50) L/h/kg, 4.99 (0.97–20.6) L/kg, and 20.5 (3.0–86.2) h, respectively. Dosing simulations showed that doses of 0.1 mg/kg every 8 h (intravenous) and 0.2 mg/kg every 8 h (enteral) achieved exposures associated with pain control and reduction in withdrawal symptoms. Based on observed exposures and model simulations, we recommend a starting dose of 0.1 mg/kg intravenous or 0.2 mg/kg enterally (max 10 mg) every 8 h. Because of wide interindividual variability, this dose should be titrated to effect.

Elranatamab, a bispecific antibody targeting B-cell maturation antigen, is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). An exposure–safety analysis was conducted using the data from patients with RRMM across four clinical studies, MagnetisMM-1, 2, 3, and 9 (NCT03269136, NCT04798586, NCT04649359, and NCT05014412). The selected safety endpoints included grade ≥3 infections, neutropenia, anemia, and thrombocytopenia. Additionally, the relationship between the elranatamab exposure and dose interruptions and discontinuation events was explored. The results showed no statistically significant relationship between elranatamab exposure and the incidence of these safety events. The flat exposure–safety relationship with the evaluated safety endpoints suggested a similar probability of experiencing these events with the 76-mg once-weekly (QW) regimen compared with lower doses within the efficacious dose range (215–1000 µg/kg, equivalent to 16–76 mg). These data support the use of a full dose of 76 mg QW and do not indicate that selecting a lower dose would significantly mitigate the risk for adverse events. Additionally, these findings support managing elranatamab adverse drug reactions through temporary dose interruption rather than dose reduction.

Bictegravir is an integrase strand transfer inhibitor available in fixed-dose combination with emtricitabine and tenofovir alafenamide for HIV treatment. The objectives of this study were to develop a population pharmacokinetic model for bictegravir during pregnancy and postpartum, identify main drivers of between-subject variability, and evaluate the role of adherence patterns in maintaining therapeutic exposure. Intensive bictegravir concentration–time data were used from IMPAACT 2026, a pharmacokinetic study of selected antiretroviral drugs during pregnancy and postpartum. Five hundred and eight bictegravir plasma concentrations from 27 participants during the second and third trimesters of pregnancy and postpartum were utilized for model development. A one-compartment structural model best described bictegravir PK. Pregnancy increased bictegravir apparent clearance (CL/F) by 61% compared to postpartum, while Black/African American race was associated with a 32% increase in apparent volume of distribution (Vd/F). Plasma albumin concentrations were associated with a 43% decrease in CL/F and body weight was associated with a 120% increase in Vd/F over the range of observed values. Monte Carlo simulations predicted median (90% prediction interval) pre-dose bictegravir concentrations of 920 ng/mL (265–2081) during the third trimester and 3399 ng/mL (1423–6391) postpartum, exceeding the protein-adjusted 95% effective concentration (162 ng/mL). Adherence simulations predicted a single missed dose at steady-state during the third trimester results in 43.7% of virtual subjects with concentrations below pharmacodynamic target, while two consecutive missed doses result in 90.4% with concentrations below target. These results show that while standard bictegravir dosing is effective during pregnancy, consistent adherence is critical to maintain effective therapeutic exposures.

Nasal epithelium is the site of infection for SARS-CoV2 viruses, with interactions of the viral spike protein with the ACE2 receptor of the host cell. Molecular docking studies have shown that ivermectin shields the spike protein and thereby prevents binding to ACE2. Nasal application of high doses of ivermectin could be the right therapeutic approach in the treatment and prevention of COVID-19. Tolerability, safety, and pharmacokinetics of ivermectin, administered nasally as 5% microsuspension (F004), were investigated in a randomized, double-blind, parallel-groups, placebo-controlled phase 1 study in 28 healthy adults. Bioavailability of a single dose of 14 mg ivermectin was determined with AUC_0–t^T of 1701.1 ng/mL h (AUC_0–∞ of 2382.7 ng/mL h, calculated), C_max of 96.2 ng/mL, T_max of 4.4 h, and T_1/2 of 59.9 h. Following 42 mg/day multiple dose (3 × 14 mg every 6 h) administered nasally over 5 days, AUC_0-∞ of 2194.4 ng/mL h was analyzed, and 96% of ivermectin concentrations were still measurable 12 h after the last dose. F004 was safe in this study and well-tolerated. Nine (F004 group) and three (placebo group) of 28 subjects reported 14 symptoms, including a few systemic but mainly local nasal adverse events (AE). The number of subjects reporting AE decreased continuously after both F004 and placebo treatment. All subjects recovered fully with no AE recorded at the end of the study. Nasal examination showed stable patterns of nasal mucosal grading, mucosal bleeding, and crusting of the mucosa. Nasally administered ivermectin is well tolerated in high concentrations and could provide systemic therapeutic benefits in addition to local effects.

Most pregnant individuals are exposed to at least one medication, whether prescription or over the counter, during pregnancy. Despite the ubiquity of medication use in pregnancy, there remains no standardized framework to guide clinicians in selecting the most appropriate pharmacotherapy that balances maternal needs with fetal safety. This gap contributes to variability in prescribing practices and uncertainty in clinical decision making. In this article, we propose a structured schema for evaluating and selecting drug therapy during pregnancy. Our approach emphasizes careful consideration of maternal and fetal factors, integration of the unique physiologic changes of pregnancy, and systematic appraisal of the best available evidence. Recognizing the frequent absence of robust pharmacokinetic and safety data, we also provide pragmatic principles and rules of thumb to guide clinicians in estimating the likelihood of placental transfer and potential fetal exposure. This framework is designed to support clinicians in making more informed, transparent, and evidence-based decisions while also identifying areas for future research.

In recent years, model-informed strategies such as the model integrated bioequivalence (MIBE) approach have gained significance due to their ability to enable decision making, streamline drug product development, and to waive bioequivalence studies, as applicable. In this work, we demonstrate the successful application of the MIBE approach that led to the waiver of a repeat fasting and fed bioequivalence studies for clopidogrel bisulfate 300 mg tablets. In the pivotal bioequivalence study, pharmacokinetic sampling in fasting and fed conditions was performed until 12 h, shorter than the recommended sampling up to at least three half-lives of the drug. The mean half-life of reference listed drug clopidogrel was 6 h. During dossier review, a query was received from the regulatory agency to assess the impact of early termination of the study on AUC_0–inf and bioequivalence assessment, although the pivotal study demonstrated average bioequivalence. To address this, a population pharmacokinetic model was developed under fasting and fed conditions based on the pilot study data that included data until 24 h. Further, the pivotal study pharmacokinetic parameters were predicted based on a model developed with pilot data and complete profiles until 10 half-lives were simulated. The model-derived parameters were utilized to assess preserving Type-1 error rate at 5% and bioequivalence was simulated. The simulations demonstrated average bioequivalence under fasting and fed conditions, and the 90% confidence intervals within 80%–125%. Overall, the MIBE approach demonstrated that truncated sampling till 12 h did not compromise the interpretability of pivotal study, thereby alleviating the need for a repeat bioequivalence study.