The Journal of Clinical Pharmacology最新文献

A preterm and term neonate to adult (PTNA) maturation equation was introduced recently to describe the glomerular filtration rate maturation from birth to adulthood for neonates of varying gestational age. This study aims to evaluate the newly developed PTNA equation against common maturation approaches like allometric scaling (AS0.75), the AS0.75 plus postmenstrual age (PMA)-based E_max (AS0.75 + PMA) equation, and the bodyweight dependent exponent equation (BDE) for the maturation of three hepatic pathways of paracetamol (PCM) from preterm and term neonates up to adults. A population pharmacokinetic analysis was conducted with pooled plasma and urine data of PCM, PCM-glucuronide (PCM-GLU), PCM-sulfate (PCM-SULF), and PCM-oxidative metabolites (PCM-OXI) (number of observations:6428) from 298 subjects, including preterm and term neonates, infants, children, and adults. PTNA, AS0.75, AS0.75 + PMA, and BDE were evaluated separately to describe the formation clearance of each PCM metabolite. Results indicated that the PTNA equation best described the formation clearance of PCM-GLU, outperforming the BDE and AS0.75 + PMA equations in both statistical and graphical evaluation metrics and inter-individual variability reduction. For PCM-SULF and PCM-OXI, the PTNA equation also had the best performance, but the improvements were smaller. The final model described the PK of PCM and its metabolites adequately among subpopulations as indicated by diagnostic plots. In conclusion, the PTNA maturation equation best describes the maturation of all hepatic elimination pathways of PCM. It can, as such, be potentially applied to other drugs and pathways when data from both preterm and term neonates and older children are part of the PK analysis.

Endoxifen is the most active metabolite of tamoxifen and plays a central role in its therapeutic efficacy. However, significant interindividual variability in endoxifen plasma concentrations, driven by both genetic and non-genetic factors, may result in subtherapeutic exposure for a substantial subset of patients. This study evaluated the influence of CYP2D6 phenotype and age on endoxifen steady-state concentrations and explored the clinical utility of therapeutic drug monitoring (TDM) to guide tamoxifen therapy. A total of 63 breast cancer patients receiving tamoxifen 20 mg daily for at least 3 months were enrolled. Patients were genotyped for CYP2D6 using TaqMan assays and classified as normal metabolizers (NMs, n = 49), intermediate metabolizers (IMs, n = 13), or ultrarapid metabolizers (UMs, n = 1). Plasma concentrations of tamoxifen and its metabolites were quantified by LC-MS/MS at steady state. Endoxifen levels were significantly lower in IMs (7.13 ng/mL; 95% CI: 3.38-15.08) compared to NMs (22.66 ng/mL; 95% CI: 18.57-27.66; P < .001). Subtherapeutic endoxifen concentrations (<6 ng/mL) were observed in 23.1% of IMs and 4.1% of NMs. These results support the combined use of CYP2D6 genotyping and TDM as the optimal strategy for personalizing tamoxifen therapy and minimizing the risk of subtherapeutic endoxifen exposure.

Oncolytic viruses are an emerging class of immunotherapies for cancer treatment. Talimogene laherparepvec (T-VEC) is a first-in-class oncolytic virus approved globally for advanced melanoma. Herein, we describe the quantitative clinical pharmacology aspects of T-VEC that supported the development of this unique therapy. As a live therapy, the exposure characteristics of T-VEC are vastly different from the pharmacokinetics (PK) of traditional small molecules or therapeutic proteins and were characterized as tumor site oncolytic viral kinetics. Relatively flat relationships between T-VEC dose, lesion exposures, and efficacy were identified based on dose–exposure–response (D-E-R) analyses of 60 adult subjects, indicating that optimal drug effect was achieved over the studied dose range (10⁶-10⁸ plaque forming unit [PFU]/mL); hence, efficacy was not sensitive to dose variations within the range. The relatively flat D-E-R relationship for T-VEC was also beneficial for biopharmaceutic aspects unique for live viruses, including bridging small variations in viral infectivity observed from batch to batch during manufacturing. Additionally, the exposures in pediatric subjects (N = 15) were within the range, although generally lower in medians than adults (N = 60). The primary safety concern of T-VEC-related herpetic infection was evaluated using a mechanistic PK-PD model which indicated minimal infection risk over the up to 5 years follow-up duration. Overall, T-VEC demonstrated favorable PK-PD profiles and was well tolerated in adults and pediatric subjects at the approved dosing regimen. Quantitative clinical pharmacology analyses have supported the optimal development of T-VEC and are poised to accelerate the development of these promising therapeutic oncolytic viruses.

Cao A, Li Q, Han M, et al. Physiologically based pharmacokinetic modeling of vancomycin and its comparison with population pharmacokinetic model in neonates. J Clin Pharm. 2025;65:87-95. https://doi.org/10.1002/jcph.6126

In the article cited above, Yanping Guan was listed as the corresponding author due to an administrative error. The correct corresponding author is Lu Tan and the contact information is listed below.

Lu Tan

Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China

[email protected]

We apologize for this error.

The pharmacokinetic characteristics of drugs are altered under high-altitude hypoxia. We aim to describe the population pharmacokinetics of nifedipine to investigate the effects of high-altitude hypoxia on the pharmacokinetics of nifedipine in hypertensive patients. A total of 206 plasma concentrations were collected from 50 patients with hypertension in plateau areas and 53 in plain areas. The PK of nifedipine in hypertensive patients in the plateau and plain area of China was described using nonlinear mixed-effects modeling. The patient's blood pressure was recorded to evaluate the antihypertensive effect of nifedipine. The pharmacokinetics of nifedipine were described by a one-compartment model with zero-order absorption and first-order elimination. The estimated apparent clearance was 18.74 L/h with 31.91% interindividual variability, and the apparent volume of distribution was 103.88 L with 22.44% interindividual variability. Plateau versus plains were identified as a significant covariate affecting nifedipine pharmacokinetics, particularly in inter-individual clearance rates. The interindividual variability of CL was reduced from 36.26% to 31.91%, and the CL of patients in the plateau area was about 1.35 times higher than that in the plain area. This study may contribute to the rational use of nifedipine in the plateau area.

Physiologically based pharmacokinetic (PBPK) models have gained interest as a tool for predicting drug transfer to human milk and assessing the exposure levels in infants. Our group previously developed an integrated lactation PBPK model framework to understand the transfer of drugs into milk and the resulting exposure in infants. As a part of the framework, the current paper focuses on performance of lactation PBPK models to predict maternal plasma and milk concentrations for drugs that are not substrates of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporters—atenolol, escitalopram, and alprazolam. PBPK models for healthy adult subjects were developed for atenolol and escitalopram in Simcyp v23 and verified against clinical data. For alprazolam, the Simcyp library model was used. The built-in lactation compartment in Simcyp was utilized for the three drugs. Atenolol and escitalopram adult healthy PBPK models showed agreement of plasma concentration–time profiles with respective clinical data. The lactation PBPK models predicted milk concentration profiles with reasonable agreement for all three drugs as well. The predicted milk concentration–time profile, milk pharmacokinetic parameters and milk-to-plasma (M/P) ratio of atenolol, alprazolam, and escitalopram were within 2-fold of the reported values, suggesting agreement between simulation and clinical data. The current work shows the potential of lactation PBPK models to predict drug exposure in human milk for drugs that are not P-gp or BCRP substrates. The approach will be further evaluated for drugs that are substrates for these active transporters known to be present in mammary tissues.

Sotorasib is a small molecule KRAS^G12C inhibitor approved for the treatment of KRAS^G12C mutated locally advanced or metastatic non-small cell lung cancer in adult patients. The effect of hepatic impairment on the pharmacokinetics (PK) of sotorasib and major metabolites M10, M18, and M24, safety, and tolerability after a single oral dose of 960 mg was assessed in a phase 1, parallel-arm, multi-center (US), open-label study. Sotorasib AUC_inf ratio for subjects with moderate (n = 7) or severe (n = 4) hepatic impairment relative to normal hepatic function (n = 7) was 0.746 (90% CI: 0.431-1.29) and 1.04 (0.545-1.97), respectively. C_max ratio for moderate and sever hepatic impairment was 0.955 (0.512-1.78) and 1.43 (0.688-2.96), respectively. Mean t_1/2 values for sotorasib were similar in subjects with normal hepatic function and subjects with moderate or severe hepatic impairment. C_max and AUC_inf of M10 and M24 increased, while M18 decreased with increasing severity of hepatic impairment. Treatment-emergent adverse events were mild in severity and no serious adverse events were reported. Overall, moderate or severe hepatic impairment did not considerably affect the exposure of sotorasib, M10, M18, and M24. This data supports that adjustments to sotorasib dosing are not indicated for moderate or severe hepatic impairment.

In Japan, the percentage of approved drugs with pediatric indications increased to 30% in 2010-2015, but no further increase was observed through 2020. The Ministry of Health, Labor, and Welfare in Japan presented draft future directions to promote pediatric drug development, where the modeling and simulation (M&S) approach was introduced as a tool to support efficacy and safety, utilizing existing data when building a flexible data package for pediatric drug approval. M&S is considered a powerful scientific tool in pediatric drug development using the pediatric extrapolation approach. We examined approval application data packages for pediatric drugs approved in Japan from January 2019 to March 2023, where 95 drug products were identified as pediatric drugs for this survey. Drugs with complete, partial, or no extrapolation accounted for 43.2%, 30.5%, and 26.3% of the total drugs, respectively. M&S was widely used as the major rationale in dose selection for pediatric clinical trials and/or the recommended dosing regimen in drug approval applications for the pediatric population (60.0%). Further use of existing data with extrapolation strategies may lead to the development of flexible and efficient data packages for pediatric drug approval. Since safety profiles may be different between pediatric and adult populations due to age-related factors, pediatric developmental safety should be incorporated into M&S in future assessments. The pharmaceutical industry, regulatory authorities, and academia need to discuss development strategies from an early stage and share lessons learned, thereby facilitating further discussions on efficient pediatric drug development and delivering drugs for children without delay in Japan.

Mian P, Valkenburg AJ, Allegaert K, et al. Population Pharmacokinetic Modeling of Acetaminophen and Metabolites in Children After Cardiac Surgery With Cardiopulmonary Bypass. J Clin Pharmacol. 2019;59:847-855. https://doi.org/10.1002/jcph.1373

In the article cited above, the obtained parameter values and relative standard errors of the estimates (RSE) for the model, presented in table 2 of the original publication, were not correct. Differences in obtained values are generally well below 30% for the structural model parameters, except for the parameters related to the oxidative metabolites, for which the new values differ considerably more. With a few exceptions stochastic model parameters also deviate less than 30%. The table with the correct parameter values is presented below.

We apologize for this error.

Mavacamten, a cardiac myosin inhibitor, is primarily metabolized by the cytochrome P450 (CYP) enzymes CYP2C19 and CYP3A4, and coadministration with strong CYP3A4 or CYP2C19 inhibitors was contraindicated in patients with obstructive hypertrophic cardiomyopathy (HCM) in the US Prescribing Information. This study assessed the safety and efficacy of modifying mavacamten posology to accommodate coadministration with strong CYP3A4 and strong/moderate CYP2C19 inhibitors. Simulations of 5000 virtual patients with obstructive HCM with an equal distribution of CYP2C19 metabolizer phenotypes were performed using population pharmacokinetic and exposure–response modeling approaches. A reference posology and variations thereof were simulated to evaluate long-term (chronic) and short-term (1-week) coadministration with CYP3A4 or CYP2C19 inhibitors. Proportions of patients with left ventricular ejection fraction (LVEF) <50% and Valsalva left ventricular outflow tract gradient (VLVOTg) <30 mm Hg were evaluated to assess safety and efficacy, respectively. Compared with the reference posology, a modified posology, which used a 2.5-mg starting dose with coadministration being stopped if LVEF was <50% at any time when receiving 2.5 mg, resulted in a similar peak proportion of CYP2C19 poor metabolizers and CYP2C19 ultrarapid metabolizers with LVEF <50% when initiating mavacamten with a CYP3A4 or CYP2C19 inhibitor, respectively. Achievement of optimal efficacy was delayed in some patients owing to dose reduction. Initiation of CYP3A4 or CYP2C19 inhibitor treatment in patients receiving stable mavacamten therapy was accommodated through mavacamten dose reduction by one level. Interruption of mavacamten during short-term administration of inhibitors transiently increased VLVOTg for the duration of interruption, with no effect on LVEF.