The Journal of Clinical Pharmacology最新文献

Understanding adalimumab pharmacokinetics (PK) in pediatric inflammatory rheumatic diseases (PIRD) could facilitate individualized treatment strategies. This pharmacometric (PMX) analysis, utilizing prospectively collected data, aimed to develop a PMX model investigating associations between disease-specific factors and adalimumab exposure in PIRD. PK data originating from a prospective two-center study including 36 children with PIRD (weight IQR: 33-55 kg) receiving subcutaneous adalimumab (IQR: 30-40 mg biweekly; n = 28 at steady state, n = 8 after first dose, i.e., treatment naïve) were analyzed. A total of 72 adalimumab concentrations were available for PMX analysis, measured at 1-9 days and 10-14 days post-dose. In addition to disease type (juvenile idiopathic arthritis [JIA] vs idiopathic uveitis) and disease activity (inactive/mild/minimal/moderate/severe), associations between methotrexate (MTX) co-administration and duration of adalimumab treatment with apparent clearance (CL/F) were investigated. A one-compartment model with standard allometric scaling adequately described adalimumab concentration–time data, with higher inter-individual variability in apparent clearance (63%). CL/F showed trends of association with disease type (52% higher in JIA vs idiopathic uveitis, P < .1), disease activity (12% higher in active vs inactive disease, P < .1), and duration of adalimumab (higher with longer duration, P < 0.1) but not MTX co-administration (n.s.). However, none of these factors could be incorporated into the model with sufficient precision, except for bodyweight. While this PMX analysis suggests disease-specific factors may influence adalimumab exposure in children with PIRD, additional prospective studies are warranted to further characterize influence of disease-specific factors on drug exposure and their effects on drug response with goal to facilitate implementation of personalized dosing strategies in pediatric rheumatology.

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This study aimed to characterize the pharmacokinetics (PK) of etrolizumab, an IgG1-humanized monoclonal anti-β7 integrin antibody, and assess its exposure–response (ER) relationship for key clinical outcomes in patients with moderately-to-severely active Crohn's disease. ER analyses were based on data from Phase 3 BERGAMOT trial, which evaluated etrolizumab at 105 or 210 mg during induction phase and 105 mg during maintenance phase. Population pharmacokinetic analysis was performed to characterize etrolizumab PK and identify influential covariates. ER analyses were conducted at end of induction and maintenance for clinical remission, endoscopic improvement, and endoscopic remission. ER modeling was performed using logistic regression, and full covariate model was used to examine the impact of baseline covariates on clinical outcomes. Pharmacokinetics of etrolizumab was best characterized using a two-compartment model with first-order absorption, demonstrating a time-dependent decrease in clearance. Typical maximum reduction of clearance was 22.0% (95% CI: 20.5%-23.5%) with onset half-life of 3.45 (95% CI: 2.84-4.04) weeks. Baseline body weight, albumin, and C-reactive protein were the most impactful covariates for etrolizumab exposure. Based on population PK results, trough concentration at Week 4 of induction was selected as exposure metric. Etrolizumab exposure–response slope was significant (P < .05) for clinical remission, endoscopic improvement, and endoscopic remission final models in maintenance phase, but none of final ER models of induction phase. For all induction ER endpoints, tumor necrosis factor (TNF)-naive patients had significantly higher probability of a favorable outcome at end of induction compared to TNF-experienced patients. In summary, exposure–response was more evident at end of maintenance than at end of induction.

Quantitative decision making using the population pharmacokinetic (PPK) approach is useful not only in drug development but also in clinical practice. A previous study investigating the labeling of new active substances (NASs) approved between 2012 and 2015 in Japan and the United Sates reported a significant gap in the percentage of drug labeling providing PPK-related information between Japan (17.6%) and the United States (56.6%). However, whether the state of Japanese labeling has improved compared with the US and European Union (EU) labeling after a Japanese guideline on PPK analysis was released in 2019 has not been investigated yet. This study evaluated the labeling of 138 NASs approved in Japan, the United States, and the EU in or after 2019 and found that the percentage of NASs which provide PPK-related information in the drug labeling with an explicit statement that it was based on PPK analysis was 50.0%, 46.2%, and 76.9% in Japan, the United States, and the EU, respectively, indicating a remarkable improvement in Japan labeling. However, we also found that Japan labeling was still considerably behind the US/EU labeling in terms of application of quantitative decision making by the PPK approach. This is because the percentage of NASs with PPK-derived information used to support dosing recommendations in special populations was much lower in Japan labeling than in the US/EU labeling. While the PPK guideline played an important role in improving Japan's drug labeling, more utilization of PPK-derived information in quantitative decision making is required for healthcare professionals and patients in Japan.

Accurate kidney function assessment supports healthcare and clinical decision-making in practice and drug development. Measured glomerular filtration rate (mGFR) via iohexol clearance is the gold standard, but cost, supply issues, and logistical challenges limit its clinical use. Iopamidol, another iodinated contrast agent widely used in CT imaging, has not been studied in humans for mGFR assessment. This study aims to evaluate the pharmacokinetic interchangeability of iohexol and iopamidol for mGFR assessment and to develop a limited sampling strategy to facilitate clinical implementation. In a parallel-group, single-dose pharmacokinetic study, 24 healthy adult volunteers with varying kidney function, as defined by the 2021 CKD-EPI eGFRcr equation (range: 35-140 mL/min; median: 72 mL/min), received iohexol and iopamidol. Plasma concentrations were measured using liquid chromatography-mass spectrometry, and population pharmacokinetic modeling estimated drug clearance. Clearance estimates for both agents showed strong agreement (R² = 0.82, P < .005), with Bland–Altman analysis indicating minimal bias (mean difference: 15.69 mL/min; LoA: −3.76 to 35.15). A limited sampling strategy using one (1-h, R² = 0.91) or two (1 and 5 h, R² = 0.92) time points yielded accurate clearance estimates. These findings suggest that iopamidol may be a viable alternative to iohexol for mGFR determination. Broader access to accurate kidney function testing can enhance drug dosing, reduce misclassification, and improve care for patients with chronic kidney disease. Further research should validate these findings in larger, more diverse populations, including those with advanced kidney impairment.

The aim of this study was to evaluate the impact of demographic covariates on pharmacokinetic (PK) similarity assessment. A total of 30 PK similarity studies were analyzed to compare the use of analysis of covariance (ANCOVA) and analysis of variance (ANOVA). Trial simulations were conducted to further compare the two statistical approaches by varying sample size and covariates. Our analyses showed that ANCOVA and ANOVA were generally comparable in establishing PK similarity between the two products in the PK similarity studies. However, ANCOVA was observed to produce narrower confidence intervals and thus demonstrate higher power, particularly when the sample size was small.

Tranexamic acid (TXA) is used for the treatment and occasionally prevention of postpartum hemorrhage (PPH); however, questions still remain regarding dosing regimen optimization. This study evaluated TXA pharmacokinetic (PK) data from four clinical trials (NCT: 04274335, 03287336, 00872469, and 02797119) conducted in pregnant participants receiving intravenous, intramuscular, or oral TXA to prevent or treat PPH. The goal of this analysis was to comprehensively characterize TXA PK in a large, heterogeneous population of pregnant individuals to (1) assess the need for weight-based dosing and (2) compare exposure target attainment for alternative routes of administration. A population PK analysis was performed using nonlinear mixed-effects modeling in Pumas, and a stepwise approach was implemented to select the structural model and identify significant covariates. A total of 211 pregnant participants who received between 0.35 and 4 g of TXA intravenously, orally, or intramuscularly offered 1303 TXA plasma concentrations for model development. A two-compartment model with first-order elimination and first-order absorption for both intramuscular and oral administration best described the disposition of TXA. Actual body weight was the only statistically significant covariate identified, but inclusion into the model did not explain a substantial amount of the observed variability. Simulations of virtual pregnant individuals indicated minimal differences in TXA exposure between fixed and weight-based dosing regimens, supporting the use of fixed dosing. Intramuscular TXA was additionally found to be a viable alternative to intravenous administration, achieving similar target exposure metrics.

Alfentanil is an opioid analgesic and anesthetic agent used in surgical procedures. Despite its widespread use in children, the U.S. Food and Drug Administration label lacks specific dosing recommendations for those under 12 years. A population pharmacokinetic analysis was performed using NONMEM (v7.5) to characterize alfentanil's disposition in children. The study included 58 plasma concentrations from 42 patients who received intravenous alfentanil as part of usual care. Median age was 7.57 years (range: 0.33-17.80) and median dosing was 12.5 mcg/kg (range: 4-43). A one-compartment model with first-order elimination best described alfentanil's pharmacokinetics. Among body size measures, total body weight (WT) significantly influenced clearance (CL [L/h]) = 7.42 × (WT/70)^0.75) and volume of distribution (V [L]) = 12.6 × (WT/70)1). Inter-individual variability decreased after the inclusion of WT, coefficients of variation were reduced from 104% to 58% and from 169% to 83%, for CL and V, respectively. The final model facilitated simulations to achieve target efficacious analgesic and anesthetic concentrations. For analgesia, an initial 10 mcg/kg bolus (for the first hour) followed by an 8 mcg/kg/h infusion (starting at 1 h) achieved the efficacious targeted concentrations (10-100 ng/mL). For procedures that typically require minimal or moderate sedation, a 25 mcg/kg bolus followed by a 20 mcg/kg/h infusion (starting at 5 min) achieved the targeted concentrations (50-200 ng/mL, depending on the procedure). These regimens should be prospectively evaluated to ensure their safety and confirm their efficacy. Overall, this study provides valuable insights into pharmacokinetics and dosing of alfentanil in children.

To assess the antitussive effects of dextrorphan (DOR) relative to its parent compound, dextromethorphan (DEX) a double-blind, randomized, placebo-controlled crossover study was conducted in 23 healthy volunteers using citric acid cough challenge test after administering placebo, DEX, or DOR. Plasma concentrations and cough frequency were monitored over 24 h, followed by model independent analysis and pharmacokinetic-pharmacodynamic (PKPD) modelling to discern the relative potency of each moiety. Model-independent pairwise analysis of the area under the effect curve (AUEC₀₋₂₄ _h) showed no significant difference between DOR, DEX, and placebo's antitussive effects (P > .06), indicating the influence of considerable inter-individual variability and the need for larger sample sizes. The model-based analysis established DOR's relative potency at 26% compared to DEX, with maximum cough inhibition of 23% and IC50 of 0.3 ng/mL. PKPD measures were more accurate for DEX than DOR, particularly at lower baseline cough counts. In conclusion, while DOR retains some antitussive potency, since it is substantially less potent than DEX, higher relative concentrations are required to reach the same effect. Although separate administration of metabolite on its own is considered gold standard to establish its relative potency compared to parent compound, the variability in effect may prevent clear demonstration of effects without modelling particularly when these take benefit of the perturbing the balance of parent/metabolite ratios (e.g. via inhibition) or using the natural variational of such ratios in different individuals.

Fruquintinib (FRUZAQLA^TM) is a highly selective tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors (-1, -2, and -3). Two Phase 1, open-label, single-dose studies investigated the impact of hepatic or renal impairment on the pharmacokinetics and tolerability of fruquintinib. Participants with moderate renal impairment (creatinine clearance [CrCl] 30-59 mL/min; eight participants) and matched healthy controls (eight participants for each study) received fruquintinib 5 mg. Participants with moderate hepatic impairment (Child–Pugh B; eight participants) and severe renal impairment (CrCl 15-29 mL/min; eight participants) received fruquintinib 2 mg. Pharmacokinetic samples were collected over 240 h. Fruquintinib pharmacokinetics were similar between participants with moderate hepatic impairment and healthy controls; geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (C_max), area under the plasma concentration–time curve from 0 to time of last measurable concentration (AUC_0-t), and AUC from 0 to infinity (AUC_0-inf) were 1.04 (0.87-1.24), 0.89 (0.64-1.23), and 0.91 (0.66-1.26), respectively. Fruquintinib pharmacokinetics were similar between participants with severe or moderate renal impairment and healthy controls. Compared with healthy controls, the respective GMRs (90% CIs) for C_max, AUC_0-t, and AUC_0-inf for participants with severe renal impairment were 0.89 (0.78-1.03), 0.97 (0.83-1.14), and 1.01 (0.85-1.19), and for participants with moderate renal impairment were 0.95 (0.78-1.15), 1.06 (0.89-1.26), and 1.07 (0.89-1.28). Fruquintinib was generally well tolerated. These results support fruquintinib use without dose adjustment (5 mg daily, 3 weeks on, and 1 week off) in patients with moderate hepatic impairment or moderate to severe renal impairment.

Adult users of traditional tobacco products like combustible cigarettes (CC) or moist smokeless tobacco (MST) products can reduce exposure to toxicants by switching to potentially less harmful alternatives such as tobacco-free nicotine pouches (NP). Nicotine exposure assessment is an important consideration to determine the switching potential of NPs. These measurements are often conducted using randomized clinical studies. However, characterizing nicotine exposure under real-world use conditions can further inform these assessments. We propose a framework based on physiologically based pharmacokinetic (PBPK) modeling that integrates typical use patterns and clinical pharmacokinetic (PK) data to predict nicotine exposure under actual use conditions. A tissue permeation model precedes the PBPK modeling and is characterized by two physiological parameters, nicotine diffusivity, and effective tissue thickness, which were determined and validated using literature data. A product-specific tissue uptake fraction was determined by regression of nicotine pharmacokinetics measured under controlled use conditions and applied consistently for alternative use scenario analyses. Nicotine PK profiles were predicted under various use scenarios for cigarette smoking or MST use and compared to that from the use of two NPs, namely on!^® and on! PLUS™ NPs (Test Products). The nicotine PK parameters predicted under real-world use conditions were not higher for Test Products relative to cigarettes or MST. The proposed modeling here can further inform nicotine exposure under actual use conditions. PBPK modeling can be a fit-for-purpose tool for predicting nicotine exposure under various use scenarios.