Clinical Pharmacokinetics最新文献

Background and objective: Oncolytic viruses (OVs) are a growing immuno-oncology therapeutic class that rely on their capability to activate the dormant endogenous anti-tumor immune response in order to control or eradicate tumor cells. Given their intrinsic mechanisms of action and their biological nature, development of antidrug antibodies (ADA) represents an important aspect to consider during clinical evaluation. ADAs can potentially affect viral kinetics and/or dynamics, ultimately resulting in reductions or even loss of drug efficacy. Here, we present a semi-mechanistic pharmacokinetic/pharmacodynamic model characterizing the interplay between V937 and neutralizing ADA in cancer patients receiving the V937 oncolytic virus.

Methods: The quantitative framework has been developed integrating viral load and ADA titers from 208 cancer patients who received V937 following intratumoral or intravascular administration, in monotherapy or in combination with pembrolizumab.

Results: The model successfully captured both V937 time course and the dynamics of ADAs under the different settings, showing no meaningful impact of ADAs on viral kinetics. Moreover, tumor response was neither affected by the preexistence or development of ADAs, which can be explained by the primary role of the immune system in the response.

Conclusions: This quantitative and (semi-) mechanistic framework can be expanded to other oncolytic viruses and used to explore under which scenarios a relevant impact could be observed, thus supporting the development of novel oncolytic viral therapies.

Background and objectives: Brensocatib, an oral, competitive, and reversible inhibitor of dipeptidyl peptidase 1 (DPP1), reduces exacerbations and lung function decline in non-cystic fibrosis bronchiectasis (NCFBE). This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of brensocatib in adults with cystic fibrosis (CF), comparing these findings with data from previous trials in healthy adults and in those with NCFBE to inform dose selection for future clinical trials.

Methods: A phase IIa, single-blind, randomized, placebo-controlled trial was conducted to assess the PK, PD, safety, and tolerability of brensocatib in adults with CF. Participants were randomly assigned to receive once-daily brensocatib (10 mg, 25 mg, or 40 mg) or placebo for 28 days. The study planned enrollment of up to 34 adults, stratified on the basis of their CF transmembrane conductance regulator (CFTR) modulator use, to evaluate the PK profile of brensocatib and its safety compared with placebo. Primary PK parameters, including maximum plasma concentration (C_max), time to maximum concentration (T_max), area under the concentration-time curve from 0 to 24 h (AUC_0-24), and half-life (t_1/2), were determined on day 1 and day 28. Dose-dependency of brensocatib exposure was analyzed, and safety and tolerability were assessed through treatment-emergent adverse events. Data from participants were compared with previous data from healthy adults and from those with NCFBE.

Results: A total of 29 participants were randomized to treatment, with 21 stratified to the CFTR modulator group. Baseline characteristics were similar among cohorts. Mean age was 37.9 (standard deviation (SD) 14.6) years, and most participants exhibited mild-to-moderate lung disease. PK analysis showed dose-dependent and predictable brensocatib exposure, with comparable profiles between participants with and without use of CFTR modulators. In addition, PK profiles in participants were comparable to those of healthy adults and of those with NCFBE. Pharmacodynamic analysis revealed dose-dependent reduction in neutrophil serine protease (NSP) activity, reaching saturation around the 25-mg dose, particularly in blood. Brensocatib at all doses was well tolerated with no new identified safety signals.

Conclusions: Brensocatib demonstrated consistent PK profiles independent of CFTR therapy and comparable to those of healthy and NCFBE adults. Brensocatib reduced blood and sputum NSP levels. The safety profile was comparable to previous studies, with no new safety concerns identified, supporting the use of similar dosing for adults with CF as for other populations. These findings advocate for further investigation of brensocatib in CF.

Clinical trial registration: NCT05090904.

Background: Efsubaglutide alfa, as a novel glucagon-like peptide-1 receptor agonist, was developed for the treatment of type 2 diabetes mellitus. Its effect on the rate and extent of absorption of concomitant oral medications (digoxin and metformin) was evaluated in healthy participants.

Methods: We conducted a single-center, open-label, fixed-sequence clinical trial involving 32 healthy participants who were assigned to either digoxin (N = 16) or metformin (N = 16) groups. The participants received oral doses of digoxin (0.25 mg, single dose) or metformin (1000 mg at first dose, 500 mg twice daily for 2 days) before and after subcutaneous injections of 3 mg efsubaglutide alfa at steady state. Pharmacokinetic parameters of digoxin and metformin before and after the administration of efsubaglutide alfa injections were measured, and safety assessments were conducted throughout the study.

Results: Efsubaglutide alfa slightly delayed the time to reach peak plasma concentration (T_max) of digoxin but had no substantial effect on its elimination. While the maximum concentration (C_max) of digoxin decreased by approximately 24% (from 1.75 ± 0.673 to 1.37 ± 0.545 ng/mL), and AUC_0-inf increased by about 15% (from 20.2 ± 3.53 to 23.2 ± 4.04 ng/h/mL). In the metformin group, efsubaglutide alfa did not noticeably affect T_max, C_max,ss, or the overall pharmacokinetics, as demonstrated by a consistent AUC_0-tau (from 7557 ± 2155 to 8737 ± 2852 ng/h/mL). Adverse events with efsubaglutide alfa and co-administered medication were comparable to those reported during treatment with efsubaglutide alfa alone and were mostly gastrointestinal-related.

Conclusions: No clinically significant pharmacokinetic change of digoxin and metformin was identified, and no new safety issues were observed with the co-administration of efsubaglutide alfa injection. These findings suggest that no dose adjustments are required for digoxin and metformin when co-administration with efsubaglutide alfa.

Clinicaltrials:

Gov identifier: NCT05694221.

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the liver that binds to low-density lipoprotein (LDL) receptors, which leads to a decreased ability of the liver to clear LDL-C from circulation. By inhibiting PCSK9, it is possible to provide early intervention to achieve clinical benefits.

Methods: The database was built using data derived from seven clinical studies, population pharmacokinetic/pharmacodynamic (PopPK/PD) and PK/PD analyses were conducted via nonlinear mixed effects analysis with NONMEM software. The parameter estimation of the model was performed using the first-order conditional estimation with interaction (FOCE-I) method. The stepwise covariate method (SCM) was used to develop and evaluate the final model.

Results: A target-mediated drug disposition model (TMDD) model and an indirect response model were developed to illustrated the PopPK profile and PK/PD profile of recaticimab. The PopPK final model was described as a one-compartment TMDD model with a combined residual error model. The PopPK/PD final model was described as an indirect response model with an additive residual error model. Body weight, body mass index, age, statin therapy, and sex were introduced on the model as significant covariates.

Discussion: No adjustment of clinical dosage is required based on the PopPK and PopPK/PD covariates. Estimated glomerular filtration rate and anti-drug antibodies are not significant covariates for any PopPK parameter. After achieving a steady state, switching the dosing regimen and prolonging the dosing interval should not cause concerns about drug efficacy.

Trial registration: NCT03634436, NCT03944109, NCT05370950, NCT04455581, NCT04849000, NCT04885218, NCT04844125.

Background and objective: Acyclovir is a primary treatment for central nervous system (CNS) infections caused by herpes simplex virus (HSV) and varicella-zoster virus (VZV). However, patient outcomes remain suboptimal, despite acyclovir treatment. Given the lack of alternative therapies, there is a pressing clinical need to revisit acyclovir dosing for viral encephalitis. This study aimed to evaluate current and alternative acyclovir dosing regimens using a Bayesian CNS physiologically based pharmacokinetic (PBPK) modeling approach.

Method: A full Bayesian analysis was performed using LeiCNS3.0 model to describe acyclovir's CNS distribution. Simulations were performed for standard dosing (10 mg/kg TID) and various alternative dosing regimens. Drug efficacy was evaluated using 50%fT > IC₅₀ (50% of the dosing interval with drug concentration above IC₅₀) and C_min > IC₅₀ (minimum concentration of the drug exceeding IC₅₀). A toxicity threshold of 25 mg/L for plasma peak concentration was applied.

Results: The standard regimen (10 mg/kg TID) achieved the 50%fT > IC₅₀ target but failed to consistently meet the C_min > IC₅₀ target, particularly for VZV. Alternative regimens of increasing the dosing frequency to QID or extending infusion durations to 1.5 h or 2 h improved efficacy while maintaining safety. Prolonged infusion durations reduced peak plasma concentration thus lowered toxicity risks CONCLUSIONS: The Bayesian CNS PBPK modeling approach demonstrated robust predictive capacity for CNS PK. Current acyclovir dosing regimens may be inadequate for treating HSV and VZV encephalitis. Alternative dosing strategies involving increased frequency or extended infusion durations appear more effective and safer. Future efforts should focus on refining the PK/pharmacodynamic (PD) relationship between acyclovir exposure and antiviral efficacy to improve therapeutic outcomes.

Introduction: Tacrolimus treatment is complicated by its narrow therapeutic range and large inter- and intra-patient variability. This study aimed to develop a population pharmacokinetic model and dosing algorithm to predict an individual's dose requirement following living and deceased donor kidney transplantation.

Methods: In this international, multicenter, retrospective study, data was collected from patients who had received a living or a deceased donor kidney and received tacrolimus twice daily. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM).

Results: This study included 13,427 tacrolimus concentrations from 1180 kidney transplant recipients. A two-compartment model with first-order absorption best described the data. The mean absorption rate was 6.59/h, apparent clearance 20.7 L/h, central volume of distribution 705 L, and peripheral volume of distribution 7670 L. Higher age, creatinine, and hematocrit, as well as lower height, were associated with lower tacrolimus clearance. Tacrolimus clearance was higher for cytochrome P450 (CYP) 3A5*1 carriers compared with CYP3A5*3/*3 individuals, and lower for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients. Together, these covariates explained 19.3% of the inter-individual variability in clearance. From the full model, a starting dose algorithm was developed with age, height, and the CYP3A4 and CYP3A5 genotypes as covariates. Both the full model and the starting dose algorithm were successfully internally validated.

Conclusions: In this international, multicenter study, age, CYP3A4 and CYP3A5 genotype, creatinine, height, and hematocrit were identified as significant covariates associated with tacrolimus pharmacokinetics, and can be used to predict the optimal individual's dose requirement for both living and deceased donor kidney transplant recipients.

Background and objective: In pediatric trial design, it is particularly essential to maximize data utilization and ensure robust designs while minimizing sample collection. A common criterion to justify pediatric pharmacokinetic study designs is based on parameter precision (PP) evaluation, recommended by the US Food and Drug Administration. Here, we propose an alternative approach to design evaluation based on accuracy for dose selection (ADS).

Methods: This work was conducted using a simulation-and-reestimation framework, based on a real-case scenario of designing the single-dose pharmacokinetic study of the anti-tuberculosis (TB) drug pretomanid, with the aim of selecting doses for the next multidose long-term study. The study powers were computed using the ADS approach under scenarios with (1) real-case conditions, (2) high variabilities, (3) available options of tablet doses for selections. The study power using a PP approach was computed to compare with the ADS approach.

Results: The ADS approach suggested that the design selected accurate doses with study power >80% in almost all dosing weight groups, whereas the PP approach found the design underpowered for clearance. The ADS-based power was decreased to ~65% in the smallest weight groups given high variability. Varying the options of dose levels affected the ADS-based power non-monotonically, although fewer levels generally yielded higher power.

Conclusion: The ADS approach practically evaluates the precision in dose selection, providing a directly relevant decision criterion for designing pediatric pharmacokinetic studies and could be an alternative for power evaluation when the study is focused on determining doses using discrete tablet sizes.

Background and objective: Epidural sufentanil is widely used for intraoperative analgesia and is recognized as a safe and effective route of administration when carefully monitored and administered at the lowest effective doses. Optimizing drug dosing requires a precise understanding of its pharmacokinetics. While it is known that sufentanil concentrations in the blood decline more slowly after epidural administration compared with intravenous administration, and the flip-flop phenomenon has been observed in this context, a pharmacokinetic model accounting for this phenomenon has not yet been described.

Methods: This study aimed to develop a pharmacokinetic model of sufentanil following epidural administration, with a focus on its absorption from the epidural space. The study was performed in 23 patients, aged 30-83 years with an American Society of Anesthesiologists (ASA) classification of 2-3, undergoing major abdominal (oncologic and non-oncologic) surgery under general anesthesia and epidural analgesia. Blood samples were collected, and sufentanil concentrations were measured at time points ensuring coverage of the absorption phase. Population analysis was performed using a full Bayesian approach implemented in Stan/Torsten programs with the "cmdstanr" and "bbr.bayes" packages in RStudio.

Results: The Bayesian approach helped incorporate prior information about sufentanil disposition. A two-compartment disposition model with two-compartmental absorption best described the data, featuring a fast absorption rate constant into plasma and the peripheral compartment, and a slow redistribution process from the epidural fat compartment.

Conclusions: This study mechanistically describes the flip-flop pharmacokinetics of sufentanil and allows for more precise dosing of epidural sufentanil (NCT06069219).