Clinical Pharmacology & Therapeutics最新文献

Juvenile idiopathic arthritis (JIA) is the most prevalent pediatric rheumatic disease. While disease-modifying antirheumatic drugs (DMARDs), especially biologics, have greatly transformed the management of JIA, there remain some unmet medical needs that require new treatment options. The objective of this work was to describe and apply a modeling and simulation approach to extrapolate upadacitinib efficacy from the adult diseases, rheumatoid arthritis (RA) and psoriatic arthritis (PsA), to their respective pediatric diseases, polyarticular course JIA (pcJIA), and juvenile PsA (JPsA). A population pharmacokinetic model characterized upadacitinib pharmacokinetics in pediatric patients using data from two phase I studies in pediatric patients with pcJIA (N = 51) or atopic dermatitis (N = 33). Efficacy simulations were conducted using previously developed exposure-response models in adults with RA and PsA. Real-world pcJIA and JPsA patient databases were leveraged to construct representative patient profiles for the targeted population. Following administration of the proposed weight-based dosing regimen, the model-predicted median upadacitinib plasma exposures in pediatric patients were within 20% of those in adult RA and PsA patients receiving the approved adult regimen. Simulations demonstrate that upadacitinib efficacy in pcJIA and JPsA is predicted to be non-inferior to that in adults with RA or PsA, respectively. The results of this work enabled recent approvals of upadacitinib for the treatment of polyarticular JIA and JPsA in the United States. Upadacitinib safety in pediatrics is being further evaluated in ongoing clinical trials.

Rare diseases, affecting millions globally, present significant drug development challenges. This is due to the limited patient populations and the unique pathophysiology of these diseases, which can make traditional clinical trial designs unfeasible. Quantitative Systems Pharmacology (QSP) models offer a promising approach to expedite drug development, particularly in rare diseases. QSP models provide a mechanistic representation of the disease and drug response in virtual patients that can complement routinely applied empirical modeling and simulation approaches. QSP models can generate digital twins of actual patients and mechanistically simulate the disease progression of rare diseases, accounting for phenotypic heterogeneity. QSP models can also support drug development in various drug modalities, such as gene therapy. Impactful QSP models case studies are presented here to illustrate their value in supporting various aspects of drug development in rare indications. As these QSP model applications continue to mature, there is a growing possibility that they could be more widely integrated into routine drug development steps. This integration could provide a robust framework for addressing some of the inherent challenges in rare disease drug development.

Mosunetuzumab, a T-cell engaging bispecific antibody targeting CD20xCD3, is approved for treating relapsed/refractory follicular lymphoma. This research supports the approved intravenous clinical dose regimen, summarizing the exposure-response relationships for clinical safety and efficacy. A population pharmacokinetic model and E_max logistic regression exposure-response models for safety and efficacy were developed using data from 439 patients with relapsed/refractory non-Hodgkin lymphoma and 159 patients with relapsed/refractory follicular lymphoma, respectively, from a Phase I/II study (NCT02500407). Data from 0.2 to 60 mg across fixed dosing (Cohort A) and Cycle 1 step-up dosing (Cohort B) were used. Exposure-response models, using two-cycle area-under-the-concentration curve (AUC_0-42) as the primary exposure endpoint, accurately depicted the complete response and objective response rate data across a 600-fold AUC_0-42 range. The approved clinical dose regimen of 1/2/60/30 mg achieved near-maximal efficacy, with model-estimated CR and ORR (90% confidence interval) of 63.1% (49.7-75.0) and 79.1% (69.1-87.7), respectively. The exposure-response analysis for Grade ≥ 2 cytokine release syndrome identified receptor occupancy (%) within the first two cycles as a driver, with CRS dissipating beyond the first dosing cycle. No exposure-dependent increases were observed for other serious adverse events, including neutropenia and infections. The approved intravenous step-up dose regimen (i.e., step doses of 1 and 2 mg on Day 1 and 8, respectively) mitigated severe CRS risk, allowing safe administration of loading (60 mg) and target doses (30 mg every 3 weeks) to achieve a favorable benefit-risk profile.

The CRISPR-based gene editing therapy exagamglogene autotemcel (exa-cel) recently received FDA approval for patients with severe sickle cell disease (SCD). The approval was based on a phase III trial (CLIMB SCD 121), which showed 97% efficacy of this treatment in eliminating vaso occlusive crises (VOCs) for 12 consecutive months. To help contextualize results from this trial, we aimed to investigate the proportion of patients with severe SCD who remain VOC-free for a 1-year period in routine clinical care. Using Medicaid claims data (2000-2018), we identified a cohort of patients, 12-35 years old with severe SCD, defined by ≥ 2 VOCs per year for 2 consecutive years, who met other exa-cel trial inclusion criteria to mimic a trial-like population. A VOC was identified using ICD diagnosis codes during hospitalization and ER visits. The primary outcome was the proportion of patients with no VOCs during a 1-year follow-up. A total of 7,425 patients with severe SCD [mean (SD) age: 20.5 (6.0) years, 54.6% females, 84% African Americans], had a mean of 5.2 VOCs, 5.1 ER visits and 3.5 hospitalizations per year during the baseline period. The proportion of patients with no VOCs during the 1-year follow-up was 7.7% (95% confidence interval: 7.1%-8.3%). In conclusion, less than one in 12 patients with severe SCD achieved VOC-free status within 1 year in routine clinical care. These findings suggest that the high efficacy observed for exa-cel in the trial, if replicated in routine clinical care, could translate into a significant public health impact.

The mainstay of antiretroviral therapy (ART) has been combination oral therapy. While oral ART is highly effective, nonadherence remains a chief concern. Addressing this concern in recent years is the emergence of long-acting antiretrovirals for the treatment and prevention of HIV-1 infection. The most recently approved long-acting antiretroviral is the first-in-class capsid inhibitor lenacapavir (LEN) for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Due to its biannual subcutaneous dosing scheme to inhibit the HIV-1 capsid, LEN exhibits unique pharmacokinetics and reinforces an evolving era of ART. In this review, we evaluate published and accepted research articles, conference proceedings, and clinical trial records to provide a comprehensive overview of LEN for treatment and preliminary data for the prevention of HIV-1 infection. These data include clinical trials outcomes, in vitro and in vivo resistance profiles, and preclinical data supporting downstream indications. We also discuss the unique clinical pharmacology of LEN with the goal of serving as a resource toward subsequent physiologically based, population-based, and other miscellaneous pharmacometric-focused analyses. Given the dynamic nature of the HIV treatment and prevention research fields, we also discuss ongoing studies related to LEN for treatment-naïve adults and for prevention. Lastly, we discuss important pharmacologic gaps in special populations, drug-drug interactions, and at the sites of action germane to HIV treatment and prevention. The information discussed in this review will provide knowledge and understanding of the unique pharmacologic properties of LEN to assist clinicians and researchers as they navigate the dynamic HIV research landscape.

Trichuris trichiura is a soil-transmitted helminth causing intestinal disease. Albendazole is the standard treatment despite its moderate efficacy, which is improved when co-administered with ivermectin. A fixed-dose combination adds practical advantages mainly for mass drug administration. The aim of this article is to define the population pharmacokinetic models and exposure-response of an innovative albendazole/ivermectin combination. Data were obtained from a phase I clinical trial in healthy adults and from a phase II trial in children and adolescents infected with T. trichiura. Nonlinear mixed-effects models were built for albendazole and ivermectin using NONMEM®. Area under the curve was calculated using the empirical Bayes estimates of the pharmacokinetic parameters of each individual and used for evaluation of exposure-response between cure rate and pharmacokinetic exposure. The pharmacokinetics of albendazole was described using a two-compartmental model with first-order absorption and the pharmacokinetics of ivermectin was described using a two-compartmental model with zero-order followed by first-order absorption. Clearance and volume of distribution increased with body weight for both albendazole and ivermectin. Day 1 area under the curve of albendazole and ivermectin from the children and adolescents treated with the combination regimens were similar to the healthy adults treated with control drugs. A flat exposure-response relationship was observed between the cure rate and drug exposure. Population pharmacokinetic of a combination of albendazole and ivermectin in children, adolescents, and adults, either healthy or infected by T. trichiura was described. The dosage selected in the phase II trial was appropriate for the subsequent phase III.

Effectively treating multidrug-resistant bacterial infections remains challenging due to the limited drug development pipeline and a scarcity of novel agents effective against these highly resistant pathogens. Bacteriophages (phages) are a potential addition to the antimicrobial treatment arsenal. Though, phages are currently being tested in clinical trials for antibiotic-resistant infections, phages lack a fundamental understanding of optimal dosing in humans. Rationally designed preclinical studies using in vitro and in vivo infection models, allow us to assess clinically relevant phage +/- antibiotic exposure (pharmacokinetics), the resulting treatment impact on the infecting pathogen (pharmacodynamics) and host immune response (immunodynamics). A mechanistic modeling framework allows us to integrate this knowledge gained from preclinical studies to develop predictive models. We reviewed recently published mathematical models based on in vitro and/or in vivo data that evaluate the effects of varying bacterial or phage densities, phage characteristics (burst size, adsorption rate), phage pharmacokinetics, phage-antibiotic combinations and host immune responses. In our review, we analyzed study designs and the data used to inform the development of these mechanistic models. Insights gained from model-based simulations were reviewed as they help identify crucial phage parameters for determining effective phage dosing. These efforts contribute to bridging the gap between phage therapy research and its clinical translation.