Integrated Exposure-Response of Dupilumab in Children, Adolescents, and Adults With Atopic Dermatitis Using Categorical and Continuous Efficacy Assessments: A Population Analysis.

BACKGROUND: While the majority of patients with atopic dermatitis (AD) achieve disease control with dupilumab treatment, there is variability in which patients achieve clear disease. The predictors of these responses are currently unclear. Integrated models were developed to evaluate the exposure-response (E-R) relationship of dupilumab in children, adolescents, and adults with AD. METHODS: Data from six Phase II and III clinical studies were pooled (2,366 adults [> 18 years], 243 adolescents [≥ 12 to < 18 years] and 359 children [≥ 6 to < 12 years]) for model development. Efficacy was assessed using the Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA). Indirect response models were applied to link measures of efficacy and functional serum dupilumab concentrations. The covariates on individual placebo-corrected response were assessed. Clinical trial scenarios were simulated to compare E-R relationships across age groups. Safety was not explored. RESULTS: After correcting for differences in placebo response and dupilumab exposure: 1) older age, higher body weight, lower baseline thymus and activation-regulated chemokine, and Asian race were associated with slightly lower EASI response, and no clear covariates were identified on IGA response; 2) clinical trial simulations generally showed slightly higher response at a given dupilumab concentration in children compared to adults and adolescents with severe and moderate AD. CONCLUSIONS: The collectively tested covariates explain some of the variability in dupilumab response in patients with AD. Patients in all age groups showed adequate response to dupilumab; however, children showed slightly higher drug effects compared to adults and adolescents at equivalent concentrations.

Population pharmacokinetics modeling and exposure-response analyses of cemiplimab in patients with recurrent or metastatic cervical cancer.

A population pharmacokinetic (PopPK) model was previously developed for cemiplimab in patients with solid tumors, including advanced cutaneous squamous cell carcinoma (CSCC). Here, we update the existing PopPK model and characterize exposure-response relationships using efficacy and safety data obtained in patients with recurrent or metastatic cervical cancer (R/M CC). To improve model stability and robustness of the existing PopPK model in 1062 patients, the random-effect error model was revised, and structural covariates were removed from the base model to be tested in the covariate analysis. The updated model was used for external validation of cemiplimab pharmacokinetics (PK) in patients with R/M CC on cemiplimab monotherapy (350 mg every 3 weeks intravenously) from a phase III study (NCT03257267). Exposure-response relationships for cemiplimab efficacy (overall survival [OS], progression-free survival [PFS], duration of response [DOR], objective response rate [ORR]), and safety (immune-related adverse events [irAEs]) were analyzed in 295 patients with R/M CC from the aforementioned study. The updated PopPK model showed improved stability with 94.8% successful bootstrap runs vs. 47.6% in the prior model. Cemiplimab exposure was similar across tumor types, including basal cell carcinoma, CSCC, and non-small cell lung cancer. External validation showed the updated model adequately described cemiplimab PK in patients with R/M CC. In exposure-response efficacy analyses, Cox proportional hazard modeling (CPHM) showed no trend between exposure and OS, Kaplan-Meier plots showed no trend between exposure and PFS or DOR, and logistic regression analyses conducted on ORR showed no exposure-response relationship. In exposure-response safety analyses, CPHM showed no trend between exposure and irAEs.

Development of a Population Pharmacokinetic Model for the Diroximel Fumarate Metabolites Monomethyl Fumarate and 2-Hydroxyethyl Succinimide Following Oral Administration of Diroximel Fumarate in Healthy Participants and Patients with Multiple Sclerosis.

INTRODUCTION: Diroximel fumarate (DRF) is a next-generation oral fumarate that is indicated in the USA for relapsing forms of multiple sclerosis (MS). A joint population pharmacokinetic model was developed for the major active metabolite (monomethyl fumarate, MMF) and the major inactive metabolite (2-hydroxyethyl succinimide, HES) of DRF. METHODS: MMF and HES data were included from 341 healthy volunteers and 48 patients with MS across 11 phase I and III studies in which DRF was administered as single or multiple doses. Population modeling was performed with NONMEM version 7.3 with the first-order conditional estimation method. RESULTS: Estimated MMF clearance (CLMMF), volume of distribution, and absorption rate constant (Ka) were 13.5 L/h, 30.4 L, and 5.04 h-1, respectively. CLMMF and HES clearance (CLHES) increased with increasing body weight. CLHES decreased with decreasing renal function. CLMMF and CLHES were 28% and 12% lower in patients with MS than in healthy volunteers, respectively. Ka was reduced in the presence of low-, medium-, and high-fat meals by 37%, 51%, and 67%, respectively, for MMF; and by 34%, 49%, and 62%, respectively, for HES. CONCLUSIONS: Age, sex, race, and baseline liver function parameters such as total bilirubin, albumin, and aspartate aminotransferase were not considered to be significant predictors of MMF or HES disposition.