Farina Hellmann 1, Ziheng Hu 2, Xiaowei Zang 2, Nele Plock 1, Keyur Parmar 2, Radha A. Railkar 2, S. Y. Amy Cheung 1, Brian M. Maas 2, Ferdous Gheyas 2
1 Certara (Radnor, USA), 2 Merck & Co., Inc. (Rahway, USA)
Introduction: Clesrovimab (MK-1654), a monoclonal antibody with an extended half-life targeting the respiratory syncytial virus (RSV) fusion protein, is being developed for the prevention of RSV disease in all infants entering or during RSV Season 1. Three infant studies have been conducted to characterize efficacy, safety, and pharmacokinetics (PK) of clesrovimab, including one Phase 1b/2a study, one Phase 2b/3 study CLEVER, and one Phase 3 study SMART.
Objectives: The objective was to develop a population pharmacokinetic (popPK) model for clesrovimab in preterm and term infants, and to evaluate the influence of intrinsic factors on clesrovimab PK in infants.
Methods: Clesrovimab was administered as a single intramuscular (IM) injection at doses ranging from 20 mg to 105 mg across the 3 infant studies. The popPK analysis was based on 5850 serum concentration samples from 2942 participants across the 3 studies. Covariates such as time-varying body weight (BW), time-varying age, gestational age (GA), sex, race, ethnicity, chronic lung disease (CLD), congenital heart disease (CHD), and time-varying anti-drug antibodies (ADA) were evaluated. PopPK analysis was conducted using nonlinear mixed effects modeling approach with NONMEM, v7.5.1. Model fit was assessed by the objective function value, goodness-of-fit diagnostics, and visual predictive checks [1]. Based on the final model, simulations were conducted to quantify the magnitude of covariate effects.
Results: A 2-compartment model with first order absorption and elimination best described the PK of clesrovimab in infants. An informative prior from the adult popPK model was included on absorption rate constant (Ka) and apparent peripheral volume of distribution, as well as inter-individual variability (IIV) on Ka and central volume of distribution. Residual error was described by a combined (additive + proportional) error model. The half-life for clesrovimab estimated by popPK modeling was 44.0 days. Clearance (CL), absorption rate constant, and central volume of distribution had low IIV. BW was included as a covariate on all clearance (CL, Q) and volume parameters with estimated allometric scaling exponents, centered on a BW of 5 kg. A maturation function further described the change in CL with increasing infant age [2]. In addition to BW and maturation function, the final model contained an effect of race on CL. Sex, ethnicity, GA, CHD, CLD, and ADA positivity did not significantly impact clesrovimab RSV Season 1 PK. All model parameters were estimated precisely with relative standard errors < 22%. While BW, age, and race were identified as statistically significant covariates, the magnitude of the effect of these covariates on clesrovimab exposures was small (<30%), and therefore not considered clinically meaningful. Conclusion: The popPK modeling results support a single 105 mg IM administration for all infants in their first RSV season, including in healthy infants, infants with CHD or CLD, and in infants born prematurely. References: [1] Karlsson MO, Holford N. 2008. A tutorial on visual predictive checks Annual Meeting of the Population Approach Group in Europe 17. www.page-meeting.org/?abstract=1434 [2] Robbie GJ, Zhao L, Mondick J, Losonsky G, Roskos LK. Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and children. Antimicrob Agents Chemother. 2012 Sep;56(9):4927-36. doi: 10.1128/AAC.06446-11.
Reference: PAGE 34 (2026) Abstr 11963 [www.page-meeting.org/?abstract=11963]
Poster: Drug/Disease Modelling - Paediatrics