Anne Chain (1), Aziz Ouerdani (2), Rid de Greef (2), Arun Balakumaran (1), Scott J Diede (3)
(1) MSD, New Jersey, USA, (2) Certara Strategic Consulting, The Netherlands (3) MSD, Pennsylvania, USA
Introduction: Pembrolizumab is globally approved in adults with various solid tumor as well as hematological cancer indications. To date, it is also approved in paediatric patients with classical Hodgkin lymphoma (cHL) and microsatellite instability high (MSI-H) cancers. A pooled population pharmacokinetic (PK) analysis was initially conducted using data from adults with different types of caner. Subsequently, this was extended to include PK data from paediatric patients. The current work summarizes the PK analysis including paediatric subjects to guide the dosing recommendation in patients < 18 years old with cHL.
Objectives:
- Describe the PK analysis in paediatric patients
- Assess the impact of covariates such as cancer indication, age and body weight of pembrolizumab pharmacokinetics
- Summarize simulation results supporting the recommended dosing regimens in paediatric patients
Methods: The present analysis was built on an existing population PK model in patients with melanoma or NSCLC for pembrolizumab as described in [1]. Pharmacokinetic data from paediatric patients (N=34) as well as adult cHL patients (N=229)were added to the dataset. As a first step the parameters from the existing model (including covariate effects) were re-estimated. Subsequently, potential refinements to the model were explored, with a focus on an optimal characterization of the potential effects of age and body weight in the paediatric population.
Reliability and robustness of the subsequent final model was assessed by a range of goodness of fit plots. Posthoc parameter estimates from the final model were used to compare pharmacokinetic parameters between paediatric and adult populations. Due to the limited number of patients available from the pembrolizumab paediatric study, simulation dataset was augmented with additional data (demographic / covariate information from 171 subjects) from another oncology program. Simulations from the final model were performed to assess the exposure of pembrolizumab in paediatric patients at the recommended dosing regimens of 2 mg/kg Q3W or 200 mg Q3W by age-group including adults.
Results: Overall, the updated model was generally consistent with the previously developed model [1] in terms of model structure and parameter estimates, showing a lack of clinically meaningful impact of the inclusion of data from paediatric and cHL studies. In addition to the effects of body weight on pembrolizumab pharmacokinetic parameters as incorporated in the existing model, an effect of age was also found within the paediatric subgroup, resulting in decreasing clearance and central volume of distribution with decreasing age.
Despite clear effects of lower body weight on clearance and volume of distribution in the youngest age groups, no major differences were apparent between these populations in terms of exposure parameters (AUC, Cmin, Cmax). Simulation results of exposures in paediatric patients down to age of 6 years demonstrated that predicted exposures at 2 mg/kg Q3W for 6-12 years old patients are similar to adolescents and adults administered with 200 mg Q3W. In the group of 2-6 years old, predicted exposures at 2 mg/kg Q3W are ~30% higher than in adults.
Conclusion:
- Inclusion of PK data from the paediatric and cHL studies do not lead to any meaningful change in the parameter estimates of the population PK model for pembrolizumab.
- Within the paediatric population, lower age is associated with lower clearance and volume of distribution.
- The weight based dosing regimen of 2 mg/kg Q3W assures similar pembrolizumab exposures across different paediatric age groups down to 6 years and in comparison to adults. In 2-6 years old, exposure to pembrolizumab is ~30% higher in comparison to adults. In
References:
[1] Li, Hongshan et al. J Pharmacokinet Pharmacodyn (2017) 44:403-414
Reference: PAGE 27 (2018) Abstr 8692 [www.page-meeting.org/?abstract=8692]
Poster: Drug/Disease Modelling - Oncology