PKPD Modeling of Dose-Response & Time Course of B-Cell Depletion in Cynomolgus Monkeys
I. Matthews (1), E. Pigeolet (1), G. Pillai (1), S. Balser (2), A. Berghout (2), V. Koppenburg (2), U. Kronthaler (2), I. Meyer (2)
(1) Novartis M&S; (2) Sandoz
Objectives: The pharmaceutical industry has a poor record of selecting the correct dose at the time of drug registration. The trend is that the frequency of dose changes (usually a reduction) post-registration has increased in recent years. In the wake of increased sensitivity to safety aspects of new drugs, Health Authorities have recently been asking for evidence of the minimum effective dose. This poster reports on a model-based estimation of dose response using B-cell counts following rituximab treatment in monkeys. B-cell depletion is a biomarker on the causal path for efficacy readouts for oncology indications which represents the first approved use of rituximab therapy.
Methods: A sequential population PKPD model was built in NONMEM using data from two pre-clinical monkey studies. Study A was a 4-week, weekly IV administration toxicity study at 20 mg/kg. Study B was a single dose IV administration at 0.06, 0.2 or 5 mg/kg with PKPD assessments for 4 weeks. One- and two-compartment PK models were fit to rituximab concentration data. A turnover model with stimulation of B cell removal linked to rituximab concentrations was fit to B-cell count data. Time course of drug effect was modeled using a parameterization involving the rate of B cell removal (Kout), baseline B-cell count (Base), maximum stimulatory effect of the drug on Kout (Smax) and the drug concentration that produces 50% of the maximum response (SC50). Identification of parameter variability and influence of potential covariates was examined, and the model was subjected to standard goodness of fit diagnostics.
Results: PK was adequately described by a two compartment disposition model. Influential covariates on population typical parameters were: weight on CL, Q, V1 and V2, high dose group on CL (20mg/kg doses have a lower CL) and high dose group on V1 (20mg/kg doses have a larger V1). Rituximab PD was adequately described with the turnover model that had a stimulatory effect on the removal of B cells (Kout). The stimulatory effect is non-linear with respect to drug concentration in the plasma and can be described using a sigmoid Emax type model. No influential covariates on population typical PD parameters were found.
Conclusions: This model based analysis was able to characterize the time course of drug effect for animals receiving different doses. Simulations from the model guided the clinical team to select among drug candidates to optimize attainment of pre-specified target levels of B cell reduction. The approach can be extended to inform decisions regarding sampling and trial duration – the challenge is to further extend this approach to use the analysis of animal data to inform human clinical dose–response.