2002
   Paris, France

Assessment of the Contribution of Components in a Combination Drug Product Using Population PK Modeling

Elena Mishina and Mehul Mehta

US FDA

Drug A has a highly variable pharmacokinetics (PK) with a short half-life, nonlinear at high doses, inactivated by metabolism, and influenced by circadian fluctuation. Modulation of its PK aimed half-life prolongation and decrease of metabolism. A new proposed combination drug product BC contains a prodrug of Drug A, Drug B, and an endogenous substance C, potential competitor of A for metabolizing enzyme.

Purpose: To evaluate the contribution of substance C in the combination BC by applying the population modeling of PK data from the study of combination BC.

Methods: BC was administered orally as single ascending doses (1-4 units) and chronic daily doses of 3 units. Blood samples were obtained on four occasions: post single dose and on days 8, 15 and 28 after the multiple doses and assayed for A, B, and C. Data were analyzed with NONMEM.

Results: The model described B and C kinetics independently. The estimated low value of the fraction conversion B to A was consistent with the previously proposed intracellular mechanism of this process. The full model described a competitive inhibition of drug A elimination by the endogenous substance C. The obtained IC50 value correlated with Km values for C in tissues obtained in vitro and indicated that the influence of C on A elimination was marginal.

Conclusions: This population PK model described a complex system of prodrug, active metabolite, and interaction of the latter with the competitor. It enhanced the FDA's ability to interpret scientific information regarding the contribution of components in combination drug products. In conjunction with medical data, the results of this modeling challenged the claim in the NDA that C contributed to the efficacy of new combination product.