Population pharmacokinetic modeling of the interaction between the P-glycoprotein inhibitor PSC-833 and mitoxantrone in pediatric leukemia patients

Abstract

Aim PSC 833 is a safer and more potent P-glycoprotein inhibitor than its parent drug, cyclosporine. It has significant pharmacokinetic (PK) interactions with common chemotherapeutic drugs. To examine and quantify this interaction, we modeled the change in clearance of the antileukemic drug mitoxantrone (MTX) upon the co-administration of PSC. Methods PSC and MTX PK data on 14 patients were obtained from a Phase I clinical trial with pediatric patients having acute leukemia. On day 1, patients received MTX as an IV infusion of 10mg/m2 over 15 min. From day 2 to 5, the dose was halved and PSC was given as a 2mg/kg loading dose over 2h along with a continuous infusion at varying dose levels (8, 10, 12.5 and 15 mg/kg/day) for 5 days. Both the PSC and MTX data were fit to 2-compartment models. The effect of PSC on MTX clearance was modeled as follows: CLMTX= CL0+(CL1−CL0) * PSC/(PSC+EC50) where CL0 is the baseline clearance, CL1 is the asymptotic value of CL (when PSC ∞) for large concentrations of PSC. Results The population parameter estimates (%CV) obtained using NONMEM were: CLPSC=1.2 L/h (58%), V1PSC=2.4 L, V2PSC=41.5 L (473%) CL0= 16.5 L/h (47%), CL1=6.12 L/h (64%), EC50=0.5 mg/L, V1MTX=23.2 L, V2MTX=98.5 L. Conclusions We successfully modeled PSC and MTX PK and their interaction in pediatric leukemia patients. Our model allows us to estimate CLMTX at different PSC concentrations. PSC has a large effect on CLMTX (73% reduction). Clinical Pharmacology & Therapeutics (2005) 77, P32–P32; doi: 10.1016/j.clpt.2004.12.013