F. Boakye-Agyeman,1 M. Menefee,2 C. Erlichman,1 D. Northfelt,3 S. H. Kaufmann,1 D. Satele,1 B. C. Brundage,4 J. M. Reid1; 1Mayo Clinic, Rochester, MN, 2Mayo Clinic, Rochester, FL, 3Mayo Clinic, Scotsdale, AZ, 4University of Minnesota, Minneapolis, MN
BACKGROUND: Veliparib (ABT-888, VPB) is an orally administered small molecule inhibitor of poly (ADP-ribose) polymerase (PARP) that is under investigation in combination with topotecan for the treatment of ovarian cancer. Previous population (P) pharmacokinetics (PK) studies of VPB were based on doses below 100 mg/day and linear PK. The goals of this study were to characterize the PPK of VPB over a broader dose range, especially at very high doses that have not been investigated previously, and to define other factors contributing to VPB PK variability.
METHODS: The PK of VPB were determined in a phase I trial of escalating doses of oral VPB (10 mg - 50 mg qd and 50 mg - 400 mg bid) given with IV doses of topotecan (2 - 4 mg/m2). one-, two- and three-compartments and saturable and parallel disposition models were considered for the PPK studies using nonlinear mixed effect modeling. Competing models were distinguished by their predictive performance, goodness of fit plots (GOF), visual predictive checks (VPC), objective function values.
RESULTS: Data from 51 patients were best fit using a two-compartment model with first-order absorption and elimination. The CL, Vc, Vp, KA, Q and their RSEs were 19.2(8%), 25.3(18%), 148(38%), 0.246(14%) and 9.28(19%), respectively. Weight was identified as significant covariate on inter-compartmental clearance of VPB. Other Covariates tested (dose and serum creatinine) did not significantly improve the model.
CONCLUSION: The PPK of VPB was successfully characterized and results were consistent with previous reports at low doses.
Supported in part by UM1 CA186686, P39 CA015083, T32 GM868516 grants