Pharmacokinetics of Daunorubicin and its metabolite Daunorubicinol in the absence and presence of a potent P-gp inhibitor, Zosuquidar.3HCl (LY335979).
Sophie Callies 2, Dinesh P de Alwis 1, Michael Burgess 1, and Leon Aarons 2
1Eli Lilly and Company Limited, Surrey, U.K.
Objectives: Clinical investigations have shown that P-glycoprotein inhibitors dramatically decrease the systemic clearance of co-administered oncolytics. The potential impact of zosuquidar.3HCl, a potent inhibitor of the P-gp efflux transporter on the pharmacokinetics (PK) of daunorubicin (DAUN) and its metabolite daunorubicinol (DAUNOL) was examined in a phase I dose escalation trial using a population approach. In addition, a relationship between plasma concentrations of Zosuquidar.3HCl and P-gp inhibition as measured ex vivo was determined.
Methods: The pharmacokinetics of DAUN and DAUNOL were studied following two sequential administrations: on day 1, patients received DAUN (50 mg/m2 IV over 10 min) alone and on day 3, patients received Zosuquidar.3HCl IV (200 or 300 mg/m2 over 6 h or 400 mg 3 h) and DAUN, administered as previously, 1 and 0.5 hour after the start of the 6 and 3 hour infusion of Zosuquidar.3HCL, respectively. A total of 16 patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled.
Results: A three-compartment PK model adequately described the DAUN concentration time profiles. A five compartment or a four compartment pharmacokinetic model adequately described the combined DAUN-DAUNOL PK profiles in the absence or presence of Zosuquidar.3HCl, respectively (three compartment for DAUN and two or one compartment for DAUNOL). The additional distribution compartment for DAUNOL permitted the model to fit adequately the two peaks observed in DAUNOL PK in the absence of Zosuquidar.3HCl.
The overall impact of short IV infusion of Zosuquidar.3HCL (6 h or less) on coadministered DAUN was minimal with an approximately 10 % reduction in DAUN clearance (CL). The population model predicted a 50 % decrease on DAUNOL apparent clearance (CL/fm) in the presence of either a 3 h or 6 h infusion of Zosuquidar.3HCl.
Pharmacodynamic measurements of inhibition of Rhodamine 123 P-gp-mediated-efflux in CD56 lymphocytes, showed that the Zosuquidar.3HCl dosing schedules administered in this study lead to maximal P-gp inhibition. A direct reversible concentration-effect relationship between Zosuquidar.3HCl plasma concentrations and inhibition of Rhodamine efflux in CD56 lymphocytes was defined by a sigmoid Emax model. The IC50 was 31.6 +/- 12.0 µg/L. Plasma concentrations in excess of the IC90 (172.4 µg/L) were readily achieved during 6 h and 3 h infusions of zosuquidar.3HCL and provided maximal P-gp inhibition during the distribution phases of DAUN.
Conclusions: Both infusion regimens of zosuquidar.3HCL provided maximal P-gp inhibition. The decrease in DAUN CL (10 %) and DAUNOL CLm/fm (50 %) in the presence of zosuquidar.3HCl likely reflects inhibition of P-gp by zosuquidar.3HCl in the bile canaliculi impeding biliary excretion of DAUN and DAUNOL. The results reported in this study need to be interpreted carefully due to the sequential nature of DAUN administration and analysis. It is critical to assume that both DAUN and DAUNOL PK are concentration and time independent. A randomised study is currently ongoing to assess the validity of this hypothesis and confirm these research findings.