ALTERATION OF ETOPOSIDE PHARMACOKINETICS AND PHARMACODYNAMICS BY CYCLOSPORINE IN A PHASE-I TRIAL TO MODULATE MULTIDRUG RESISTANCE

Purpose: To determine the effects of high-dose cyclosporine (CsA) infusion on the pharmacokinetics of etoposide in patients with cancer. Patients and Methods: Sixteen patients were administered 20 paired courses of etoposide and CsA/etoposide. Etoposide was administered daily for three days, alone or with CsA, which was delivered by a loading dose and 3-day infusion. Etoposide was measured by high-performance liquid chromatography (HPLC) and serum CsA by nonspecific immunoassay. Etoposide pharmacokinetics included area under the concentration-time curve (AUC), total and renal clearance (CL), half- life (T 1/2 ), and volume of distribution at steady state (Vss). Results: CsA concentrations more than 2,000 ng/mL produced an increase in etoposide AUC of 80% (P < .001), a 38% decrease in total CL (P < .01), a greater than twofold increase in T 1/2 (P < .01), and a 46% larger Vss (P = .01) compared with etoposide alone. CsA levels ranged from 297 to 5,073 ng/mL. Higher CsA levels (< 2,000 ng/mL v > 2,000 ng/mL) resulted in greater changes in etoposide kinetics: Vss (1.4% v 46%) and T 1/2 (40% v 108%). CsA produced a 38% decrease in renal and a 52% decrease in nonrenal CL of etoposide. Etoposide with CsA levels greater than 2,000 ng/mL produced a lower WBC count nadir (900/mm3 v 1,600/mm3) compared with baseline etoposide cycles. Conclusions: High-dose CsA produces significant increases in etoposide systemic exposure and leukopenia. These pharmacokinetic changes are consistent with inhibition by CsA of the multidrug transporter P-glycoprotein in normal tissues. Etoposide doses should be reduced by 50% when used with high-dose CsA in patients with normal renal and liver function. Alterations in the disposition of other multidrug resistance (MDR)-related drugs should be expected to occur with modulation of P-glycoprotein function in clinical trials.