A phase I trial of doxorubicin, paclitaxel, and valspodar (PSC 833), a modulator of multidrug resistance

Purpose: P-glycoprotein is an efflux pump for many drugs including doxorubi cin and paclitaxel, This study evaluated the coadministration of these drug s with the P-glycoprotein inhibitor valspodar (PSC 833) with the aim of det ermining: (a) maximum tolerated doses (MTDs) of doxorubicin followed by pac litaxel (DP); (b) the MTD of DP combined with PSC 833 (DPV), without and wi th filgrastim (G-CSF); and (c) the pharmacokinetic interactions of PSC 833 with doxorubicin and paclitaxel, Experimental Design: For the first cycle, patients received doxorubicin as a 15-min infusion followed by paclitaxel as a 1-h infusion. For the second cycle, patients received reduced doses of DP with PSC 833 at 5 mg/kg p.o., four times a day for 12 doses. Results: Thirty-three patients with various refractory malignancies were en rolled and assessable, The MTD of DP without PSC 833 was 35 mg/m(2) doxorub icin and 150 mg/m2 paclitaxel, The MTD of DPV without G-CSF was 12.5 mg/m2 doxorubicin and 70 mg/m2 paclitaxel, The dose-limiting toxicity for both DP and DPV was neutropenia without thrombocytopenia. With G-CSF, the MTD for DPV was 20 mg/m2 doxorubicin and 90 mg/m2 paclitaxel, No grade 4 nonhematol ogical toxicities were observed. Five partial and two minor tumor remission s were observed, Paired pharmacokinetics with and without PSC 833 revealed substantial drug interactions with both doxorubicin and paclitaxel, Conclusions: PSC 833 can be administered safely with doxorubicin and paclit axel, The pharmacokinetic profiles of these drugs are significantly affecte d by PSC 833, requiring similar to 60% dose reductions for equivalent degre es of myelosuppression.