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A Phase I Trial of Doxorubicin, Paclitaxel, and Valspodar (PSC 833), a Modulator of Multidrug Resistance¹

Oncology Division, Stanford University School of Medicine, Stanford, California 94305-5151 [R. A., G. A. F., B. L. L., J. Hau., J. Hal., B. I. S.], and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936 [M. L.]

Purpose: P-glycoprotein is an efflux pump for many drugs including doxorubicin and paclitaxel. This study evaluated the coadministration of these drugs with the P-glycoprotein inhibitor valspodar (PSC 833) with the aim of determining: (a) maximum tolerated doses (MTDs) of doxorubicin followed by paclitaxel (DP); (b) the MTD of DP combined with PSC 833 (DPV), without and with 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 enrolled and assessable. The MTD of DP without PSC 833 was 35 mg/m² doxorubicin 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 nonhematological toxicities were observed. Five partial and two minor tumor remissions 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 paclitaxel. The pharmacokinetic profiles of these drugs are significantly affected by PSC 833, requiring 60% dose reductions for equivalent degrees of myelosuppression.

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