1. ¹Alvin J Siteman Cancer Center and the Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
2. ²Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

Correspondence: Dr PM Fracasso, Department of Medicine, Washington University School of Medicine, 660 South Euclid St, Box 8056, St Louis, MO 63110, USA. E-mail: fracasso@wustl.edu

Received 23 February 2005; Revised 28 April 2005; Accepted 9 May 2005; Published online 7 June 2005.

Abstract

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20–25 mg m^-2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m^-2 and escalated in an accelerated titration design to 25 mg m^-2. Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m^-2. The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10–73) ml h^-1 m^-2 in cycle 1 to 18 (3–37) ml h^-1 m^-2 with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m^-2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.