Clinical pharmacokinetics of doxorubicin in combination... : Anti-Cancer Drugs (original) (raw)

Clinical study: PDF Only

Clinical pharmacokinetics of doxorubicin in combination with GF120918, a potent inhibitor of MDR1 P-glycoprotein

Sparreboom, Alex; Planting, André ST; Jewell, Roxanne C1; van der Burg, Maria EL; van der Gaast, Ate; de Bruijn, Peter; Loos, Walter J; Nooter, Kees; Chandler, LuWanda H1; Paul, Elaine M1; Wissel, Paul S1; Verweij, Jaap

Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3008 AE Rotterdam, The Netherlands. 1Glaxo Wellcome Inc, Research Triangle Park, NC 27709, USA.

Abstract

Previous clinical investigations with doxorubicin indicated that modulators of P-glycoprotein dramatically decrease the systemic clearance of the drug, which complicates the interpretation of toxicity and response data. In the present study, we examined the pharmacokinetics of doxorubicin and GF120918, a novel potent P-glycoprotein inhibitor, in cancer patients in a search for more selective modulation of multidrug resistance (MDR). Seven cohorts (46 patients) received sequential treatments with doxorubicin alone by a 5 min i.V. bolus (50–75 mg/m2), oral GF120918 alone (50 mg q.d.-400 mg b.i.d.), and the combination of doxorubicin and GF120918. Serial blood and urine samples were taken during both treatment courses and analyzed for doxorubicin and its metabolite doxorubicinol by a liquid Chromatographie assay. The pharmacokinetic characteristics of doxorubicin in the presence or absence of GF120918 indicate a very minor overall effect of the modulator, except at the highest combined dose level (i.e. 75 mg/m2 plus 400 mg b.i.d.). A limited number of patients experienced significantly increased exposure to doxorubicinol upon combined treatment, which was associated with concomitantly higher plasma levels of GF120918. Sigmoidal maximum-effect models revealed significant correlations (p<0.02) between the area under the curve of doxorubicinol and the percent decrease in neutrophils and platelets. Sigmoidicity factors in the fitted Hill equation were similar between both treatment courses, suggesting no pharmacodynamic potentiation of doxorubicinol myelotoxicity by GF120918. Our data indicate that GF120918 at the tested doses of combination treatment achieves plasma concentrations that reverse MDR in experimental models and it lacks the significant kinetic interaction with doxorubicin observed previously with other modulators. Hence, it may be possible in future trials to assess the contribution of a potent inhibitor of P-glycoprotein activity to the toxicity and activity of doxorubicin with the knowledge that profound plasma pharmacokinetic interactions are unlikely.