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

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 th e present study, we examined the pharmacokinetics of doxorubicin and GF1209 18, 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/m(2)), oral GF120918 alone (50 mg q.d.-400 mg b.i .d.), and the combination of doxorubicin and GF120918. Serial blood and uri ne samples were taken during both treatment courses and analyzed for doxoru bicin and its metabolite doxorubicinol by a liquid chromatographic assay, T he pharmacokinetic characteristics of doxorubicin in the presence or absenc e of GF120918 indicate a very minor overall effect of the modulator, except at the highest combined dose level (i.e. 75 mg/m(2) plus 400 mg b.i.d.). A limited number of patients experienced significantly increased exposure to doxorubicinol upon combined treatment, which was associated with concomita ntly higher plasma levels of GF120918, Sigmoidal maximum-effect models reve aled significant correlations (p < 0.02) between the area under the curve o f doxorubicinol and the percent decrease in neutrophils and platelets. Sigm oidicity factors in the fitted Hill equation were similar between both trea tment courses, suggesting no pharmacodynamic potentiation of doxorubicinol myelotoxicity by GF120918. Our data indicate that GF120918 at the tested do ses of combination treatment achieves plasma concentrations that reverse MD R in experimental models and it lacks the significant kinetic interaction w ith 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 wit h the knowledge that profound plasma pharmacokinetic interactions are unlik ely. [(C) 1999 Lippincott Williams & Wilkins].