PHASE-I TRIAL OF CREMOPHOR EL WITH BOLUS DOXORUBICIN

Cremophor EL (cremophor), a component of the paclitaxel formulation, c an potentially reverse P-glycoprotein-associated multidrug resistance, A Phase I trial of cremophor as a 6-h infusion every 3 weeks was perf ormed with bolus doxorubicin (50 mg/m(2)), The cremophor dose was esca lated from 1 to 60 ml/m(2). A standard paclitaxel premedication was gi ven before cremophor, Using a bioassay, potentially active cremophor l evels (greater than or equal to 1 mu l/ml) were measured in plasma fro m patients receiving cremophor doses of 30, 45, and 60 ml/m(2). A cros s-over design was used to assess the influence of cremophor 30 mym2 on the pharmacokinetics of doxorubicin and doxorubicinol, The plasma are a under the concentration versus time curve (AUC) of doxorubicin incre ased from 1448 +/- 350 to 1786 +/- 264 ng/ml.h (P = 0.02) in the prese nce of cremophor, whereas the AUC of doxorubicinol increased from 252 +/- 104 to 486 +/- 107 ng/ml.h (P 0.02), This pharmacokinetic interact ion was associated with significantly increased neutropenia, With redu ction of the doxorubicin dose to 35 mg/m(2), the cremophor dose was in creased to 60 mym2. Dose-limiting toxicities occurred in two of six pa tients after 45 mL/m(2) and two of four patients after 60 mL/m(2), whi ch included febrile neutropenia and grade III cremophor-related toxici ties of rash, pruritus, headache, and hypotension. All patients who re ceived 45 ml/m(2) cremophor reached plasma levels greater than or equa l to 1.5 mu l/ml, but at 60 ml/m(2), only two of four reached this lev el, and the calculated plasma clearance of cremophor was significantly faster at this dose, One patient with hepatoma resistant to epirubici n achieved a near-complete response. Cremophor 45 ml/m(2) over 6 h wit h 35 mg/m(2) doxorubicin is recommended for further studies. The pharm acokinetic interaction between cremophor and doxorubicin is quantitati vely similar to that described in trials of paclitaxel with doxorubici n and suggests that the cremophor in the paclitaxel formulation is res ponsible.