A dose-finding and pharmacokinetic study of reversal of multidrug resistance with SDZ PSC 833 in combination with doxorubicin in patients with solid tumors.

摘要: Forty-two patients with advanced solid tumors were entered into a dose-finding study of the combination doxorubicin cyclosporin analogue SDZ PSC 833 (PSC), given by oral route. Patients received at escalating doses, ranging from 2.5 to 25 mg/kg/day, for 5 days, in doses every 12 h. Doxorubicin was i.v. push on day 3 administration, 4 h after morning dose PSC. Pharmacokinetic analyses and performed. A total 38 doxorubicin, 27 alone first course. The major toxicity hematological significantly more severe than that alone; myelosuppression already observed level, which required reduction 50 35 mg/m2. At all levels PSC, up 17.5 there least two grade or toxicity, manageable less heavily pretreated patients. further escalation performed together reduced 20 this dose, central nervous system became most relevant side effect. increase combined treatment supported significant area under plasma concentration-time curve infinity (54%) 10-fold doxorubicinol. pharmacological interaction not dependent concentration body clearance decreased 30%. concentrations >1 microM time administration were, general, found 7.5 mg/kg/day higher. One patient had partial response. In conclusion, can revert multidrug resistance experimental models could be achieved who have are treated doxorubicin. However, marked between led substantial dose. Further may warranted, association investigation P-glycoprotein expression drugs tumor tissues.