RELATIONSHIP BETWEEN THE PHARMACOKINETICS OF IRINOTECAN AND DIARRHEA DURING COMBINATION CHEMOTHERAPY WITH CISPLATIN

Two phase I trials of irinotecan (CPT-11) in combination with cisplati n were conducted. In both cases, the dose-limiting toxicities were leu kopenia and/or diarrhea. During these trials the pharmacokinetics of C PT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38 ), were investigated to evaluate the relationship between pharmacokine tic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twen ty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 a t 80 or 90 mg/m(2) plus cisplatin at 60 mg/m(2). The other 13 patients received CPT-11 at 80 or 90 mg/m(2) plus cisplatin at 80 mg/m(2) with the granulocyte colony-stimulating factor support (2 mu g/kg X 16 day s). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, an d 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. Th e maximum tolerated dose of CPT-11 Has 90 mg/m(2) in both phase I tria ls. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h a fter the start of CPT-11 infusion had a higher incidence of Eastern Co operative Oncology Group grade 3-4 diarrhea than those with a lower SN -38 level (P=0.0003). stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the developme nt of diarrhea (P=0.0021). We conclude that there is a clear relations hip between the SN-38 concentration and diarrhea during chemotherapy w ith CPT-11 plus cisplatin.