Relationship between the Pharmacokinetics of Irinotecan and Diarrhea during Combination Chemotherapy with Cisplatin

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Abstract
Two phase I trials of irinotecan (CPT‐11) in combination with cisplatin were conducted. In both cases, the dose‐limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT‐11 and its active metabolite, 7‐ethyl‐10‐hydroxycamptothecin (SN‐38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT‐11 and cisplatin. Twenty‐three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT‐11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2. The other 13 patients received CPT‐11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony‐stimulating factor support (2 μg/kg × 16 days). CPT‐11 was given as a 90‐min intravenous infusion on days 1, 8, and 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. The maximum tolerated dose of CPT‐11 was 90 mg/m2 in both phase I trials. 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 after the start of CPT‐11 infusion had a higher incidence of Eastern Cooperative 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 development of diarrhea (P=0.0021). We conclude that there is a clear relationship between the SN‐38 concentration and diarrhea during chemotherapy with CPT‐11 plus cisplatin.