Limited-sampling models for irinotecan pharmacokinetics-pharmacodynamics: Prediction of biliary index and intestinal toxicity

Purpose: To construct limited-sampling models (LSMs) for irinotecan (CPT-II) pharmacokinetic [PK] measures. Materials and Methods: The recommended phase II dose of weekly CPT-11 administered as a 90-minute infusion is 145 mg/m(2) with granulocyte colony-stimulating factor (G-CSF) and maximal antidiarrheal support. Diarrhea is the dose-limiting toxicity. Previously, we demonstrated a highly significant correlation between severity of diarrhea and biliary index (BI), the estimated biliary exposure of SN-38. Bs was the product of total CPT-II area under the concentration-time curve (AUG) and the relative area ratio of SN-38 to SN-38 glucuronide (SN-38G). At 145 mg/m(2), PK data were available for 40 patients; 36 were also assessable for intestinal toxicity. Total plasma concentrations of CPT-11, SN-38, and SN-38G from 1.0 to 11.5 hours from the start of the infusion were evaluated. CPT-11 concentration at each rime point, t, is denoted by CPT-11(t). LSMs were constructed by stepwise linear regression, on a training set (n = 25), and were validated on a test set (n = 15). Results: LSMs for CPT-11, SN-38, and SN-38G AUCs displayed excellent fit to the training set (R(2) = .87, 0.75, and .98, respectively). AUC(CPT-11) = 5.25 . CPT-11(3.0) + 20.60 . CPT-11(11.5) + 1,520.53; AUC(SN-38) = 5.38 . SN-38(3.5) + 33.61 . SN-38(11.5) - 7.73; and AUC(SN-38G) = 10.73 . SN-38G(9.5) + 20.66 . SN-38(11.5) + 142.69. BI at each time point (denoted BIt) was calculated as CPT-11(t) . (SN-38(t)/SN-38G(t)). Several promising LSMs were defined by BI3.5 paired with BI7.5 (R(2) = .63) or BI9.5 (R(2) = .76), or BI5.5 paired with BI9.5 (R(2) = .76). predicted BI from each model (categorized into low, intermediate, or high) accurately predicted observed intestinal toxicity grade (P less than or equal to .005). Conclusion: These LSMs appear to accurately predict PK parameters of CPT-11. Notably, BI, predicted from several LSMs, accurately predicted intestinal toxicity and thus may be useful for future trials that use adaptive control with feedback. (C) 1996 by American Society of Clinical Oncology.