Exposure-toxicity relationships for tipifarnib in cancer patients

What is already known about this subject • Several clinical studies have shown that the toxicity of tipifarnib in cancer patients is acceptable. • However, previous exposure vs. toxicity analyses have been only performed for a limited range of toxic effects and were based on a single study involving a limited number of patients. What this study adds • This study represents the first comprehensive and large-scale exposure vs. response analysis based on five clinical studies, involving more than 600 patients and evaluating more than 10 different toxicities. • The results have defined the relationship between haematological toxicities and tipifarnib exposure in patients with solid tumours. The occurrence of exposure-related nonhaematological toxicities was low regardless of tumour type. Aims To explore the potential relationship between systemic exposure to tipifarnib and the incidence of toxicity in cancer patients. Methods Data from 673 subjects (540 receiving tipifarnib and 133 receiving placebo) were included in the analysis. Tipifarnib was administered in doses ranging from 100 mg to 850 mg twice daily under fed conditions for 21 days in a 28 day cycle. Univariate and multivariate logistic regression models were used to evaluate the relationships between tipifarnib exposure and haematological (neutropenia and thrombocytopenia) and nonhaematological toxicities. Tipifarnib exposure was quantified as the area under the curve during the first cycle of chemotherapy (AUC), the maximum plasma concentration (Cmax), the time above plasma tipifarnib concentrations of 400 (T400) and 600 ng ml−1 (T600), the cumulative area under the curve (AUCT), and the area under the curve density (AUCD), defined as the ratio AUCT to the duration of treatment. The nonhaematological toxicities measured were elevation of AST, ALT, bilirubin and serum creatinine, the occurrence of a skin rash, CNS or peripheral neuropathy, nausea and vomiting, diarrhoea and inflammation of the gastrointestinal tract. Odds ratios (OR) associated with drug exposure were used to measure the effect of the drug. Results Tipifarnib AUC exhibited a positive and significant association with neutropenia grade ≥3 (OR 1.69, 95% CI 1.47, 1.95) and thrombocytopenia grade ≥3 (OR 1.41, 95% CI 1.21, 1.63) in patients with solid tumours, but not in refractory or relapsed AML patients. The incidence of exposure-related nonhaematological toxicity is small regardless of tumour type. No association was found between tipifarnib AUC and the elevation of AST, ALT and total bilirubin, and nausea and vomiting. There was a weak relationship between tipifarnib AUC and serum creatinine elevation (OR 1.18, 95% CI 1.11, 1.26), CNS (OR 1.05, 95% CI 1.01, 1.10) and peripheral neurotoxicity (OR 1.10, 95% CI 1.03, 1.18), diarrhoea (OR 1.14, 95% CI 1.08, 1.21), gastrointestinal tract inflammation (OR 1.13, 95% CI 1.07, 1.19), and skin rash (OR 1.10, 95% CI 1.04, 1.17). Conclusions In those patients who develop severe toxicity, dose reduction may improve the tolerability of tipifarnib. However, an exposure-guided approach to dosage adjustment to limit haematological and nonhaematological toxicity is not warranted.