Paclitaxel exposure-toxicity analysis reveals a pharmacokinetic determinant for dose-limiting neutropenia in East-Asian solid tumor patients: results from two prospective, phase II studies.

PURPOSE: The time of a paclitaxel (PTX) concentration remains above 0.05 muM (Tc > 0.05) has been associated with PTX-induced adverse effects in Caucasians, while limited studies were reported in Asians. This study was aimed to explore the characteristics of Tc > 0.05 and the relationship between PTX exposure and toxicity in East-Asian patients. METHODS: This study was based on two prospective phase II clinical trials and patients with advanced nasopharyngeal cancer (NPC) and non-small cell lung cancer (NSCLC) who were naive to PTX were included independently. Eligible patients receive PTX (175 mg/m(2)) and carboplatin (AUC = 5) treatment every 3 weeks. PTX pharmacokinetic analysis was accessed. The relationship between PTX exposure and toxicities after first cycle as well as clinical efficacy was evaluated. RESULTS: A total of 93 NPC and 40 NSCLC patients were enrolled. PTX exposure was consistent in two trials with average Tc > 0.05 duration of 38.8 h and 38.4 h, respectively. Average Tc > 0.05 in patients with grade 3/4 neutropenia was significantly higher than those without severe neutropenia in NPC patients (P = 0.003) and NSCLC patients (P = 0.007). Cut-off value of Tc > 0.05 were identified from the NPC cohort and then verified in the NSCLC cohort, dividing patients into high exposure Tc > 0.05 group (> 39 h) and low exposure group (</= 39 h). Incidence of grade 3/4 neutropenia were significantly higher in the high exposure group in NPC cohort (43.3% vs 10.0%, P < 0.001) and NSCLC cohort (42.1% vs 9.5%, P = 0.028). No significant relationship between Tc > 0.05 and efficacy were observed. CONCLUSION: Patients with PTX Tc > 0.05 duration above 39 h experience more severe neutropenia than those under 39 h. Prospective studies are needed to verify this threshold.