Phase I targeted systemic exposure study of paclitaxel in children with refractory acute leukemias

Clearance of anticancer drugs in children is highly variable, leading to wi de variability in the systemic exposure associated with each dosage escalat ion in Phase I studies, The purpose of this Phase I study was to escalate t argeted systemic exposure to paclitaxel, rather than dose, to attenuate the impact of pharmacokinetic variability at each escalation level, Children w ith recurrent acute leukemias received paclitaxel as 24-h infusions at esca lating levels of paclitaxel systemic exposure [i.e,, area under the concent ration-versus-time curve (AUC)]. Plasma paclitaxel concentrations were meas ured by high-performance liquid chromatography-UV detection. A Bayesian alg orithm using a two-compartment model with saturable distribution and satura ble elimination was used to estimate clearance during the first 8 h of infu sion; the infusion rate was adjusted 12 h after the start of infusion to ac hieve the target AUG. Toxicity and evidence of activity were assessed after each course. Six boys and one girl received eight courses of paclitaxel, T he target AUC ranged from 31.5 to 45 mu M.h, Five of the seven evaluable co urses had AUCs between 75% and 125% of the target after adjustment (median, 100.2%; range, 51-151%), whereas none of the seven courses was projected t o be in the target range had no change in dose been made (P = 0.021), The r atio of the achieved AUC to the target AUC was inversely related to clearan ce (r = -0.857; P = 0.014). Mucositis was the exposure-limiting toxicity, a t AUCs lower than were expected based on Phase I studies in children with s olid tumors. Pharmacokinetically-guided dosing strategies reduced variabili ty in systemic exposure, Alternatives to traditional Phase I studies may be important in the setting of childhood leukemias because these patients sho w poor tolerance to Phase I therapy.