Table 2 Pharmacokinetics of clofarabine Variable Value Volume of distribution (L/m2) 172 Protein binding (%) 47 Terminal half-life (hours) 5.2 Elimination via urine (49%–60%) Systemic clearance (L/h/m2) 28.8 Metabolism Phosphorylated by deoxycytidine kinase phosphorylated to active metabolite clofarabine triphosphate Derived from data of Bonate et al 2004. 40 pediatric patients aged 2–9 years (21 males/19 females) with relapsed or refractory ALL or AML. Clofarabine pharmacokinetics was weight dependent, suggesting the importance of dosing on a body surface area (BSA) basis, although similar concentrations were obtained over a wide range of BSAs at the given 52 mg/m2 dose (Bonate et al 2004). Clofarabine was 47% bound to plasma proteins, mainly albumin. Systemic clearance and volume of distri- bution at steady state were estimated to be 28.8 L/h/m2 and 172 L/m2, respectively. The terminal half-life was estimated to be 5.2 hours (Bonate et al 2004). The half-life of the active clofarabine triphosphate metabolite could not be adequately characterized in the pediatric phase 2 studies but was esti- mated to be greater than 24 hours (Bonate et al 2004). It is believed that the conversion from the monophosphate to the diphosphate moiety is the rate-limiting step in the formation of the triphosphate. It appears that clofarabine triphosphate formation is very rapid, and once formed, it remains trapped in the cell with a prolonged elimination half-life (Xie and Plunkett 1995; Bonate et al 2004). In pediatric patients 49%–60% of the clofarabine dose is excreted unchanged in the urine. The pathways of non-renal elimination remain unknown (Gandhi et al 2003; Bonate et al 2004). Clofarabine does not appear to be metabolized by the cytochrome P450 enzymes and CYP450 inhibitors and inducers are not likely to affect the metabolism of clofarabine, although no clinical drug-drug interaction studies have been conducted to date (Clolar® package insert). Special populations Clofarabine pharmacokinetics is similar in patients with ALL and AML or in males and females. The pharmacokinetics of clofarabine remains to be evaluated in patients with renal or hepatic dysfunction (Bonate et al 2004). According to the manufacturer, its use in patients with hepatic or renal dysfunction should be undertaken only with the greatest caution. Therapeutics and Clinical Risk Management 2008:4(2) Clofarabine in pediatric leukemias Clofarabine was found to be teratogenic in reproductive studies conducted in rats and rabbits, with reduced fetal body weight, increased fetal loss, and skeletal malformations observed. Therefore, although there are no adequate studies in pregnant women using clofarabine, women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with clofarabine (Clolar® package insert). Efﬁcacy studies Phase I studies in pediatrics Based on a 16% overall response rate seen in adults with leu- kemia in a phase I single-agent trial of clofarabine (Gandhi et al 2003; Kantarjian et al 2003b; Faderl et al 2005a), a pediatric phase I trial was conducted to deﬁne the dose-limiting toxicity (DLT) and maxinimu tolerated dose (MTD) for children with acute leukemia (Jeha et al 2004). Six dose levels, ranging from 11.25 to 70 mg/m2 for 5 days, were studied in 25 pediatric patients (8 patients with AML and 17 patients with ALL). Most patients were heavily pretreated, with 36% having undergone prior stem cell transplantation (Jeha et al 2004). Hyperbilirubinemia and skin rash were dose-limiting and the recommended dose schedule for the phase 2 pediatric studies was 52 mg/m2 daily for 5 days. Complete response (CR) was reported in 4 (24%) of 17 patients with ALL (Table 3). One patient (6%) had a partial response (PR), for an overall response rate (CR + PR) for ALL of 30%. Complete responses were seen at 30 mg/m2, 40 mg/m2, and 52 mg/m2 (Jeha et al 2004). Respond- ers included a 13-year-old female with t(9,22) refractory to 3 consecutive induction attempts including idarubicin, ﬂudara- bine, and cytarabine, as well as a 17-year-old female with T-cell ALL refractory to 3 consecutive inductions including nelarabine (Jeha et al 2004). The overall response rate for patients with AML was 38% (Table 3). One out of 8 patients (13%) achieved CR and 2 patients (25%) achieved PR (Jeha et al 2004). Phase II studies in children with acute leukemia A phase II, open-label, multicenter clofarabine study was conducted in 61 pediatric patients in the US with refractory Table 3 Response to clofarabine in phase I trials Responses/Total (%) Response ALL AML CR 4/17 (24%) 1/8 (13%) PR 1/17 (6%) 2/8 (25%) CR + PR 5/17 (30%) 3/8 (38%) Derived from data of Jeha et al (2004). Abbreviations: CR, complete response; PR, partial response. Total 5/25 (20%) 3/25 (12%) 8/25 (32%) 331