Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer

Abstract

Clofarabine for injection is a second-generation nucleoside analog approved in the United States (Clolar(®)) and Europe (Evoltra(®)) for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. This report describes the population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with hematologic malignancies or solid tumors. Clofarabine pharmacokinetics were best described by a 2-compartment model with linear elimination and first-order absorption after oral administration. Clofarabine was rapidly absorbed following oral administration with a mean absorption time of less than 2 h and bioavailability of 57.5%. The important covariates affecting clofarabine pharmacokinetics were age, weight, and estimated creatinine clearance (eCrCL). No difference in pharmacokinetics was observed between sexes, races, or disease type. The elimination half-life was dependent on all the covariates but was generally less than 7 h in all cases. A difference in clofarabine pharmacokinetics was observed between adults and children. For a pediatric patient 3 years old weighing 16 kg with an eCrCL of 138 mL/min/1.73 m(2), the population estimates for total systemic clearance and volume of distribution at steady-state were 18.3 L/h (1.14 L/h/kg) and 92.9 L (5.81 L/kg), respectively. α- and β-half-life were 0.9 and 4.4 h, respectively. For an elderly patient 82 years old weighing 96 kg with an eCrCL of 46 mL/min/1.73 m(2), the population estimates for CL and Vdss were 21.5 L/h (0.22 L/h/kg) and 257.4 L (268 L/kg), respectively. α- and β-half-life were 0.5 and 10.6 h, respectively. Because of the difference in pharmacokinetics, adults have higher exposure than children given a similar dose standardized to body surface area. The exact mechanism of this difference is not understood. As eCrCL decreased, exposure increased due to reduced total systemic clearance. In the case of moderate (eCrCL 30 to 60 mL/min/1.73 m(2)) and severe (eCrCL <30 mL/min/1.73 m(2)) renal impairment, dose reduction may be needed to maintain similar exposure in an equivalent patient of the same age, weight, and normal renal function after both oral and intravenous administration. 6-Ketoclofarabine was a minor metabolite with peak plasma concentrations occurring about 1 h after the start of the infusion and having a metabolite ratio averaging less than 5% and not more than 8% for any particular individual. 6-Ketoclofarabine was rapidly cleared from plasma with an average apparent half-life of 4.9 h (range 3.9 to 6.2 h). No accumulation of 6-ketoclofarabine was observed with predose samples all below the limit of quantification on Days 8 and 15. Further monitoring of 6-ketoclofarabine is not required in future studies.

Clofarabine-associated acute kidney injury in patients undergoing hematopoietic stem cell transplant

“…Figure 3(B) illustrates the statistically significant positive association between baseline GFR and dose 1 clofarabine clearance (p = 0.008). The effect of reduced GFR on clofarabine CL has previously been documented [20]. …”

Clofarabine in the treatment of myelodysplastic syndromes

“…daily for 5 days and PK samples were collected on days 1 and 5 with the first cycle. The PK of clofarabine fit a two-compartment model and plasma clofarabine concentrations were similar across a wide range of body surface areas [17]. Clofarabine was only 47% bound to plasma proteins, primarily albumin and the estimated volume of distribution was 172 l/m 2 suggesting extensive tissue distribution.…”

“…Clofarabine was only 47% bound to plasma proteins, primarily albumin and the estimated volume of distribution was 172 l/m 2 suggesting extensive tissue distribution. For a 40 kg person, the estimated systemic clearance was 28.8 l/h/m 2 and the primary route of elimination was renal excretion, with 57% of the dose excreted unchanged in the urine [17]. However, the pathways involved in extra-renal excretion have not been elucidated.…”

“…The population pharmacokinetics (PK) of plasma clofarabine and intracellular clofarabine triphosphate has been well characterized in pediatric patients with advanced hematologic malignancies by Bonate et al [17]. Forty pediatric patients aged 2 --19 years (19 females and 21 males) with relapsed or refractory ALL (n = 24) and AML (n = 16) were treated with clofarabine 52 mg/m 2 i.v.…”

Simultaneous determination of fludarabine and clofarabine in human plasma by LC–MS/MS

“…A number of methods have been reported for the determination of FDB[8–10] and CFB [11–13]. However, methods for the simultaneous determination of these two nucleoside analogues have not yet been reported.…”