title: 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.
authors.affiliation: Genzyme Corporation, 4545 Horizon Hill Boulevard, San Antonio, TX 78229, USA. peter.bonate@gmail.com
authors.forename: Peter L
authors.initials: PL
authors.lastname: Bonate
authors.forename: Casey C
authors.initials: CC
authors.lastname: Cunningham
authors.forename: Paul
authors.initials: P
authors.lastname: Gaynon
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.forename: Richard
authors.initials: R
authors.lastname: Kadota
authors.forename: Gilbert N
authors.initials: GN
authors.lastname: Lam
authors.forename: Bassem
authors.initials: B
authors.lastname: Razzouk
authors.forename: Michael
authors.initials: M
authors.lastname: Rytting
authors.forename: Peter
authors.initials: P
authors.lastname: Steinherz
authors.forename: Steve
authors.initials: S
authors.lastname: Weitman
mesh_terms: D000227:Adenine Nucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D003404:Creatinine / Q000097:blood / Q000652:urine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D055815:Young Adult
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D000077866:Clofarabine; D003404:Creatinine