Pharmacokinetics of clofarabine in patients with high-risk inherited metabolic disorders undergoing brain-sparing hematopoietic cell transplantation.
Clofarabine, a newer purine analog with reduced central nervous system toxicity, may prove advantageous in hematopoietic cell transplantation in patients for whom neurotoxicity is a natural part of disease progression. This study evaluated clofarabine pharmacokinetics in adult and pediatric patients undergoing hematopoietic cell transplantation for the treatment of high-risk, inherited metabolic disorders. Clofarabine (40 mg/m(2)/d) was administered intravenously on days -7 to -3. Kinetic sampling occurred with doses 1 and 5, along with a single level collected on day of transplant (day(0)). Sixteen patients were studied with a median (range) age and body surface area (BSA) of 7.5 years (0.5-43) and 0.94 m(2) (0.31-2.3), respectively. Clofarabine area under the concentration-time curve from time 0 to infinity was 931 ng·h/mL (685-1876), maximum concentration was 226 ng/mL (162-600), and minimum concentration was 3.2 ng/mL (1.7-5.6). Clofarabine clearance was 1.6 L/h/kg (0.7-2.4) and weakly correlated with weight (r(2) = 0.33) and BSA (r(2) = 0.26). No difference in plasma concentrations was found between dose 1 and dose 5 (all P > .05). All concentrations were below the limit of quantification (1 ng/mL) on day(0) in patients with normal renal function. Variability in clofarabine clearance was approximately 3-fold and was not adequately explained by covariates describing renal function and body size. In patients with adequate renal function, no drug accumulation occurs with consecutive daily dosing.
Long-Boyle
Janel
J
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Huang
Jiayin
J
Rydholm
Nancy
N
Smith
Angela
A
Orchard
Paul
P
Tolar
Jakub
J
Jacobson
Pamala
P
D000227:Adenine Nucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000293:Adolescent; D000328:Adult; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001830:Body Surface Area; D001835:Body Weight; D020739:Brain Diseases, Metabolic, Inborn / Q000097:blood / Q000601:surgery*; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D016903:Drug Monitoring; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008910:Minnesota; D008954:Models, Biological; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods*; D055815:Young Adult
D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D000077866:Clofarabine