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.
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
Janel
J
Long-Boyle
Jiayin
J
Huang
Nancy
N
Rydholm
Angela
A
Smith
Paul
P
Orchard
Jakub
J
Tolar
Pamala
P
Jacobson
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