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Plasma and Intracellular Population Pharmacokinetic Analysis of Fludarabine in Pediatric Allogeneic Hematopoietic Cell Transplant (alloHCT) Recipients

Track: BMT Tandem "Scientific" Meeting
Wednesday, February 26, 2014, 4:45 PM-6:45 PM
Texas B (Gaylord Texan)
Janel Long-Boyle, PharmD, PhD , Department of Clinical Pharmacy, UCSF, San Francisco, CA
Nancy Sambol, PharmD , Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA
Christopher C. Dvorak, MD , University of California San Francisco Medical Center, San Francisco, CA
Morton J Cowan, MD , Pediatric Allergy Immunology and Blood and Marrow Transplant Division, UCSF Benioff Children's Hospital, San Francisco, CA
Shirley Lee, PharmD , Department of Pharmacy, UCSF, San Francisco, CA
Liusheng Huang, PhD , Drug Research Unit, Department of Clinical Pharmacy, UCSF, San Francisco, CA
Biljana Horn, MD , Pediatric Allergy Immunology and Blood and Marrow Transplant Division, UCSF Benioff Children's Hospital, San Francisco, CA
Melisa Stricherz, PharmD , Department of Pharmacy, University of Minnesota Amplatz Children's Hospital, Minneapolis, MN
Jakub Tolar, MD, PhD , University of Minnesota, Minneapolis, MN
Paul Orchard, MD , University of Minnesota, Minneapolis, MN
Pamala Jacobson, PharmD , Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN
Francesca Aweeka, PharmD , Drug Research Unit, Department of Clinical Pharmacy, UCSF, San Francisco, CA
Audio File Recorded Presentation
METHODS:

A prospective study was conducted to characterize the pharmacokinetics (PK) of fludarabine plasma (f-ara-A) and intracellular triphosphate (f-ara-ATP) in children undergoing alloHCT and receiving fludarabine with their conditioning regimen.  Plasma and peripheral blood mononuclear cells (PBMCs) were collected over the 3-5 days of fludarabine treatment for quantitation of f-ara-A and f-ara-ATP, respectively, using a validated liquid chromatography/tandem mass spectrometry assay.  Nonlinear mixed effects modeling was used to develop the population PK model, including identification of covariates that influenced drug disposition.

RESULTS:

Fifty-four children (median age 2 years, range 0.25-17) undergoing alloHCT for a variety of malignant and nonmalignant disorders underwent PK assessments.  A 2-compartment model with linear elimination best described the PK of f-ara-A while a third compartment representing PBMCs linked f-ara-A to f-ara-ATP. Final parameter estimates and relative standard errors for f-ara-A are as follows: clearance, 5.8 L/h (5.4%), volume of central compartment, 16.6 L (9.0%), volume of peripheral compartment, 16.6 L (5.8%), and intercompartmental clearance, 3.0 L/h (14.1%). Covariates significantly impacting f-ara-A clearance included body weight, age, and creatinine clearance (CrCL).  Dose-normalized PK exposure was highest among very small, young children or subjects with renal dysfunction.  Predicted f-ara-A clearance was reduced 40% in subjects with CrCL ≤ 50 mL/min compared to those with normal renal function (120 mL/min).  Additionally, the rate of f-ara-A into PBMCs and/or transformation to f-ara-ATP (modeled with a first order rate constant) decreased over the course of therapy, resulting in 42% lower intracellular f-ara-ATP exposure following the third versus first dose.     

IMPACT:

These results will help inform better dosing strategies for fludarabine, particularly in young infants with small body size or in children with pre-existing renal dysfunction. Re-evaluation of the optimal dosing regimen for fludarabine is warranted given the decrease in intracellular exposure to f-ara-ATP with time.

Disclosures:
Nothing To Disclose
See more of: Oral Abstracts - Session A - Allogeneic Transplants
See more of: BMT Tandem "Scientific" Meeting
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