Sarapee Hirankarn (1), Nick Holford (2), Erin Dombrowsky (1), Dimple Patel (1), Jeffrey S. Barrett (1)
(1) Clinical Pharmacology & Therapeutics Division, The Children's Hospital of Philadelphia (CHOP), Philadelphia, Pennsylvania 19104, USA, (2) Department of Pharmacology & Clinical Pharmacology University of Auckland, New Zealand
Objectives: The current management of high-dose methotrexate (HDMTX) therapy typically involves a complex process to reduce toxicity. Nonetheless, the incidence of life-threatening toxicity continues to occur in approximately 1%. Better understanding of MTX pharmacokinetics (PK) could be helpful in improving the management of MTX therapy. The objectives of this analysis were 1) to develop a population pharmacokinetic model of HDMTX in pediatric cancer patients from routine clinical data and 2) to evaluate the predictable components of variability in MTX PK.
Methods: A total of 956 concentrations collected from 56 patients administered MTX by IV infusion of 1 to 12 g/m2 over 20 min to 24 h). Data were analyzed using NONMEM® 7.2. A two compartment model was parameterized in terms of clearance (CL), central volume of distribution (V1), intercompartmental clearance (Q) and peripheral volume of distribution (V2). Size related differences in CL, V1, Q and V2 were predicted by theory based allometric scaling using total body weight (TBW) and fat free mass (FFM). Creatinine clearance (CLcr) was predicted using the Schwartz formulae. CL was split into a component that varied with urine pH (renal clearance tubular, CLtub) and a component that varied with renal function (renal clearance glomerular, CLgfr) predicted from the ratio of CLcr to normal glomerular filtration rate based on age, TBW and FFM. Random between subject (BSV) and between occasion variability (BOV) were estimated assuming log-normal distribution of the CL, V1, Q and V2. The covariance between CL, V1, Q and V2 for BSV and for BOV were estimated. Residual unidentified variability was described by a proportional residual error model.
Results: CL were predicted by TBW and renal function. There was no significant improvement from using urine pH to predict clearance. The population mean parameters (%RSE) for CLtub, CLgfr, V1, Q, and V2 were estimated to be 19.0 (19.1%) L/h/70kg, 5.4 (28.6%) L/h/70kg, 145.0 (20.8%) L/70kg, 0.9 (26.1%) L/h/70kg and 22.3 (33.7%) L/70kg, respectively. The BSV in CL was 65% and BOV in CL was 56%. 20% of total population variance in CL (BSV and BOV) was explained by differences in TBW. Only 3% of variance in CL was explained by differences in renal function.
Conclusion: TBW but not body composition differences can predict some of the differences in MTX clearance. CLcr has no clinically relevant value in predicting MTX clearance in a typical population requiring HDMTX.
References:
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Reference: PAGE 21 (2012) Abstr 2466 [www.page-meeting.org/?abstract=2466]
Poster: Paediatrics