Mirjam N Trame (1), Mats O Karlsson (1), Ulrike Nowak-Göttl (2)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) Institute of Clinical Chemistry, Thrombosis and Heamostasis Unit, University Hospital Kiel, Kiel, Germany
Objectives:Enoxaparin, a low-molecular-weight-heparin, is used off-label in children for prevention of symptomatic thromboembolism. However, little is known regarding its pharmacokinetics (PK) in children. The aim of this investigation was to further evaluate the PK by using additional data and covariate analysis combined with previous study data. [1]
Methods:Data from 126 patients (median age: 5.9 years; median weight (WT): 24 kg) receiving enoxaparin either as a once or twice daily dose regimen, were analysed. All studied patients received enoxaparin during secondary prophylaxis therapy. Using NONMEM, steady-state plasma concentration-time data were analysed. The following patient characteristics were assessed as covariates on PK parameters using conventional and linearised stepwise covariate model (SCM) building: age, WT, body surface area (BSA), serum creatinine, estimated Glomerular Filtration Rate (eGFR), Body Mass Index, and Antithrombin. Missing covariates were handled using: a Slope-Intercept model for WT imputation from postmenstrual age (PMA); the Boyd equation, using the imputed WT as an independent variable, to calculate missing BSA values [2]; the Mosteller formula to calculate missing heights from the imputed BSA and WT; and either the Lund-Malmö equation or the updated Schwartz equation for eGFR imputation, depending on age or height availability, respectively. [3,4]
Results:A two-compartment first-order absorption model with interindividual variability (IIV) on clearance (CL/F), central volume of distribution (V1/F), and absorption rate konstant (ka) best described the data. WT as covariate was pre-specified in the base model on CL/F and V1/F. As enoxaparin is mainly cleared renally it was hypothesised that CL might be parameterised as a sum of an eGFR-dependent renal and a WT- or BSA-dependent non-renal component. However, the SCM did not find any parameter-covariate relations statistically significant for inclusion. Final parameter estimates (IIV %) were: CL 15 mL/h/kg (54%), V1/F 169 mL/kg (24%), intercompartimental clearance (Q) 52 mL/h, peripheral volume of distribution (V2) 12 L and ka 0.404/h (68%).
Conclusions:This population PK analysis confirms our previous findings [1] that no other covariate than WT is needed for renally healthy patients to explain the PK of enoxaparin. The model describes enoxaparin disposition in all age groups in our study population from neonates to adolescents.
References:
[1] Trame MN et al. Population pharmacokinetics of enoxaparin in infants, children and adolescents during secondary thromboembolic prophylaxis: a cohort study. Journal of Thrombosis and Haemostasis,8:1950-1958
[2] Sharkey I et al. Body surface area estimation in children using weight alone: application in paediatric oncology. Br J Cancer 85:23-28
[3] Björk J et al. Prediction of relative glomerular filtration rate in adults: New improved equations based on Swedish Caucasians and standardized plasma-creatinine assays. Scand J Clin Lab Invest 2007; 67: 678-695
[4] Schwartz GJ et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629-637
Reference: PAGE 21 () Abstr 2598 [www.page-meeting.org/?abstract=2598]
Poster: Paediatrics