British journal of clinical pharmacology · 2018
Population pharmacokinetics of enoxaparin in early stage of paediatric liver transplantation.
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Oualha Mehdi, Chardot Christophe, Debray Dominique, Lesage Fabrice, Harroche Annie, Renolleau Sylvain, Treluyer Jean-Marc, Urien Saïk
Аннотация
AIMS: Preventing post-liver transplantation (LT) hepatic artery and portal vein thrombosis includes enoxaparin administration. Enoxaparin pharmacokinetics (PK) has not been investigated in children following LT. We described an enoxaparin PK model in 22 children the first week following LT.
METHODS: Anti-Xa activity time-courses were analysed using a nonlinear mixed effects approach with Monolix version 2016R.
RESULTS: Anti-Xa activity time-courses were well described by a one-compartment model with first order absorption and elimination. Bodyweight prior to surgery (BWPREOP ) and the related postoperative variation (BW(t)) were the main covariates explaining CL and V between subject variabilities. Parameter estimates were CLi = CLTYP * (BWPREOP /70)3/4 ; Vi = VTYP * (BW(t)/70)1 ; where typical clearance (CLTYP ) and typical volume of distribution (VTYP ) were 1.23 l h-1 and 14.6 l, respectively. Standard dosing regimens of 50 IU kg-1 12 h-1 were insufficient to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 . Specifically, seven children (32%) never attained the target range during the whole period of treatment and all children were at least once underdosed. According to the final results, we simulated individualized dosing regimens within 4 h following the first administration. More than 100 IU kg-1 12 h-1 are suggested to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 from the first day.
CONCLUSION: Thanks to this model, the initial and maintenance doses could be assessed to rapidly achieve the target range. Higher doses per kg, especially in the youngest children, are suggested.
METHODS: Anti-Xa activity time-courses were analysed using a nonlinear mixed effects approach with Monolix version 2016R.
RESULTS: Anti-Xa activity time-courses were well described by a one-compartment model with first order absorption and elimination. Bodyweight prior to surgery (BWPREOP ) and the related postoperative variation (BW(t)) were the main covariates explaining CL and V between subject variabilities. Parameter estimates were CLi = CLTYP * (BWPREOP /70)3/4 ; Vi = VTYP * (BW(t)/70)1 ; where typical clearance (CLTYP ) and typical volume of distribution (VTYP ) were 1.23 l h-1 and 14.6 l, respectively. Standard dosing regimens of 50 IU kg-1 12 h-1 were insufficient to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 . Specifically, seven children (32%) never attained the target range during the whole period of treatment and all children were at least once underdosed. According to the final results, we simulated individualized dosing regimens within 4 h following the first administration. More than 100 IU kg-1 12 h-1 are suggested to reach the target range of anti-Xa activity of 0.2-0.4 IU ml-1 from the first day.
CONCLUSION: Thanks to this model, the initial and maintenance doses could be assessed to rapidly achieve the target range. Higher doses per kg, especially in the youngest children, are suggested.