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Simulation‐based support of dose recommendations of entecavir for renally impaired subjects
Author(s) -
LaCreta F.,
Mould D.,
Bifano M.,
Grasela D.M.,
Pfister M.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.077
Subject(s) - medicine , entecavir , renal function , urology , pharmacokinetics , creatinine , kidney disease , pharmacology , chronic hepatitis , immunology , virus , lamivudine
Background Entecavir (ETV) is a potent and selective anti‐hepatitis B agent which is primarily eliminated by renal excretion of unchanged drug through glomerular filtration and active secretion. The objectives of this study were to develop a PK model with single dose PK data, to quantify the effect of creatinine clearance (CLcr) on entecavir pharmacokinetics (PK), and to simulate steady‐state exposure (AUCss) for alternative doses to support dose selection for renally impaired subjects. Methods 711 plasma concentrations from 34 renally impaired subjects were available for this modeling & simulation analysis. Subjects received a single dose of 1 mg entecavir and were allocated to 5 groups (n= 6–10/group) based on renal function (i.e., CLcr): group 1 (>80 mL/min); group 2 (50‐≤80 mL/min); group 3 (30‐≤50 mL/min), group 4 (<30 mL/min), and group 5 (subjects with end‐stage renal disease on dialysis). AUCss values were simulated for each group and compared with a predefined AUCss target range to select doses with ≥75% of AUCss values within the target range. Results Entecavir clearance (CL/F,[L/h]) increases in a linear manner with increasing CLcr: CL/F= 2.27+ CLcr•26.6. The following dose adjustments (% of starting dose) provide consistent steady‐state exposures for all degrees of renal impairment: groups 1, 2 (no adjustment, 100%), group 3 (50%), group 4 (30%), group 5 (20%). Conclusions Model‐based simulation is a useful tool to evaluate and support dose selection of ETV in subjects with renal impairment. Clinical Pharmacology & Therapeutics (2005) 77 , P20–P20; doi: 10.1016/j.clpt.2004.11.077