Premium
A multiphasic absorption model for characterizing single dose pharmacokinetics of divalproex‐ER in healthy subjects
Author(s) -
Dutta S.,
Reed R. C.,
Cavanaugh J. H.
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.2004.12.018
Subject(s) - divalproex , pharmacokinetics , absorption (acoustics) , chemistry , volume of distribution , pharmacology , medicine , mania , bipolar disorder , materials science , lithium (medication) , composite material
Aim Characterize the single dose pharmacokinetics of divalproex sodium extended release (ER) tablets in healthy volunteers. Methods Healthy adult volunteers (n=16) received single 500 mg doses of divalproex‐ER and intravenous valproic acid in a crossover fashion. The in vivo absorption rate profile of divalproex‐ER was inferred by deconvolution (WINNONLIN) of the divalproex‐ER plasma concentration‐time profile against the intravenous VPA concentration‐time profile. A multiphasic absorption coupled with a mono‐exponential disposition model described divalproex‐ER plasma concentration‐time profile (ADAPT). Results Divalproex‐ER exhibited extended‐release over >20 hours without any dose dumping. Estimated[95% CI] zero‐order absorption rate (A0), maximum absorption rate (Amax), gastric emptying time (GT50), small intestinal transit time (SIT50), large intestinal transit time (LIT50), sigmoidicity (g), oral clearance (CL/F) and volume of distribution (V/F) were 0.0427 (0.0418–0.0437) mg/h, .0388 (.0325–0.0452) mg/h, 0.00898 (−1.67–1.69) h, 2.55 (0.662–4.44) h, 16.7 (16.3–17.0) h, 1.88 (1.72–2.03), 0.469 (0.445–0.493) L/h, 10.3 (9.74–10.8) L, respectively. Conclusions A multiphasic absorption model optimally described an initial rapid absorption in the small intestine, an extended zero‐order absorption in the large intestine, and a subsequent rapid attenuation in the absorption rate inferred from deconvolution analysis. Clinical Pharmacology & Therapeutics (2005) 77 , P33–P33; doi: 10.1016/j.clpt.2004.12.018