A multiphasic absorption model for characterizing single dose pharmacokinetics of divalproex‐ER in healthy subjects

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