Abstracts

Enteric-coated, delayed-release divalproex with 1st-order absorption characteristics vs. extended-release divalproex with zero-order absorption: Graphical comparison and visual analysis of plasma concentration-time profiles.

Abstract number : 2.198
Submission category : 7. Antiepileptic Drugs
Year : 2010
Submission ID : 12792
Source : www.aesnet.org
Presentation date : 12/3/2010 12:00:00 AM
Published date : Dec 2, 2010, 06:00 AM

Authors :
Ronald Reed, S. Dutta, W. Liu, D. Kasteleijn Nolst-Trenite and R. Ramsay

Rationale: Most immediate-release and enteric-coated [EC] formulations of drugs, including AEDs, exhibit 1st-order absorption characteristics, with a constant fraction or % absorbed into the bloodstream per unit time upon oral administration. Certain AEDs have been engineered to markedly slow the rate of drug-release, ie., extended-release [ER] formulations, for purposes of minimizing peak-concentration-related toxicity. One such AED, divalproex extended-release, exhibits near zero-order absorption, with a constant amount of drug absorbed per unit time (Dutta, Reed, Cavanaugh, J Clin Pharmacol 2004; 44 [7]: 737-42; Dutta & Reed, J Clin Pharmacol 2006; 46 [8]: 952-7). Plasma concentrations from multiple dosing of drugs with 1st order absorption characteristics has been commonly displayed graphically in various publications & general pharmacological texts; clinicians generally recognize this pattern of oral drug absorption (superposition principle). The pattern of plasma concentration rise with multiple dosing of ER formulations with zero-order absorption has not been depicted graphically and is not well-recognized. We graphically compared the absorptive phase of plasma concentrations for an AED, divalproex, with 1st order [EC] vs. zero-order [ER] absorption. Methods: We simulated the total plasma concentration profiles of valproic acid [VPA] resulting from oral, multiple doses of two distinct divalproex formulations, EC vs ER, via parameters and formulas published previously (Reed RC & Dutta S, Am J Health-Syst Pharm 2004; 61 (21): 2284-9 and Reed RC, Dutta S & Liu W, Epilepsy Research, 2009; 87: 260-267). For divalproex EC, a ka = 0.091 (1/hr) was used; for ER, we used a k0 = 50.57 mg/h x 22 hr. Results: Linear [VPA]-concentration-time profiles from EC (1st-order, pink) vs. ER (zero-order, blue line) with resultant [VPA] after missing a dose at h = 192, plus subsequent dose replacement, are shown in the figure. The pink EC [VPA] profile displays the classic superposition principle for drugs with 1st-order absorption, with a constant north-east pointing vector, also clearly seen at steady-state and is again visually apparent with [VPA] post dose-replacement. The vector for the blue ER [VPA] profile is constantly changing, becoming flatter with each dose until a plateau is reached. Conclusions: The graphical pattern of the rise in plasma [VPA] concentrations from oral multiple-dose divalproex-[EC] possessing 1st-order absorption is clearly different from that of divalproex-[ER] with zero-order absorption. It is important to recognize these patterns as more ER-AED formulations with zero-order absorption are likely to be developed.
Antiepileptic Drugs