Abacavir: Absolute bioavailability, bioequivalence of three oral formulations, and effect of food

Citation
Ge. Chittick et al., Abacavir: Absolute bioavailability, bioequivalence of three oral formulations, and effect of food, PHARMACOTHE, 19(8), 1999, pp. 932-942
Citations number
39
Categorie Soggetti
Pharmacology
Journal title
PHARMACOTHERAPY
ISSN journal
02770008 → ACNP
Volume
19
Issue
8
Year of publication
1999
Pages
932 - 942
Database
ISI
SICI code
0277-0008(199908)19:8<932:AABBOT>2.0.ZU;2-X
Abstract
Study Objectives. Study A: to determine the absolute bioavailability of a s ingle 300-mg abacavir hemisulfate tablet. Study B: to determine the bioequi valence of two oral abacavir formulations (300-mg hemisulfate tablet, 100-m g succinate caplet), the effect of food on the bioavailability of the 300-m g hemisulfate tablet, and the bioavailability of the hemisulfate tablet rel ative to the hemisulfate solution. Design. Phase I, randomized, open-label, balanced two- (study A) and three- or four-period (study B), crossover studies. Setting. Two clinical research centers. Subjects. Six men infected with the human immunodeficiency virus (HIV), age d 27-39 years (study A), and 18 HIV-infected men and women, aged 21-50 year s (study B). Interventions. In study A, all subjects received a single, oral 300-mg tabl et of abacavir hemisulfate or a single, intravenous infusion of abacavir he misulfate 150 mg over 60 minutes. In study B, all subjects received each of three single-dose treatments: three 100-mg abacavir succinate caplets in a fasted state, one 300-mg abacavir hemisulfate tablet in a fasted state, an d one 300-mg abacavir hemisulfate tablet with a high-fat breakfast. Twelve subjects in study B also received a fourth treatment of abacavir hemisulfat e 300 mg as an oral solution in a fasted state. Plasma samples collected fo r 24 hours (study A) or 12 hours (study B), and urine samples collected for 12 hours (study A) were analyzed by validated high-performance liquid chro matographic methods. Measurements and Main Results. Abacavir pharmacokinetic parameters were cal culated using standard, noncompartmental methods. In study A, the geometric least square (GLS) mean absolute bioavailability of oral abacavir was 83% (range 65-107%). In study B, the hemisulfate tablet was bioequivalent to th e succinate caplet, but its time to maximum concentration (T-max) occurred 30 minutes earlier. Administration of the abacavir hemisulfate tablet with food had no effect on area under the curve from time zero to infinity (AUC( 0-infinity)), decreased maximum concentration (C-max) by 26%, and delayed T -max by 38 minutes. The relative bioavailability (GLS mean AUC(0-infinity) ratio) of the 300-mg abacavir hemisulfate tablet to solution was 101%, C-ma x was 11% lower, and T-max was unchanged. The most common drug-related adve rse events associated with abacavir were nausea, vomiting, abdominal pain, and headache, all of which were mild. Conclusion. Based on our results, abacavir is safe and well tolerated and c an be administered with or without meals.