Abstract
Purpose. To study the influence of large-volume high-calorie protein, fat, and carbohydrate meals and a non-caloric hydroxypropylmethyl cellulose (HPMC) viscous meal on the oral bioavailability of indinavir in HIV-infected subjects.
Methods. Seven male HIV-infected subjects received caloric meal treatments and control meals in a randomized crossover fashion and the viscosity meal as a final treatment. The total volume of each meal treatment was 500 mL and the caloric meals each contained 680 kcal. Gastric pH was also monitored by radiotelemetry from one hour before to four hours after drug and caloric meal administration. A single Crixivan™ (indinavir sulfate) dose equivalent to 600 mg indinavir was administrated orally with 100 mL of water immediately following meal administration. Indinavir plasma concentrations were obtained using reverse-phase HPLC.
Results. All meal treatments significantly decreased the extent of indinavir absorption as compared to fasted control. AUC0−∞ decreased by 68%, 45%, 34%, and 30% for protein, carbohydrate, fat, and viscosity meal treatments versus fasted control, respectively (p < 0.05). The mean Cmax was significantly decreased 74%, 59%, 46% and 36% (p < 0.05) and the mean tmax was significantly delayed from 1 hr in fasted controls to 3.8, 3.6, 2.1 and 2.0 hrs (p < 0.05) for protein, carbohydrate, fat, and viscosity meal treatments, respectively. The elimination half-life of indinavir determined in the fasted state was decreased in HIV-infected subjects as compared to the reported half-life in normal healthy subjects.
Conclusions. Reductions in indinavir plasma concentrations compared to drug administration in the fasted state are most severe with the high-calorie protein meal. This is consistent with an influence of elevated gastric pH on drug precipitation. Significant drug plasma concentration reductions observed with administration of the other meals in the absence of appreciably elevated gastric pH profile indicate that other factors are playing a role in the meal effects. The similarity in indinavir plasma profiles with protein and carbohydrate versus fat and viscosity suggests that the latter meals may reduce the impact of drug precipitation compared to the former meals.
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Carver, P.L., Fleisher, D., Zhou, S.Y. et al. Meal Composition Effects on the Oral Bioavailability of Indinavir in HIV-Infected Patients. Pharm Res 16, 718–724 (1999). https://doi.org/10.1023/A:1018880726035
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DOI: https://doi.org/10.1023/A:1018880726035