Effect of food and ranitidine on saquinavir pharmacokinetics and gastric pH in healthy volunteers.
OBJECTIVE
To assess the relative bioavailability of saquinavir after administration with ranitidine alone, ranitidine and food, and food alone; and to investigate the mechanism underlying the effects of pH and food on saquinavir absorption.


METHODS
Single-center, open-label, randomized, three-part crossover, pharmacokinetic pilot study.


METHODS
General clinical research center in Scotland.


METHODS
Twelve healthy male volunteers.


METHODS
Each subject was given a single dose of saquinavir mesylate 600 mg with one of three randomly assigned treatments: ranitidine 150 mg on the evening before and 150 mg on the day of study drug administration, without food (treatment A); ranitidine 150 mg on the evening before and 150 mg on the day of study drug administration, with food (treatment B); and with food alone (treatment C, control). After a 7-day washout period between each of the interventions, subjects received the other two treatments.


RESULTS
Blood samples were taken serially for 24 hours after each saquinavir dose, and gastric pH was measured during the 8 hours after dosing. Adverse events were monitored throughout the study. Single doses of saquinavir were well tolerated with or without ranitidine. Of the three treatments, the highest mean maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) for saquinavir occurred with treatment B; the lowest C(max) and AUC occurred with treatment A. Compared with treatment C (control), saquinavir's bioavailability was 15.9% (90% confidence interval [CI] 10-25%) after treatment A and 167% (90% CI 106-265%) after treatment B. Interindividual variability in both C(max) and AUC was slightly greater after treatments A and B than after treatment C. No correlation was found between pharmacokinetic parameters (C(max) and AUC) and gastric pH parameters, including maximum pH and pH at the time of drug delivery.


CONCLUSIONS
Plasma concentrations of saquinavir were significantly higher when the drug was administered with food and ranitidine than when it was given with food alone. However, these increases were not related to changes in gastric pH caused by ranitidine. It can be postulated that food does not increase the bioavailability of saquinavir through its effect on gastric pH.
Kakuda
Thomas N
TN
Hoffman-La Roche Inc., Nutley, New Jersey, USA. TKakuda@tibus.jnj.com
Falcon
Ronald W
RW
D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004347:Drug Interactions; D018565:Food-Drug Interactions; D005744:Gastric Acid / Q000378:metabolism; D005745:Gastric Acidity Determination; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D010865:Pilot Projects; D011899:Ranitidine / Q000494:pharmacology*; D012016:Reference Values; D019258:Saquinavir / Q000097:blood / Q000493:pharmacokinetics*; D012606:Scotland
D017320:HIV Protease Inhibitors; D006635:Histamine H2 Antagonists; D011899:Ranitidine; D019258:Saquinavir