2010
DOI: 10.1128/aac.00712-10
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Pharmacokinetics and Pharmacogenomics of Once-Daily Raltegravir and Atazanavir in Healthy Volunteers

Abstract: Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the UGT1A1 genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by >3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-gl… Show more

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Cited by 43 publications
(56 citation statements)
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“…Taking more samples in the 12-to 24-hour part of the curve would be ideal but is unpractical because it would require subjects to stay overnight. Consistent with published literature, age, gender, liver and renal function, and tenofovir and lopinavirritonavir comedication did not affect pharmacokinetic values (24), but atazanavir significantly increased the raltegravir AUC (4, 7), likely owing to its inhibitory effect on UDP-glucuronosyltransferase-1A1, which metabolizes raltegravir (16). Darunavirritonavir has been shown to decrease the raltegravir AUC by 29% (7).…”
Section: Discussionsupporting
confidence: 75%
“…Taking more samples in the 12-to 24-hour part of the curve would be ideal but is unpractical because it would require subjects to stay overnight. Consistent with published literature, age, gender, liver and renal function, and tenofovir and lopinavirritonavir comedication did not affect pharmacokinetic values (24), but atazanavir significantly increased the raltegravir AUC (4, 7), likely owing to its inhibitory effect on UDP-glucuronosyltransferase-1A1, which metabolizes raltegravir (16). Darunavirritonavir has been shown to decrease the raltegravir AUC by 29% (7).…”
Section: Discussionsupporting
confidence: 75%
“…In addition, RAL plasma concentrations were obtained from 2 clinical trials. The first trial included 19 healthy volunteers enrolled in an open-label crossover pharmacokinetic interaction study of RAL with and without atazanavir (ATV) (29).Treatment arms were RAL at 400 mg BID alone or 400 mg plus ATV at 400 mg once daily. In both arms, participants were instructed to take medication at least 1 h before or 2 h after eating, and the actual time of drug intake was recorded both by electronic recording (Medication Event Monitoring System [MEMS]) and in a medication log.…”
Section: Methodsmentioning
confidence: 99%
“…It is highly bound to plasma proteins (83%) (8) and eliminated primarily by UDP glucuronosyltransferase 1A1 (UGT1A1), with minor contributions from UGT1A3 and UGT1A9 (22). Although genetic variation in UGT isoenzymes may therefore affect RAL exposure, two studies performed with healthy volunteers failed to demonstrate an effect of the well-known decrease function allele UGT1A1*28 on RAL metabolism, suggesting that other UGT isoenzymes might be involved (29,48). RAL is generally well tolerated, with only 3% treatment discontinuation due to adverse effects (8,40).…”
mentioning
confidence: 99%
“…An increase in plasma bilirubin levels is generally not seen following liver enzyme induction, but is usually indicative of impaired hepatic bile flow, accelerated red blood cell destruction, or decreased bilirubin metabolism (Boone et al 2005;Jonker, Liddleb, and Downes 2011). Additionally, competitive inhibition of bilirubin conjugation by drugs (such as Atazanavir that inhibits UDP-glucuronyltransferase isoenzyme, 1A1) may lead to a dose-related, asymptomatic, unconjugated hyperbilirubinemia in humans and in rats (Neely et al 2010;Zucker et al 2001), which is clearly non-adverse and normally not accompanied by histopathological evidence of hepatic degeneration (Neely et al 2010). When accompanied by increased serum bile acids, increased bilirubin is a reliable indicator of hepatic toxicity and loss of hepatic function (Levin and Schwartz 1965).…”
Section: Bilirubin/bile Acidsmentioning
confidence: 99%