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-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods. UGT1A1 promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir C tau , or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval, P value) for plasma raltegravir C tau , area under the concentration-time curve from 0 to 12 h (AUC 0-12 ), and raltegravirglucuronide/raltegravir AUC 0-12 were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a UGT1A1 reductionof-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the C tau with a once-daily raltegravir dose of 400 mg similar to the C tau with the standard twice-daily dose. UGT1A1 promoter variants did not significantly influence this interaction.In 2007, 4 million HIV-infected patients were taking antiretroviral medications in countries with low to middle income levels, according to the World Health Organization (WHO) (24). According to the 2009 update (23) of the WHO treatment guidelines (22), recommended first-line therapies should include two nucleoside reverse transcriptase inhibitors (NRTI) and either efavirenz or nevirapine. However, efavirenz is classified by the United States Food and Drug Administration (FDA) as a "D" drug during pregnancy, due to teratogenic potential demonstrated in monkeys and in retrospective human data, which means it is not recommended for women of child-bearing age who cannot practice reliable contraception. Nevirapine has a "black box" warning advising of increased risk of severe or fatal hepatotoxicity if used in women with CD4 ϩ cell counts of Ͼ250 cells/ml. Therefore, there is room for additional first line and even salvage agents that are potentially affordable, safe, well-tolerated, and independent of current, widely used first-or second-line therapies. Raltegravir could be one of these new drugs, but its high cost, which is prohibitive for most of the world's HIV-infected patients (16), warrants investigation into strategies, such as boosting, to redu...

Pharmacokinetics of and Short-Term Virologic Response to Low-Dose 400-Milligram Once-Daily Raltegravir Maintenance Therapy

“…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).…”

Population Pharmacokinetic Analysis and Pharmacogenetics of Raltegravir in HIV-Positive and Healthy Individuals

“…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.…”

“…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).…”

Liver Hypertrophy

“…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).…”