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Pharmacokinetics and Pharmacogenomics of Once-Daily Raltegravir and Atazanavir in Healthy Volunteers
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Antimicrob. Agents Chemother. 2010,


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 Ctau, 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 Ctau, area under the concentration-time curve from 0 to 12 h (AUC0-12), and raltegravir-glucuronide/raltegravir AUC0-12 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 reduction-of-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 Ctau with a once-daily raltegravir dose of 400 mg similar to the Ctau 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+ cell counts of >250 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 reduce the dose.

Raltegravir was approved by the FDA in October 2007. It is the first-in-class and, currently, sole FDA-approved inhibitor of viral integrase, an HIV-1-specific enzyme that is required for viral replication (9). Inhibition of integrase prevents the insertion of linear HIV-1 DNA into the host cell genome, a critical step in the life cycle of the virus. Raltegravir is primarily metabolized by UDP-glucuronosyl transferase 1A1 (UGT1A1) and not by the P450 cytochromes.

Atazanavir-mediated inhibition of UGT1A1, which also conjugates bilirubin, results in mild hyperbilirubinemia in most patients treated with atazanavir. When given as a single dose in addition to a steady-state regimen of atazanavir 400 mg daily in healthy volunteers, the maximum concentration (Cmax), 12-h postdose concentration (C12), and area under the time-concentration curve (AUC) of raltegravir were 53%, 95%, and 72% higher, respectively, than when raltegravir was given alone (11). With ritonavir-boosted atazanavir, these metrics were 10 to 20% lower, which is not surprising given the ability of ritonavir to induce drug-metabolizing enzymes, including glucuronyl transferase, in addition to its inhibitory effect on cytochrome P450 2D6 (CYP2D6), CYP3A4, or P-glycoprotein (6).

The combination of raltegravir and atazanavir has potential as an initial or salvage regimen. Both drugs are potent inhibitors of HIV-1 replication, have minimal impact on the lipid profile, are generally well tolerated, and do not require refrigeration. We hypothesized that at steady state, boosting of raltegravir plasma concentrations by atazanavir would be sufficient to permit a reduced daily dose of raltegravir by eliminating one of the two doses in the standard regimen of 400 mg twice daily. Such a dosing regimen could lower the cost of raltegravir and increase the feasibility of combination with atazanavir, which is routinely dosed once daily. We also hypothesized that the UGT1A1 genotype may influence the magnitude of a raltegravir-atazanavir interaction.

(Data from the investigation were presented in part at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Cape Town, South Africa, July 2009.)


In this healthy adult volunteer population, despite reduced formation of plasma raltegravir-glucuronide, there were only small (and nonsignificant) increases in raltegravir plasma concentrations when raltegravir was dosed once daily with atazanavir. We found that the degree of raltegravir boosting in plasma by atazanavir was insufficient to ensure that raltegravir 400 mg once daily would result in concentrations at the end of the dosing interval that would be at least similar to those with current standard dosing. Overall, at steady state, the boosting effect of atazanavir (without ritonavir) on raltegravir was less than in a previously reported single-dose study (11).

Does the lack of boosting by atazanavir mean that once-daily raltegravir dosing is out of the question? We do not believe that our data force this conclusion, for three reasons. The first reason is that a minimally effective plasma concentration relative to in vitro viral susceptibility has not been established for raltegravir. In early dose-ranging studies, 100 mg twice daily in treatment-naïve patients had the same 48-week virologic and immunologic efficacy as doses up to 600 mg twice daily (15). In triple-class experienced patients, the 24-week virologic efficacy was the same in the 200-mg twice-daily group as in the 600-mg twice-daily group, although the CD4 cell count gains in the 200-mg group were less than in the other groups (7).

The second reason to consider once-daily raltegravir dosing as a still-viable strategy is the persistent binding of the drug to its intracellular target, the preintegration complex. Although there are as yet few published data on the intracellular pharmacokinetics of raltegravir, it is known in vitro to disassociate from the preintegration complex with a half-time that is longer than the half-time of the complex itself, effectively making the binding irreversible (9). This may be analogous to zidovudine: recognition that the active moiety had a prolonged intracellular half-life enabled a decrease in dosing frequency from five times to twice daily (20). We did not measure intracellular concentrations in this study.

The third reason that we cannot exclude the possibility of 400-mg once-daily dosing is simply that this was a healthy-volunteer study that cannot provide any efficacy data. Without a clearly defined pharmacokinetic-pharmacodynamic target, extrapolation to an effect in HIV-infected patients is impossible.

Although 400-mg once-daily raltegravir (50% of the currently recommended dose for both naïve and experienced patients) is attractive from cost and adherence perspectives, and despite the previous arguments, data from this study nonetheless highlight concerns with this dosing strategy. First, as is obvious from the results in Fig. 1 and the wide concentration ranges shown in Table 2, absorption of this drug is clearly erratic, even in the relatively controlled circumstances of this clinical study, and this raises the worrisome possibility that some patients with once-daily dosing may have particularly low concentrations, which may compromise efficacy if and when a concentration-response relationship can be described.

Second, our overall observed plasma concentrations were lower than those reported by the manufacturer in phase I studies of the same dose in young, healthy, adult participants. The AUC from 0 to 12 h (AUC0-12) for arm A was only 31% (10) or 46% (11) of the reported AUC0-12, depending on the study. However, our AUC0-12 is very similar to that found in other pharmacokinetic studies that included a group receiving raltegravir 400 mg twice daily (2, 12, 13, 19). Despite the lack of food-drug interaction reported in the package insert (, food has subsequently been shown to have a major effect on the absorption profile (18), and this may have caused the diminished concentrations relative to the more stringent fasting conditions in the manufacturer's studies, since participants in our study were allowed to eat 1 h after a dose. These lower concentrations cause one to question what concentrations were achieved in the large phase III efficacy studies, with less regulation of food intake, since none have actually reported raltegravir concentrations in participants with or without virologic suppression.

Our data suggested a circadian rhythm to raltegravir pharmacokinetics, evidenced by the arm A morning raltegravir trough concentration that was 5-fold higher than in the evening. We are the first to report this, but careful inspection of the previous pharmacokinetic study (see their Fig. 1B, inset) with atazanavir from the manufacturer shows a 3-fold higher morning trough compared to the evening trough (11). In our study, when dosed once daily, this trough-to-trough variation was not noted. Because of the similar rate of raltegravir decline in both arms, as shown in Fig. 1, this circadian rhythm is likely due to differential absorption patterns of morning versus evening doses. However, without overnight data, we are unable to verify this hypothesis. The significance is that one should use caution if extrapolating 12-h to 24-h raltegravir exposures for a regimen with two daily doses.

Especially when one considers the recent, disappointing results of the SWITCHMRK study, in which treatment-experienced, virologically suppressed patients who switched their boosted lopinavir to raltegravir were more likely to lose virologic control than those who continued lopinavir (4), it would seem that if a once-daily 400-mg raltegravir strategy were to have any application, efficacy from the ongoing 800-mg once-daily study ( must first be demonstrated and the relationship of plasma and/or intracellular raltegravir concentrations to efficacy should be established.

UGT1A1 genetic variants, while common even in this small population, did not significantly influence the degree of raltegravir glucuronidation or raltegravir plasma exposure. This is in contrast to the modest effect on plasma exposure demonstrated in a previous study (21). It is likely that the high degree of variability in raltegravir plasma concentrations in our study obscured any pharmacogenomic effects on either overall raltegravir exposure or the degree of glucuronidation. Furthermore, only one of the 19 patients with genomic and pharmacokinetic data had a homozygous reduced-function diplotype (*28/*28). Lastly, it is possible that there were polymorphisms in other regions of the gene that we did not sequence but that are associated with changes in function (e.g., *6 and *60) (1). However, these are present at a much lower frequency in the racial/ethnic groups in this study (1, 14) and, therefore, would be unlikely to contribute significantly to the substantial observed variation in raltegravir pharmacokinetics.

In summary, although atazanavir reduced the formation of the glucuronide metabolite, its steady-state boosting did not render a once-daily raltegravir dose of 400 mg pharmacokinetically similar to the standard twice-daily dose in terms of the concentration at the end of the dosing interval. Conversely, the observed concentrations of atazanavir when dosed with raltegravir were similar to those in the package insert, when adjusted for fed state, indicating that raltegravir did not influence the pharmacokinetics of atazanavir. As the relationship between raltegravir plasma exposure and efficacy is unclear, there may still be a rationale to test a simpler and cheaper single 400-mg daily dose of raltegravir, but because of highly variable interindividual plasma concentrations, it should be tested in a pilot study that includes measurement of extra- and intracellular drug concentrations. Atazanavir in such a trial would appear to add no pharmacological benefit. Results from the ongoing study of 800 mg once daily and better characterization of the relationship between plasma/intracellular concentrations and efficacy are crucial prerequisites of any study of reduced-dose raltegravir.

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