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Higher Atazanavir Levels Sync With Higher Raltegravir Levels in Dual Combo
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11th International Workshop on Clinical Pharmacology and HIV Therapy, April 7-9, 2010, Sorrento
Mark Mascolini
Higher area under the curve (AUC) and trough levels of the protease inhibitor atazanavir--unboosted by ritonavir--correlated with higher concentrations of the integrase inhibitor raltegravir in HIV-infected adults taking these two antiretrovirals with no others [1]. But pharmacokinetic interactions between unboosted atazanavir and raltegravir were complex in this 22-person study.
Raltegravir metabolism depends on glucuronidation mediated by the uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) isoenzyme, and atazanavir strongly inhibits UGT1A1. In healthy volunteers without HIV infection, atazanavir raised raltegravir levels about 50% [2], but pharmacokinetics in people with HIV do not always mirror those in people without HIV. Raltegravir plus unboosted atazanavir has attracted attention as a potential nucleoside-sparing combination [3-5] because the drugs are potent, have relatively good safety profiles, and inhibit HIV at different steps of the viral life cycle.
To gauge the impact of unboosted atazanavir on raltegravir levels in HIV-infected people, researchers in Milan and Bergamo measured steady-state raltegravir concentrations in 22 adults with no documented resistance to PIs who might benefit from a switch to atazanavir plus raltegravir. Study participants took 400 mg of raltegravir twice daily and 300 mg of atazanavir twice daily at the same time with food. The investigators conducted intensive sampling at least 14 days after the switch to atazanavir/raltegravir. They compared raltegravir results with levels measured in HIV-infected people who took raltegravir alone for 10 days in an earlier study [6].
Of the 22 study participants, 18 were white and 16 were men. Their age averaged 45 years (+/- 6.7 standard deviation), and their body mass index averaged 24 kg/m(2) (+/- 5). Their median CD4 count stood at 550, and they had normal creatinine, lipids, and liver enzymes. Two people had raltegravir 0-to-12-hour AUC readings (AUC0-12h) above 35,000 ng x h/mL, and the investigators excluded them from the analysis.
Daily raltegravir concentration profiles were unusual, showing multiple peaks over 12 hours, limited absorption, and polymodal distribution. Raltegravir geometric mean AUC0-12h in study participants (6166 ng x h/mL, 90% confidence interval [CI] 2772 to 15,615) was equivalent to the AUC0-12h in historical controls [6] infected with HIV and taking only raltegravir (6851 ng x h/mL, 90% CI 3667 to 12,835). Maximum concentration and 12-hour (trough) concentration were also similar in study participants and historical controls.
Atazanavir geometric mean AUC0-12h (14,622 ng x h/mL, 90% CI 4052 to 45,707) varied widely in study participants (coefficient of variation 68.3%). The investigators proposed that this variability may have "diluted" atazanavir's effect on raltegravir metabolism.
Using linear regression analysis, the Milan/Bergamo team found a significant correlation between raltegravir and atazanavir AUC0-12h (r = 0.611, P < 0.001). People with an atazanavir AUC0-12h above 14,621 ng x h/mL had a raltegravir AUC twice higher than people with lower atazanavir exposure (raltegravir geometric mean AUC0-12h 8736 versus 4027 ng x h/mL, P = 0.021). Higher atazanavir troughs also meant higher raltegravir troughs (r = 0.452, P = 0.039).
The investigators asked whether trough-based monitoring is adequate to reflect the AUC interactions between atazanavir and raltegravir. They found that atazanavir troughs correlated tightly with atazanavir AUC at every sampling point (r = 0.906). The overall correlation was not as strong between raltegravir troughs and raltegravir AUC (r = 0.467), but the correlation tightened starting with samples collected 2 hours after dosing (r = 0.837).
The Milan/Bergamo researchers concluded that the pharmacokinetics of raltegravir given with unboosted atazanavir twice daily are "extremely variable and complex." This study in people with HIV did not confirm results of in vitro studies of raltegravir and atazanavir or results of studies in healthy volunteers. That "apparent discrepancy," the researchers proposed, "may be attributed to the great variability in the exposure of patients to atazanavir, eventually diluting the contribution of atazanavir to raltegravir metabolism."
But the study did find a positive linear correlation between atazanavir AUC0-12h and raltegravir AUC0-12h. In routine practice, the investigators suggested, trough concentrations will be a reliable predictor of daily atazanavir exposure in people taking the two drugs at these doses. But raltegravir samples used to predict raltegravir AUC should probably be collected 3 or 4 hours after dosing.
References
1. Cattaneo D, Ripamonti D, Baldelli S, Cozzi V, Conti F, Clementi E. Exposure-related effects of unboosted atazanavir on the pharmacokinetics of raltegravir in HIV-1 infected patients. 11th International Workshop on Clinical Pharmacology and HIV Therapy. April 7-9, 2010. Sorrento. Abstract 49.
2. Iwamoto M, Wenning LA, Mistry GC, et al. Atazanavir modestly increases plasma levels of raltegravir in healthy subjects. Clin Infect Dis. 2008;47:137-140.
3. Gupta S, Lataillade M, Farber S, Kozal MJ. Raltegravir with unboosted atazanavir 300 mg twice daily in antiretroviral treatment-experienced participants. J Int Assoc Physicians AIDS Care (Chic Ill). 2009;8:87-92.
4. Ripamonti D, Maggiolo F, Bombana E, et al. Efficacy, safety and tolerability of dual therapy with raltegravir and atazanavir in antiretroviral experienced patients. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract MOPEB067. http://www.ias2009.org/pag/PDF/2116.pdf.
5. Ruane PJ, Alas B. Dual maintenance therapy with raltegravir bid with atazanavir qd in patients with no prior PI resistance and intolerance to other ARV regimens: preliminary report. 49th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy). September 12-15, 2009. San Francisco. Abstract H-914. http://www.natap.org/2009/ICCAC/ICCAC_30.htm.
6. Markowitz M, Morales-Ramirez JO, Nguyen BY, et al. Antiretroviral activity, pharmacokinetics, and tolerability of MK-0518, a novel inhibitor of HIV-1 integrase, dosed as monotherapy for 10 days in treatment-naive HIV-1-infected individuals. JAIDS. 2006;43:509-15. Erratum in JAIDS. 2007;44:492.
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