Important note: Information in this article was accurate in March 2007. The state of the art may have changed since the publication date.
Recent reviews from HIV-druginteractions.org
HIV Treatment Bulletin - Vol. 8, No. 11&12, November/December 2007
The effect of lopinavir/r on the renal clearance of tenofovir
The findings of this study add weight to an underlying concern of an association between tenofovir-induced nephrotoxicity and concomitant boosted protease inhibitor treatment.
After adjusting for renal function, tenofovir renal clearance was 17.5% slower in HIV+ patients taking lopinavir/ritonavir versus those not taking a protease inhibitor; this is consistent with a renal interaction between the drugs. Additional studies are required to determine the exact mechanism of the interaction with the most obvious focus being on renal transporters.
Here the authors have shown that tenofovir renal clearance was 15% lower in ABCC4 3463G variants compared with wild type and this decreased renal clearance translates into a 32% increased AUC in the subjects with the variant ABCC4. However the authors clearly point out that this was a small cohort of patients and the evaluation of the relationship between genotype and phenotype was retrospective.
A prospective study will be necessary to fully evaluate the contribution of genetics to tenofovir disposition. Also, since the basis of nephrotoxicity is likely to be multifactorial the drug interaction described may just be one factor and prospective studies are clearly needed to identify patients at risk. Drug Interactions Lopinavir/ritonavir and tenofovir
Ref: Kiser JJ, Carten ML, Aquilante CL, et al. The effect of lopinavir/ritonavir on the renal clearance of tenofovir in HIV-infected patients. Clin Pharmacol Ther, 2007, (e-pub ahead of print).
T-20 increases tipranavir levels but not hepatotoxicity
In 2006, Gonzalez de Requena et al. reported an unexpected drug interaction between tipranavir/ritonavir and enfuvirtide (AIDS, 2006, 20:1977-1979).
The present paper documents a sub-analysis from RESIST and shows that among 661 patients for whom tipranavir Cmin data were available, tipranavir/ritonavir/enfuvirtide patients had a 31% higher median tipranavir Cmin than patients not on enfuvirtide. Of importance, higher median lopinavir (+19%) and saquinavir (+39%) Cmin values were also observed in lopinavir/ritonavir/enfuvirtide and saquinavir/ritonavir/enfuvirtide recipients compared with lopinavir/ritonavir or saquinavir/ritonavir without enfuvirtide.
The authors make several important points. First, the observed increase in Cmin among RESIST patients receiving enfuvirtide was not associated with increased risk of hepatotoxicity. Secondly, the authors discourage any recommendation to change tipranavir or ritonavir dosing in patients receiving enfuvirtide. Finally, the mechanism of the interaction is unknown. Drug Interactions - Enfuvirtide (T20) and boosted PIs
Ref: Raffi F, Battegay M, Rusconi S, et al. Combined tipranavir and enfuvirtide use associated with higher plasma tipranavir concentrations but not with increased hepatotoxicity: sub-analysis from RESIST. AIDS, 2007, 21(14): 1977-1980.
Atazanavir, with or without ritonavir, may increase buprenorphine and buprenorphine metabolites, requiring dose adjustment
This study examined the interaction between buprenorphine and atazanavir (400 mg once daily) or atazanavir/ritonavir (300/100 mg once daily) in opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per group) to determine effects of buprenorphine. Objective opiate withdrawal scale scores and mini-mental state examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects.
When coadministered with atazanavir, buprenorphine AUC increased from 39.5 to 76.3 ng.h/ml; a similar increase was observed when coadministered with atazanavir/ritonavir (46.2 to 77.0 ng.h/ml). Concentrations of norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronide also increased with both atazanavir and atazanavir/ritonavir. The likely complex mechanism is discussed. Buprenorphine did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir.
Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose. Drug Interactions - Buprenorphine and atazanavir (with and without ritonavir)
Ref: McCance-Katz EF, Moody DE, Morse GD et al. Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend, 2007, 91(2-3): 269-278.
Acid reducing agents and protese inhibitors
There have been two publications in October’s HIV Medicine on this important topic.
Beique et al have provided a systematic review of all the available pharmacokinetic and clinical data on drug interactions between protease inhibitors and acid-reducing agents and their clinical consequences. The table documenting the interactions is a particularly valuable resource. [1]
However, new data are constantly emerging and Luber et al have documented their findings on once daily fosamprenavir/ritonavir and atazanavir/ritonavir alone and in combination with 20 mg omeprazole in healthy volunteers.
This paper is an update of reference 12 cited by Beique et al – data initially presented at the Lisbon HIV Pharmacology Workshop in 2006. The major findings were:
References
1. Beique L, Giguere P, la Porte C, Angel J. Interactions between protease inhibitors and acid-reducing agents: a systematic review. HIV Med, 2007, 8(6):335-345.
2. Luber A, Brower R, Kim D, et al. Steady-state pharmacokinetics of once-daily fosamprenavir/ritonavir and atazanavir/ritonavir alone and in combination with 20 mg omeprazole in healthy volunteers. HIV Med, 2007, 8(7):457-464.
2008-11-01
IB070811-18
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