Drug-drug interactions

Jennifer J. Kiser, Courtney V. Fletcher, for NATAP.org

Rifampin interactions with saquinavir/r and lopinavir/r

Previous studies have shown significant hepatotoxicity in healthy volunteers receiving rifampin in combination with saquinavir/ritonavir [1] and lopinavir/ritonavir [2]. At this years Workshop, a study detailing adverse events in HIV negative volunteers receiving the combination of rifampin and lopinavir/ritonavir was presented. [3]

Volunteers received 600 mg of rifampin daily for 5 days; then either 600/150 mg or 800/200 mg of lopinavir/ritonavir was added to the rifampin. By the second day of the combination, 10/11 subjects suffered nausea and vomiting and all 11 had liver enzyme elevations and thus the study was terminated. Liver enzyme elevations peaked 2-3 days after discontinuing the combination (n=2 with grade 2, n=9 with grade 4 elevations). Liver enzymes returned to normal in all subjects during follow up and there were no signs of clinical hepatotoxicity.

The mechanism(s) for the development of severe hepatotoxicity with the combination of rifampin plus saquinavir/ritonavir or lopinavir/ritonavir in healthy volunteers is unclear. There remains a real unmet need for effective strategies for concomitant treatment of tuberculosis and HIV, and in particular whether rifampin can be given with any ritonavir-boosted protease inhibitor.

This latter question needs to be addressed in healthy volunteer studies because of the risk of suboptimal protease inhibitor concentrations; however, it is clear that the combination of ritonavir-boosted protease inhibitors and rifampin may pose significant risks to these subjects and a high degree of caution is warranted for any future studies.

Tipranavir pharmacokinetics

A phenotyping cocktail study was conducted to evaluate the in vivo effects of tipranavir on various cytochrome (CYP) P450 enzymes. [4]

Sixteen HIV negative volunteers were given single doses of caffeine (CYP1A2 probe), warfarin (CYP2C9 probe), and dextromethorphan (CYP2D6 probe) at baseline and 10 hours after a first dose and a steady-state dose of tipranavir/ritonavir 500/200 mg twice daily.

At steady state, tipranavir/ritonavir was found to induce CYP1A2 and CYP2C9 because the ratios of caffeine and warfarin AUCs at steady state tipranavir/ritonavir vs. baseline were 0.57 and 0.88, respectively. The ratio of dextromethorphan AUC at steady state tipranavir/ritonavir vs. baseline was 6.24 suggesting tipranavir/ritonavir is a potent inhibitor of CYP2D6.

Data presented by the same group at the 2007 CROI demonstrated that tipranavir/ritonavir is a potent intestinal CYP3A inhibitor and has modest effects on P-glycoprotein [5].

Collectively, these data provide some insight into the complex mechanisms of previously identified interactions with tipranavir/ritonavir including the ability to inhibit and induce different drug elimination pathways simultaneously, and may assist in prediction of other interactions with this compound. Enzyme and transporter phenotyping studies are emerging as a new tool to aid in the prediction of drug-drug interactions. At this time, the greatest benefit of probe studies appears to be in identifying potential drug interactions that do not need further clinical evaluation.

Tadalafil dose adjustments with tipranavir/r

The Department of Health and Human Services Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents recommends starting with a 5 mg dose of tadalafil (not to exceed 10 mg in a 72 hour period) for the treatment of erectile dysfunction in persons with HIV on a protease inhibitor.

The results of an HIV negative volunteer study presented at the Workshop suggest that this lower 5 mg dose of tadalafil only needs to be used during the first few days of initiating a tipranavir/ritonavir-based regimen, but after 7-10 days on tipranavir/ritonavir, no tadalafil dose adjustment is necessary. [6]

Unexpected interaction between darunavir/r and pravastatin

Pravastatin is one of the most widely used HMG-CoA reductase inhibitors in persons with HIV because of its low propensity for CYP-mediated drug interactions. However, Vanitha Sekar presented data on an unexpected interaction between darunavir/ritonavir and pravastatin in 14 HIV negative volunteers. [7]

In this study, pravastatin AUC and Cmax were increased 81% and 63%, respectively (on average) when combined with darunavir/ritonavir 600/100 mg twice daily. Interestingly, there was substantial interindividual variability in the magnitude of this interaction, with not all volunteers having an increase in pravastatin exposure with the addition of darunavir/ritonavir and others having up to a 3 to 10 fold increase.

The mechanism for this interaction is speculative, but is likely mediated by darunavir and/or ritonavirs inhibition of organic anion transporting polypeptide 1B1 (OATP1B1) located on the basolateral side of the hepatocyte. Pravastatin is a high affinity substrate for OATP1B1. A previously presented study identified a similar unexpected interaction between another OATP1B1 substrate, rosuvastatin, and lopinavir/ritonavir. [8]

A study is ongoing to elucidate the purported mechanism for the interaction between darunavir/ritonavir and pravastatin. Clinicians may wish to avoid the combination of darunavir/ritonavir and pravastatin until more data are available.

References

Unless stated otherwise, abstract references are to the Programme and Abstracts of the International Workshop on clinical Pharmacology of HIV Therapy, 16-18 April 2007 Budapest Hungary.

Schutz M. 6th International Workshop on Clinical Pharmacology of HIV Therapy, 2005, abstract 35.
La Porte CJL. AAC 2004;48(5):1553-1560.
Nijland H et al. Unexpected high incidence of nausea, vomiting and asymptomatic elevations of AST/ALT enzymes in healthy volunteers receiving rifampin + adjusted doses of lopinavir/ritonavir tablets. Abstract 51.
Vourvahis M et al. Effects f tipranavir/ritonavir (TPV/r) on the activity of cytochrome p450 (CYP) enzymes 1A2, 2C9 and 2D6 in healthy volunteers. Abstract 52.
Vourvahis M et al. 14th CROI, 2007. Abstract 563.
Durant J et al. The effect og tipranavir/ritonavir (TPV/r) on the pharmacokinetics of tadalafil in healthy volunteers. Abstract 61.
Seker VJ et al. Pharmacokinetic drug-drug interaction between the new HIV protease inhibitor darunavir (TMC-114) and the lipid lowering agent pravastatin. Abstract 54.
Hoody DW et al. 14th CROI, 2007. Abstract 564.