Coinfection

ICAAC 2011: HCV Drug Telaprevir Shows No Problematic Interactions with Raltegravir

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The new hepatitis C virus (HCV) protease inhibitor telaprevir (Incivek) does not appear to have clinically relevant drug-drug interactions with the HIV integrase inhibitor raltegravir (Isentress), according to a study presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011) last month in Chicago.

An estimated one-third of people with HIV are coinfected with HIV. Coinfection is associated with faster liver disease progression and poorer response to interferon-based hepatitis C therapy. This population is in need of better treatment options, but faces added challenges related to drug interactions and additive side effects with antiretroviral therapy (ART).

Telaprevir is currently being studied in HIV/HCV coinfected patients; preliminary promising results were presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2011) this past March.

In that study participants could use ART regimens containing either efavirenz (Sustiva) or atazanavir (Reyataz) plus tenofovir (Viread, also in the Truvada and Atripla coformulations) and emtricitabine (Emtriva) or lamivudine (3TC; Epivir). These drugs were chosen based on studies in healthy volunteers indicating minimal or manageable interactions with telaprevir.

In the study presented at ICAAC, the Tibotec/Vertex research team looked at interactions between telaprevir and raltegravir, again in healthy volunteers with neither HIV nor HCV.

Telaprevir is a substrate and inhibitor of the CYP3A liver enzyme and P-glycoprotein (P-gp), which play a role in drug metabolism, the investigators noted as background. This could potentially raise or lower concentrations of telaprevir and concurrently administered agents. Raltegravir is not metabolized via CYP3A, but it is a P-gp substrate and is glucuronidated, or metabolized to raltegravir-glucuronide, by the UGT1A1 enzyme.

This open-label cross-over study included 20 HIV and HCV negative volunteers; all were men, about 65% were black, and the median age was 37 years. Participants were randomly assigned to receive 2 treatments separated by at least 14 days, all with food:

  • 750 mg telaprevir every 8 hours as monotherapy for 6 days, with a morning dose on day 7;
  • 400 mg raltegravir twice-daily as monotherapy for 4 days, immediately followed by co-administration of raltegravir plus 750 mg telaprevir every 8 hours for 6 days, followed by a morning dose of raltegravir and morning and afternoon doses of telaprevir on day 11.

Results

  • Co-administration of raltegravir did not influence telaprevir exposure or pharmacokinetics.
  • The least square means ratios for telaprevir minimum concentration (Cmin), maximum concentration (Cmax), and area under the curve (AUC8h) were 1.14, 1.07, and 1.07, respectively.
  • Co-administration of telaprevir increased exposure to raltegravir by 31%.
  • The least square means ratios for raltegravir Cmin, Cmax, and AUC12h were 1.78, 1.26, and 1.31, respectively.
  • Exposure to the raltegravir-glucuronide metabolite increased similarly, by 37%.
  • The least square means ratio for the AUC ratio of raltegravir-glucuronide to raltegravir was 1.05.
  • The 2 drugs were generally well-tolerated.
  • All adverse events were mild-to-moderate (grade 1-2) and no participants discontinued early due to adverse events.

"Co-administration of raltegravir did not affect telaprevir," the researchers concluded. "Exposure to raltegravir was increased by 31% during co-administration of telaprevir, possibly due to inhibition of intestinal P-gp by telaprevir."

Telaprevir did not influence UGT1A1 activity, they continued, as indicated by the similar AUC ratio of raltegravir-glucuronide to raltegravir with or without co-administration of telaprevir.

Overall, "the effect of telaprevir on raltegravir was not considered to be clinically relevant," they summarized, indicating that no dose adjustment of either drug will be necessary.

Taken together with the studies presented at CROI, telaprevir appears to have no problematic interactions with an HIV protease inhibitor, a non-nucleoside reverse transcriptase inhibitor (NNRTI), and now an integrase inhibitor, giving coinfected patients a range of antiretroviral choices while undergoing hepatitis C treatment with telaprevir.

Investigator affiliations: Tibotec BVBA, Beerse, Belgium; Vertex Pharmaceuticals Inc., Cambridge, MA; Tibotec Inc., Titusville, NJ.

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Reference

R. Van Heeswijk, V. Garg, G. Boogaerts, et al. The Pharmacokinetic Interaction between Telaprevir and Raltegravir in Healthy Volunteers. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011). Chicago, September 17-20, 2011. Abstract A1-1738a.