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10/03/2012
CROI: Interactions between HCV drug daclatasvir and HIV antiretrovirals are minimal or manageable

One factor that delays studies of new agents in the coinfected population is concern that drugs for the 2 diseases might interact.

The investigational hepatitis C virus (HCV) NS5A inhibitor daclatasvir (formerly BMS-790052) showed no clinically relevant effects on blood levels of 3 classes of antiretroviral agents, and changes in daclatasvir levels can likely be overcome by dose adjustment, according to a data presented at the 19th Conference on Retroviruses and Opportunistic Infections (CROI 2012) in Seattle.



Direct-acting antivirals (DAAs) for hepatitis C have ushered in a new era of treatment. The 2 HCV protease inhibitors approved so far -- boceprevir (Victrelis) and telaprevir (Incivek) -- are indicated only for HIV negative people, but HIV/HCV coinfected patients also urgently need better treatment options and clinicians may treat them off-label.



One factor that delays studies of new agents in the coinfected population is concern that drugs for the 2 diseases might interact. Some drugs can raise or lower levels of other agents metabolized by the same pathways; this can lead to elevated drug levels that cause intensified side effects, or conversely, reduced levels that risk viral breakthrough and treatment failure.



To minimize this risk, community treatment advocates have urged pharmaceutical companies to perform relevant drug-drug interaction studies in the laboratory and in healthy volunteers before moving into clinical trials of coinfected patients.



As reported at CROI, researchers at Bristol-Myers Squibb (BMS) conducted drug-drug interaction studies in healthy volunteers, looking for interactions between daclatasvir and antiretrovirals from 3 classes:



  • Atazanavir (Reyataz) used with a boosting dose of ritonavir, both HIV protease inhibitors (Study AI444032);


  • Efavirenz (Sustiva), a non-nucleoside reverse transcriptase inhibitor (NNRTI) (Study AI444034);


  • Tenofovir disiproxil fumarate (Viread, also in the Truvada and Atripla coformulations), a nucleotide reverse transcriptase inhibitor (Study AI444033).




Daclatasvir is a substrate and inhibitor of P-gp and a substrate of CYP3A4 -- 2 common drug processing pathways -- suggesting that it may interact with several antiretroviral agents.



The BMS investigators conducted 3 open-label pharmacokinetic (PK) studies in which healthy volunteers received daclatasvir with one of the antiretrovirals. Participants in the atazanavir (n=14) and efavirenz (n=15) studies first received 60 mg daclatasvir once-daily for 4 days, followed by a combination of daclatasvir plus their respective antiretroviral for up to 18 days. In the tenofovir study, 20 participants took 60 mg once-daily daclatasvir, 300 mg once-daily tenofovir, or both, for 7 days in a cross-over design.



Results



  • Levels of both atazanavir/ritonavir and efavirenz did not change significantly when co-administered with daclatasvir.


  • Daclatasvir AUC (area under the curve, a measure of total drug exposure) was 110% higher and Cmax (maximum concentration) was 35% higher when given with atazanavir/ritonavir.


  • Daclatasvir AUC was 32% lower and Cmax was 67% lower when administered with efavirenz.


  • Levels of both daclatasvir and tenofovir remained within expected ranges when administered together.


  • Daclatasvir was generally well-tolerated with all 3 antiretroviral drugs, and no serious adverse events occurred in any of the studies.




Based on these findings, the investigators concluded that "no clinically relevant drug-drug interactions" occurred between daclatasvir and tenofovir. Daclatasvir likewise "did not appear to have any clinically significant effects" on efavirenz or atazanavir/ritonavir levels.



However, daclatasvir levels were altered when co-administered with atazanavir/ritonavir or efavirenz. The researchers calculated that lowering the daclatasvir dose to 30 mg once-daily when given with atazanavir/ritonavir, or raising it to 90 mg once-daily when used with efavirenz, "are expected to provide daclatasvir exposure similar to that for 60 mg daclatasvir administered alone."



A Phase 3 clinical trial of daclatasvir plus pegyalted interferon/ribavirin for HIV/HCV coinfected patients is currently enrolling (www.clinicaltrials.gov/ct2/show/NCT01471574).



BMS has made these findings freely available on its company website at http://www.bms.com/research/investigational/hepatitis/Pages/DCV-BMS-790052.aspx.



By Liz Highleyman



Reference



M Bifano, C Hwang, B Oosterhuis, et al. Assessment of HIV ARV Drug Interactions with the HCV NS5A Replication Complex Inhibitor BMS-790052 Demonstrates a Pharmacokinetic Profile which Supports Co-administration with Tenofovir Disoproxil Fumarate, Efavirenz, and Atazanavir/ritonavir. 19th Conference on Retroviruses and Opportunistic Infections. Seattle, March 5-8, 2012. Abstract 618.



Other Source



Bristol-Myers Squibb. Bristol-Myers Squibb Posts Data Update on Daclatasvir, an NS5A Inhibitor in Phase III Development for the Treatment of Hepatitis C. Press release. March 8, 2012.