Darunavir/cobicistat once daily for the treatment of HIV

Abstract

A current focus in HIV management is improving adherence by minimizing pill burden with convenient formulations, including fixed-dose combinations (FDCs). Darunavir, a HIV protease inhibitor, co-administered with low-dose ritonavir (800/100 mg once daily), is recommended in guidelines in combination with other antiretrovirals for HIV patients with no darunavir resistance-associated mutations. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels of darunavir among other antiretrovirals. Cobicistat is a more specific cytochrome P450 3A inhibitor than ritonavir without enzyme-inducing properties. This review describes the differing effects of cobicistat and ritonavir on metabolic enzymes, which explains their differing drug–drug interactions, and summarizes some of the studied drug–drug interactions for cobicistat. It also outlines the clinical development and data for a once-daily darunavir/cobicistat FDC. This FDC thus allows for a once-daily treatment regimen (including background antiretrovirals) with reduced pill burden.

Keywords:

• cobicistat
• darunavir
• drug–drug interactions
• efficacy
• fixed-dose combination
• HIV
• pharmacokinetics
• ritonavir
• safety

Acknowledgements

The authors are grateful to members of the Janssen team, in particular D Anderson, B Baugh and J Mrus, and M Fordyce from Gilead for their input. The authors thank C Whittaker, at Gardiner-Caldwell Communications, an Ashfield company, Macclesfield, UK, and Julia Woodman, who assessed the searches, reviewed the material and prepared the outline, and also P Matthews, and I Woolveridge, who prepared the first daft and incorporated author comments, both at Gardiner Caldwell Communications; this support was funded by Janssen Pharmaceuticals. The article was invited by the journal. All authors are employees of Janssen Pharmaceuticals.

Financial & competing interests disclosure

All authors are employees of Janssen Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. C Whittaker, Gardiner-Caldwell Communications, part of the KnowledgePoint360 Group, an Ashfield company and J Woodman, Freelancer writer both assessed the searches, reviewed the material and prepared the outline. P Matthews and I Woolveridge, Gardiner-Caldwell Communications, part of the KnowledgePoint360 Group, an Ashfield company prepared the first daft and incorporated author comments.

Key issues

• Certain HIV drugs, including darunavir, require boosting by a pharmacokinetic enhancer such as ritonavir.

• Ritonavir has been used for many years, but its potential for drug–drug interactions, plus its potential impact on lipid metabolism in the long term, needs to be managed.

• Cobicistat is a new pharmacokinetic enhancer that is a more selective inhibitor of CYP3A than ritonavir, and without enzyme-inducing properties.

• A fixed-dose combinations (FDC) of darunavir/cobicistat will provide patients with the convenience of taking one less tablet.

• Phase I studies in healthy volunteers demonstrated:

• Comparable darunavir bioavailability following darunavir 800 mg once daily co-administered with cobicistat 150 mg once daily, either as single agents (GS-US-216-0115 [49]) or as two prototype FDC formulations (G003 and G004), to that of darunavir/ritonavir 800/100 mg once daily (TMC114FD1001 [50]).

• bioequivalence of the final FDC G006 of darunavir/cobicistat 800/150 mg once daily versus the single agents given separately, both under fasted and fed conditions (TMC114IFD1003 [52]).

• Results of the GS-US-216-0130 48-week, Phase IIIb, single-arm, US multicenter study [53,54] showed that the darunavir pharmacokinetics, virologic and immunologic responses with darunavir/cobicistat 800/150 mg once daily (administered as single agents) plus two fully active N(t)RTIs in 313 HIV-1-infected adults with no darunavir RAMs were consistent with previously published data for darunavir/ritonavir 800/100 mg once daily. Darunavir/cobicistat 800/150 mg once daily was generally well tolerated, with no new safety concerns.

• A comparative statistical analysis of the 48-week virologic response (Snapshot algorithm) of once-daily darunavir/cobicistat versus once-daily darunavir/ritonavir in HIV-1-infected adults, using patient data from GS-US-216-0130, ARTEMIS and ODIN, [60], demonstrated comparable efficacy of darunavir/cobicistat and darunavir/ritonavir.

• Cobicistat 150 mg once daily as a standalone agent is currently approved in the US, Canada and EU for use as a pharmacokinetic enhancer of single-agent darunavir 800 mg once daily or atazanavir 300 mg once daily. The darunavir/cobicistat FDC formulation has been approved in Canada and US, the EMA CHMP has granted a positive opinion.

• A further FDC has been developed, consisting of darunavir, cobicistat, emtricitabine and tenofovir alafenamide and is currently being evaluated.

Notes