This year the PK Workshop was notable for a number of important studies on ARVs that are already advanced in the pipeline. Please see the study abstract and Liverpool University report for more details on each study.
Quad is an investigational four-drug single pill formulation of the integrase inhibitor elvitegravir with the booster cobicistat plus tenofovir and FTC that is currently submitted to the FDA (with a decision expected by August 2012). Several studies at the workshop provided drug interaction data on components of this and other Gilead pipeline compounds.
An oral presentation included three separate PK interactions studies.1
Coadministration of elvitegravir/cobicistat with rosuvastatin (10 mg single dose) had no significant effect on elvitegravir exposure, but increased rosuvastatin AUC by 38% and Cmax by 89%, although this was not considered clinically relevant.
Coadministration of elvitegravir/cobicistat and rifabutin (300 mg once daily alone or 150 mg every other day with EVG/COB) in a 13 day study reduced elvitegravir Ctrough by 67%. Although rifabutin exposure remained similar, the active metabolite increase by 4.8 to 6.3‐fold, increasing antimycobacterial activity by 21%. Coadministration is not recommended based on the reduction in elvitegravir Ctrough.
A third component of this study reported that using a reduced dose of elvitegravir/cobistat (85 mg/150 mg) with atazanavir (300 mg daily) -- using the cobicistat to boost both elvitegravir and atazanavir -- resulted in modest reductions in atazanavir Cmax (GMR 76.1; 90%CI 59.1, 96.9) and Ctrough (GMR 80.5; 90%CI 55.6, 117) and comparable AUC and Cmax for elvitegravir, with higher Ctrough. (GMR 192; 90%CI 163, 225) compared to elvitegravir/cobicistat 150 mg/150 mg.
Although most research has until now used cobicistat dosed at 150 mg once-daily, a study reported that used twice-daily (150 mg BID) this resulted in approximately 4-fold higher exposure (compared to once-daily). While cobicistat had a similar impact to ritonavir when boosting darunavir, this was not seen with tipranavir. Tipranavir exposure was markedly lower when boosted by cobicistat and cobicistat exposure was 90% lower compared to cobicistat alone.2
Comparable bioavailabilty results were also presented for two fixed dose formulations of darunavir/cobicistat (800 mg/ 150 mg) compared with darunavir/ritonavir (800 mg/100 mg).3
Although selection of the 25 mg dose for single compound of the tenofovir prodrug GS7340 has been reported, a pharmacokinetic interaction reporting that cobicistat boosts GS7340 is now supporting use of 10 mg doses in coformulations.4
Dolutegravir, an integrase inhibitor in development by ViiV, is primarily metabolised by UGT1A1, but uses CYP3A as a minor route (10-15%) but it does not have a clinical impact of inducing or inhibiting major CYP, UGT or transported pathways (except OCT2).
A helpful review of currently known interactions presented at the workshop, included significantly increased dolutegravir exposure with atazanavir (boosted and unboosted) and reduced exposure with darunavir, fosamprenavir, tipranavir, efavirenz and rifabutin (by 30%-75% and not considered clinically significant for treatment naive patients).7
However, etravirine reduced dolutegravir by 88% but this might be overcome if coadministered with lopinavir/r or darunavir/r (which in turn increases dolutegravir exposure). Dolutegravir needs to be given twice daily with rifampin. Antacids need to be separated by at least two hours, due to metal cation chelation rather than a pH effect.
A follow-up integrase compound from GSK/ViiV called GSK-1265744 reported no interactions when the oral formulation was dosed with oral etravirine in 12 HIV negative adults.8
This study is relevant as GSK-1265744 is also being developed as a long-lasting injection formulation to compare pharmacologic properties to both oral administration, and also to the long acting formulation of the NNRTI rilpivirine, with potential use as both treatment and as PrEP.9,10
BMS-986001 is an NRTI with a similar structure to stavudine (d4T) but a safety profile that is unlikely to be associated which is a weak inhibitor of DNA synthesis in vitro and therefore unlikely to affect mitochondrial function and the associated side-effects of d4T.
The workshop included a Phase I/II dose finding study in treatment-experienced patients (off treatment for at lest 3 months). Following 10 days monotherapy, median reductions in viral load on day 11, were 0.97, 1.15, 1.28 and 1.15 log in the 100, 200, 300, and 600 mg groups, respectively (vs -0.07 in the placebo group) from median baseline levels across groups of 4.3 - 4.6 log (range 3.5-5.3 for the whole study).11
This was a new analysis by BMS from a study that was first presented two years ago.12
The development of a nanosuspension formulation of the NNRTI rilpivirine that could be given by intramuscular injection was reported several years ago. A single-dose pharmacokinetic study in HIV negative people reported prolonged exposure in plasma, genital compartments and rectal following single 300, 600, or 1200 mg doses,13 together with a study reporting a lack of negative drug interactions between rilpivirine and dolutegravir (both also presented this year at CROI).14
While this was presented for its potential to reducing the reliance on daily adherence in the context of PrEP, this might have important options for HIV treatment. This would require other ARVs with a similar formulation to construct a combination. The development of a similar formulation for dolutegravir is clearly of interest.15
A safety issue for long-acting formulations, especially in the absence of an antidote to rapidly eliminate the active compound in the event of a severe adverse reaction, might be covered by a period of oral dosing to confirm individual tolerability, especially as both integrase and NNRTI classes have been associated with hypersensitivity reactions.
A recent survey of 400 HIV positive patients attending two US clinics reported 61%, 72% and 84% interest in ART injections based on weekly, two-weekly and monthly formulation respectively, with higher interest in people with concerns about adherence, although 35% were also concerned about needle use.16
Unless stated otherwise, references are to the Programme and Abstracts of the 13th International Workshop on Clinical Pharmacology of HIV Therapy, 16-18 April 2012, Barcelona. These are published in Reviews in Antiviral Therapy & Infectious Diseases, Volume 3: 2012 and available free in PDF format online.
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