Studies on pipeline ARVs

Simon Collins, HIV i-Base

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 abstracts 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. Quad 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 increased 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 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.

Cobisistat: the PK booster in Quad

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]

GS7340 – tenofovir prodrug

Although selection of the 25 mg dose for single compound of the tenofovir prodrug GS7340 has been reported, the boosting effect that cobicistat has on GS7340 means 10 mg doses are being studied in coformulations. [4]

These include with elvitegravir/cobicistat/FTC in a new version of Quad (Quad+) and with darunavir/cobicistat/FTC in a single-pill PI-based fixed dose combination. [5, 6]


Dolutegravir, an integrase inhibitor in development by ViiV, is primarily metabolised by UGT1A1, but uses CYP3A as a minor route (10-15%), However there is no clinical impact from 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 naïve 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. Studies will compare pharmacologic properties to oral administration and also to the long acting formulation of the NNRTI rilpivirine, with potential for use as both treatment and 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 as it is a weak inhibitor of DNA synthesis in vitro and therefore not expected to affect mitochondrial function and in turn cause the side-effects associated with 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]

Long acting formulations (monthly injections): rilpivirine-LA, raltegravir, patient views

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 compound was presented for its potential to reducing the reliance on daily adherence in the context of PrEP, it might also be an important option for HIV treatment. This would require other long lasting formulations of ARVs 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.

  1. Ramanathan S et al. Pharmacokinetics and drug interaction profile of cobicistat boosted-EVG with atazanavir, rosuvastatin or rifabutin. 13th PK Workshop, Barcelona, 2012. Oral abstract O_03.
  2. Ramanathan S et al. Safety/tolerability, pharmacokinetics, and boosting of twice-daily cobicistat administered alone or in combination with darunavir or tipranavir. 13th PK Workshop, Barcelona, 2012. Poster P_08.
  3. Kaduda T et al. Bioavailability of two FDC formulations of darunavir/cobicistat 800/150mg compared with darunavir/ritonavir 800/100mg co-administered as single agents. 13th PK Workshop, Barcelona, 2012. Oral abstract O_20.
  4. Ramanathan S et al. Pharmacokinetics of a novel EVG/COBI/FTC/GS-7340 single tablet regimen. 13th PK Workshop, Barcelona, 2012. Abstract O_13.
  5. Safety and efficacy of elvitegravir/cobicistat/emtricitabine/GS-7340 single tablet regimen versus elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single tablet regimen in HIV 1 infected, antiretroviral treatment-naive adults.
  6. Safety and efficacy of darunavir/cobicistat/emtricitabine/GS-7340 single tablet regimen versus cobicistat-boosted darunavir plus emtricitabine/tenofovir disoproxil fumarate fixed dose combination in HIV-1 infected, antiretroviral treatment naive adults.
  7. Song I et al. Metabolism and drug-drug interaction profile of dolutegravir (DTG, S/GSK1349572). 13th PK Workshop, Barcelona, 2012. Abstract O_17.
  8. Ford SL et al. Etravirine has no effect on the pharmacokinetics of S/GSK1265744, a novel HIV Integrase inhibitor. 13th PK Workshop, Barcelona, 2012. Poster abstract P_15.
  9. A single dose escalation study to investigate the safety, tolerability and pharmacokinetics of intramuscular and subcutaneous long acting GSK1265744 in healthy subjects.
  10. A study to investigate the safety, tolerability and pharmacokinetics of repeat dose administration of long-acting GSK1265744 and long-acting TMC278 intramuscular and subcutaneous injections in healthy adult subjects.
  11. Hwang C et a. Antiviral activity, exposure- response, and resistance analyses of monotherapy with the novel HIV NRTI BMS- 986001 in ART-experienced subjects. 13th PK Workshop, Barcelona, 2012. Oral abstract O_06.
  12. Cotte et al. A phase-Ib/IIa dose-escalation study of OBP-601 (4′-ethynyl-d4T, festinavir) in treatment-experienced, HIV-1- infected patients. 50th ICAAC, 12-15 September 2010, Boston. Abstract H-933.
  13. Else L et al. Pharmacokinetics of long-acting rilpivirine in plasma, genital tract and rectum of HIV negative females and males administered a single 600 mg dose. 13th PK Workshop, Barcelona, 2012. Oral abstract O_12.
  14. Jackson A et al. Rilpavirine-LA formulation: pharmacokinetics in plasma, genital tract in HIV negative females and rectum in males. 19th Conference of Retroviruses and Opportunistic Infections, 5-8 March 2012, Seattle. Oral abstract 35.
  15. Crauwels H et al. Absence of pharmacokinetic interaction between the NNRTI rilpivirine (TMC278) and the integrase inhibitor raltegravir. 19th Conference of Retroviruses and Opportunistic Infections, 5-8 March 2012, Seattle. Poster abstract 617.
  16. Swindells S et al. Long-acting parenteral nanoformulated antiretroviral therapy: patient interest and attitudes. 13th PK Workshop, Barcelona, 2012. Poster abstract P_01.

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