Experimental Integrase Inhibitor Elvitegravir Has Additive to Synergistic Interactions with Other Antiretrovirals in vitro and No Relevant PK Drug Interaction with Darunavir/ritonavir or Tipranavir/ritonavir

Elvitegravir (GS-9137), an experimental integrase inhibitor from Gilead Sciences, has demonstrated potent activity against HIV. Elvitegravir is in development for use in treatment-experienced patients in combination with NRTIS, NNRTIs and ritonavir-boosted protease inhibitors (PI).

A poster presented by Dr. Damian McColl of Gilead Sciences at the 4^th IAS meeting in Sydney (July 22-25, 2007) assessed the antiviral activity of elvitegravir with approved antiretroviral drugs (and with the investigational NNRTI TMC125) in combination studies in vitro [1].

A range of drug concentrations were tested in a matrix format for each drug combination with elvitegravir. All approved NRTIs (except ddC), NNRTIs including TMC125 but excluding delavirdine (DLV), protease inhibitors PIs and the entry (fusion) inhibitor enfuvirtide (T-20; Fuzeon) were tested in combination with elvitegravir. A control for antiviral antagonism, d4T (Zerit) plus ribavirin, was also tested.

MT-2 cells were pre-infected with HIV-1 III_B (MOI, 0.001), added to the drug combinations, and incubated for 5 days under standard conditions. HIV-1-mediated cytopathic effect was measured (Cell Titer-Glo, Promega).

Combination data were analyzed using the MacSynergy II software (Prichard and Shipman). Data were reported as the mean synergy volume (nM².%) at the 95% confidence interval.

Results

• Elvitegravir showed additive to synergistic interactions with all approved antiretroviral drugs.
  
  
• For the seven NRTIs tested, mean synergy volume scores ranged from 12.07 to 97.57 nM².% (additive to moderate synergy).
  
  
• For the three NNRTIs tested, efavirenz (EFV; Sustiva), nevirapine (NVP; Viramune) and TMC125, mean synergy volume scores ranged from 35.89 to 80.34 nM².% (minor to moderate synergy).
  
  
• For the nine PIs tested, the mean synergy volume scores ranged from 13.84 to 48.97 nM².% (additive to minor synergy).
  
  
• For enfuvirtide, the combination with elvitegravir resulted in a mean synergy volume score of 26.28 nM².% (minor synergy).
  
  
•  In contrast, d4T combined with ribavirin showed strong evidence of antagonism (mean synergy volume -480.93 nM².%).

Based on these results, the investigators concluded, “In vitro combination studies of elvitegravir with approved antiretroviral drugs and TMC125 demonstrated additive to moderately synergistic interactions.”

“No evidence of antiviral antagonism between elvitegravir and any antiretroviral drug was observed.”

“Elvitegravir therefore demonstrates [the] potential to be combined with other antiretroviral drug classes in highly active antiretroviral therapy.”

Elvitegravir and Darunavir

At a poster discussion session at the Sydney conference, Dr. Anita Mathias presented data from a study in healthy volunteers showing that there is a lack of pharmacokinetic interaction between ritonavir-boosted elvitegravir and the recently-approved PI darunavir (Prezista) boosted with ritonavir (DRV/r) [2]. This study evaluated the steady-state pharmacokinetics (PK) of co-administered elvitegravir and DRV/r.  

• Healthy (HIV negative) volunteers were randomized to receive: elvitegravir/r alone (125/100 mg QD), DRV/r alone (600/100 mg BID) and elvitegravir 125 mg QD plus DRV/r 600/100 mg BID, each for 14 days in a crossover design.
  
  
• Safety was assessed by clinical and laboratory monitoring.
  
  
• Steady-state pharmacokinetic (PK) assessments for elvitegravir and DRV/r were conducted.
  
  
• The study was powered to conclude lack of a PK alteration if the 90% confidence interval for the geometric mean ratio (GMR) of the primary PK parameters (AUC_tau and C_max) were within the boundaries of 70-143 % for GS-9137 and 80-125% for DRV based on the available safety/efficacy data.
  
  
• Trough concentrations (C_tau) were also assessed.

Results

• Thirty-three subjects enrolled and twenty completed the study.
  
  
• No subject discontinued for an adverse event during treatment of elvitegravir/r alone;
  
  
• Two subjects receiving DRV/r alone discontinued per protocol due to Grade 2 rash.
  
  
• Elvitegravir and DRV PK were consistent with historical data; GMR (90% CI) upon co-administration relative to treatment alone are presented below:
  

• Elvitegravir and DRV AUC_tau and C_max 90% CIs were contained within pre-specified equivalence bounds; trough concentrations were also similar;
  
  
• Ritonavir PK was unaltered upon co-administration of elvitegravir with DRV/r.
  

In conclusion, the authors stated, “GS-9137 [elvitegravir] and DRV/r do not have a clinically relevant PK drug interaction. GS-9137 [elvitegravir] can be added to DRV/r-containing HAART regimens without dose adjustments.”

Gilead Sciences Inc., Clinical Research, Foster City, United States, Gilead Sciences Inc., Biometrics, Foster City, United States, Tibotec Inc., Yardley, United States.

Elvitegravir and Tipranavir

Dr. Anita Mathias also presented a poster at the Sydney meeting demonstrating that ritonavir (RTV) PK was unaltered upon co-administration of elvitegravir with tipranavir (TPV/r) [3].

Healthy volunteers were randomized to the order in which to receive:

• GS 9137/r alone (200/100mg QD),
  
  
• TPV/r alone (500/200mg BID) or
  
  
• GS 9137 200mg QD plus TPV/r 500/200mg BID each for 14 days in a crossover design.

Safety was assessed by clinical and laboratory monitoring throughout the study. Steady state PK assessments for GS-9137 and TPV/r were conducted. The study was powered to conclude lack of a PK alteration if the 90% confidence interval for the geometric mean ratio (GMR) of primary PK parameters (AUC_tau and C_max) were within 70-143 % for GS-9137 and 80-143% for TPV as no dose adjustments are recommended upon >50% increases in TPV exposures by other drugs. Trough concentrations (C_tau) were also assessed.

Results

• Thirty-four subjects enrolled and twenty–six completed the study.
  
  
• No subject discontinued for an adverse event during treatment of GS-9137/r alone;
  
  
• 4 subjects discontinued for adverse events, including G1/2 LFT elevations or rash while receiving TPV/r.
  
  
• Elvitegravir and TPV PK was consistent with historical controls;
  
  
• GMR (90%CI) upon co-administration relative to treatment alone are presented below:
  

• GS-9137 and TPV AUC_tau and C_max 90%CIs were contained within pre-specified equivalence bounds;
  
  
• Trough concentrations were also similar;
  
  
• RTV PK was unaltered upon co-administration of GS-9137 with TPV/r.

“There is no clinically significant drug interaction when GS-9137 [elvitegravir] and TPV/r are combined,” concluded the investigators.

Gilead Sciences Inc., Clinical Research, Foster City, United States, Gilead Sciences Inc., Biometrics, Foster City, United States, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, United States.

08/03/07

References

1. R Ledford, N Margot, M Miller, and others. Elvitegravir (GS-9137/JTK-303), an HIV-1 integrase inhibitor, has additive to synergistic interactions with other antiretroviral drugs in vitro. 4^th IAS Conference. July 22-25, 2007. Sydney AU. Abstract (poster) MOPEA052.

2. A Mathias, G Shen, J Enejosa, and others. Lack of pharmacokinetic interaction between ritonavir-boosted GS-9137 (elvitegravir) and Darunavir/r. 4^th IAS Conference. July 22-25, 2007. Sydney, AU. Abstract (poster) TUPDB03.

3. A Mathias, J Hinkle, J Enejosa, and others. Lack of pharmacokinetic interaction between ritonavir-boosted GS-9137 (elvitegravir) and Tipranavir/r. 4^th IAS Conference. July 22-25, 2007. Sydney, AU. Abstract (poster) TuPDB06.