Elvitegravir (GS-9137) is an experimental HIV integrase inhibitor from Gilead Sciences in development for the treatment of HIV infection. Ritonavir-boosted elvitegravir (elvitegravir/ritonavir, 125/100 mg) displayed superior antiviral activity compared to ritonavir-boosted protease inhibitors in combination with an optimized background regimen containing NRTIs +/- enfuvirtide (T-20; Fuzeon) [1].

Etravirine (TMC125) is an experimental next generation non-nucleoside reverse transcriptase inhibitor (NNRTI) from Tibotec Therapeutics that has shown superior antiviral activity compared to placebo in combination with an optimized background regimen in treatment-experienced patients with documented NNRTI resistance [2,3].

Background

Elvitegravir is metabolized by CYP3A4 and glucuronidation. The co-administration of elvitegravir with ritonavir results in a 20-fold increase in plasma elvitegravir exposures.

Etravirine is metabolized by CYP3A4, CYP2C9, and 2C19 isoenzymes; it is an inducer of CYP3A and an inhibitor of 2C9 and 2C19.

Given their likelihood for co-administration and overlapping metabolic pathways, it is important to determine the potential for interaction between elvitegravir/ritonavir and etravirine.

The objective of the current study, presented at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago (September 17-20-2007), was to evaluate the effect of co-administration of elvitegravir/ritonavir and etravirine on the pharmacokinetics of elvitegravir and etravirine and to evaluate the safety and tolerability of short-term administration of elvitegravir/ritonavir and etravirine alone and in combination

Figure 1. Study Design

Elvitegravir/ritonavir, etravirine, and elvitegravir/ritonavir + etravirine were administered with a meal (~ 400kcal, 13 g fat).

Plasma pharmacokinetic (PK) sampling were performed over 12 hours (etravirine) or 24 hours (elvitegravir, ritonavir); elvitegravir, etravirine and ritonavir levels were determined using validated LC/MS/MS assays.

PK parameters (elvitegravir, ritonavir in Group 1; etravirine in Group 2) estimated using non-compartmental methods and WinNonlin 5.2 (Pharsight Corp). ANOVA and 90% confidence interval lack of PK alteration bounds about the geometric mean ratio (co-administration: alone) as follows:

- elvitegravir - AUCtau, Cmax, and Ctau: 70% to 143%
- etravirine - AUCtau: 80% to 125%
- ritonavir (exploratory) - AUCtau, Cmax: 70% to 143%

Demographics

• 34 healthy HIV negative subjects enrolled; 31 completed study
• 17 males, 17 females
• Mean age: 33 yrs (range: 18-45)
• Mean weight: 72.5 kg (range: 54-102)
• Ethnicity: 32 White, 2 Black

Results

Safety

• No Grade 3/4 adverse events (AEs), serious AEs
• No discontinuations due to AE, lab abnormalities
• 3 discontinuations due to withdrawn consent
• Elvitegravir/ritonavir and etravirine administered alone and in combination were generally well tolerated
• Most frequent AEs across treatment arms: headache, gastrointestinal disorders (nausea, diarrhea)
• All AEs were mild or moderate and resolved on treatment

EVG = elvitegravir; MVC = maraviroc

Pharmacokinetics

• Elvitegravir and etravirine: %GMR (90% CI) for AUCtau, Cmax, and Ctau within predefined lack of PK alteration bounds

• Ritonavir PK unaffected upon elvitegravir/ritonavir + etravirine co-administration

Commentary

Gilead Sciences, manufacturer of elvitegravir, is expected to announce plans for Phase III licensing trials of the drug before the end of this year, and Tibotec announced this week that etravirine (TMC125) likely will receive an FDA review for a license in treatment-experienced patients by mid-January 2008.

Gilead Sciences, Inc., Foster City, CA, USA; Tibotec, Inc., Yardley, PA, USA.

09/25/07

Source

S Ramanathan, S West, TN Kakuda, and others. Lack of Clinically Relevant Drug Interactions Between Ritonavir-Boosted Elvitegravir and TMC125. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 17-20, 2007. Chicago, IL. Abstract H-1407.

References

1. A Zolopa, M Mullen, D Berger, and others. The HIV integrase inhibitor GS-9137 demonstrates potent antiretroviral activity in treatment-experienced patients. 14th Conference on Retroviruses and Opportunistic Infections. February 25-28, 2007. Los Angeles, CA. Abstract 143LB.

2. J Lalezari, J Goodrich, E DeJesus, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic ART-experienced patients infected with CCR5-tropic HIV-1: 24-week results of a phase 2b/3 study in the US and Canada. 14th Conference on Retroviruses and Opportunistic Infections. Abstract 104bLB.

3. M Nelson, G Fätkenheuer, I Konourina, and others. Efficacy and safety of maraviroc plus optimized background therapy in viremic, ART-experienced patients infected with CCR5-tropic HIV-1 in Europe, Australia, and North America: 24-Week Results. 14th Conference on Retroviruses and Opportunistic Infections. Los Angeles, USA. 2007. Abstract 104aLB.