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  9th International Congress on Drug Therapy in HIV Infection
November 9-13, 2008
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Pharmacokinetics of Once-Daily Etravirine (ETR) Without and With Once-Daily Darunavir/ Ritonavir (DRV/r) in Antiretroviral-Naïve HIV-1 Infected Adults
  Reported by Jules Levin
Ninth International Congress on Drug Therapy in HIV Infection (HIV9); November 9-13, 2008; Glasgow, UK
Jacob Lalezari1, Edwin DeJesus2, Olayemi Osiyemi3, Peter Ruane4, Zachary Haigney1, Robert Ryan5, Bryan Polsonetti6, Thomas N Kakuda5, James Witek6 1Quest Clinical Research, San Francisco, CA, US; 2Orlando Immunology Center, Orlando, FL, USA; 3Triple O Medical Services, Inc , West Palm Beach, FL, USA; 4Light Source Medical, Los Angeles, CA, USA; 5Tibotec, Inc., Yardley, PA, USA; 6Tibotec Therapeutics, Bridgewater, NJ, USA
Author Conclusions
Addition of once-daily DRV/r to once-daily ETR did not have a clinically significant impact on ETR pharmacokinetics
In general, Cmax was higher, Cmin was lower and AUC was similar for once-daily ETR in treatment-naïve patients relative to twice-daily ETR in treatment-experienced patients (historical reference)
-- Mean Cmin for ETR dosed once-daily was >50-fold higher than the protein binding-adjusted EC50 for wild-type HIV, with and without co-administration of DRV/r qd
-- No relationship between PK and efficacy or safety was observed in the DUET studies
Once daily ETR was associated with good short term safety and minimal impact on metabolic parameters
PK data combined with short-term safety and efficacy support further clinical investigation of ETR 400 mg qd in HIV-1 infected patients
With a terminal half-life of 30-40 hours, and formulation improvements leading to a reduced pill burden, etravirine (INTELENCE; ETR) is a candidate for once daily (qd) dosing
In previous studies in healthy volunteers
-- ETR AUC was similar, Cmax was 44% higher and Cmin was 25% lower for qd versus twice daily (bid) dosing (Figure 1)1
-- Co-administration of darunavir (PREZISTA; DRV) with low-dose ritonavir (RTV; /r) 600/100mg bid decreased AUC of ETR 100mg bid by 37%2
Once-daily DRV/r has been shown to be effective and well-tolerated in antiretroviral (ARV)-naïve patients3
This multicenter, open-label phase IIa trial (TMC125-HIV2032) evaluated pharmacokinetic (PK) and short-term safety and efficacy of ETR 400mg qd plus tenofovir/emtricitabine (TDF/FTC) 300/200mg qd without and then with DRV/r 800/100mg qd in ARV-naïve, HIV-1-infected patients






In general, ETR Cmax was higher, Cmin was lower, and AUC was similar when comparing qd dosing in the current study to bid dosing in treatment-experienced patients (reference: DUET PK sub-study; n=24)4 (Table 3)
-- Evaluations were at Week 4 in DUET versus Day 14 for current study
-- In DUET-1 and DUET-2, all patients were treatment-experienced and received DRV/r 600/100mg bid




The median increase in CD4 cell count was 56 cells/mm3 at Day 42 (n=19)
Most common treatment-emergent AEs were nausea, headache, rash, and flatulence (Table 5)
Of the 3 cases of rash, none were considered serious or were grade 3 or 4
No serious or grade 3 or 4 AEs were reported
No AEs led to discontinuation
There were no grade 3 or 4 AST, ALT or lipid elevations
One case of grade 3 neutropenia was reported during Treatment A



1. Peeters M, et al. Ann Pharmacother 2008; 42:757-65.
2. Scholler-Gyure M, et al. Antivir Ther 2007;12(5):789-96.
3. Ortiz R, et al. AIDS 2008; 22:1389-13972.
4. Kakuda TN, et al. IWCPHIV 2008. Abstract P34.
5. DeJesus E, et al. ICAAC 2007. Abstract H-718b.
6. Data on file.