Exposure/Response Analysis of Once-daily Elvitegravir Administered as Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Single-tablet Regimen in HIV-1+ Patients
Srini Ramanathan, X Wei, J Szwarcberg, S Chang, A Cheng, and B Kearney
Gilead Sci, Foster City, CA, US
Background: The elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; QUAD) single-tablet regimen has demonstrated non-inferior efficacy and an improved tolerability profile to efavirenz (EFV)/FTC/TDF or atazanavir/ritonavir (ATV/r) + FTC/TDF in treatment-naïve subjects. The pharmacokinetics, exposure-efficacy, and exposure-safety relationships of EVG were evaluated in phase 2 and phase 3 studies. In their development, EVG and COBI were subject to detailed assessments resulting in dose selection at the plateau-phase of their dose/response relationships for viral suppression and anti-CYP3A (boosting), respectively. EVG antiviral activity is correlated with Ctrough values.
Methods: Data were obtained from a phase 2 and 2 phase 3 double-blind, randomized, active-controlled studies of QUAD in which EVG pharmacokinetics was assessed both in pharmacokinetic sub-studies and by population pharmacokinetics-modeling (n = 62 and 419, respectively). EVG pharmacokinetic parameters were assessed as quartile, quintiles, or octiles of exposure. The EVG pharmacokinetic/pharmacodynamic relationship between efficacy and Ctrough was evaluated using pure virologic failure defined as not achieving 2 consecutive HIV RNA <50 copies/mL or rebound to ≥50 copies/mL by week 48. EVG pharmacokinetics/pharmacokinetics relationships between AUC or Cmax vs safety was evaluated based on the status (yes/no) for the most frequently observed adverse events of headache, nausea, or diarrhea in subjects receiving the QUAD single-tablet regime.
Results: Virologic response rates were high and comparable across the EVG Ctrough quartiles (Q1 [lowest] to Q4 [highest]: 89%, 88%, 93%, and 87%, respectively). Similar results were obtained using quintile/octile-based exposure-efficacy analyses (response in lowest octile of EVG Ctrough was 87%). Potent reduction in HIV-1 RNA was observed at week 2 (median change from baseline: –2.6 log10 copies/mL), with no relationship observed versus EVG Ctrough quartiles. Mean (%CV) EVG Ctrough (451 ng/mL (58)) yielded IC95 (IQ95: Ctrough/IC95) >10; all subjects had Ctrough >IC95. Overall EVG mean (%CV) AUC and Cmax were 22,960 (32) ng•h/mL and 1730 (23) ng/mL, respectively, consistent with historical data. No relationship was observed between EVG AUC or Cmax and any adverse events across the range of EVG exposures.
Conclusions: QUAD provided EVG Ctrough that provided high and consistent rates of virologic response and overall EVG exposures with a favorable safety/tolerability profile.