Background:
Intramuscular cabotegravir and rilpivirine (IM CAB/RPV) are used once viral load suppression is achieved on another antiretroviral regimen. While CAB/RPV are substrates of UGT1A1/CYP3A4, efavirenz induces these enzymes therefore switching from an efavirenz containing regimen to IM CAB/RPV could possibly result in a time window with suboptimal drug levels. The aim of this study was to simulate the initial IM CAB/RPV concentrations after stopping efavirenz using physiologically based pharmacokinetic (PBPK) modelling.
Methods:
The in-house PBPK model implemented with a mechanistic intramuscular framework was validated against observed clinical data. Prior to simulate IM CAB/RPV concentrations after switching from efavirenz, we firstly verified the models for CAB, RPV, and efavirenz separately. Secondly, we simulated the switch from efavirenz to oral RPV and dolutegravir (another UGT1A1 substrate). The model was considered validated when the predictions were within 2-fold of clinical data. A cohort of 100 virtual individuals (20-50 years old, 50% female, 18-30 kg/m2) was generated to simulate IM CAB/RPV concentrations over time when administering CAB/RPV (600/900 mg) 12 hours after the last oral dose of efavirenz (600 mg). IM CAB/RPV concentrations during the switch period were compared to those in absence of residual efavirenz concentrations.
Results:
The model was successfully verified as all predictions were within 2-fold of observed clinical data. Initiating IM CAB/RPV 12 hours after the last dose of efavirenz was predicted to have a minimal effect as IM CAB concentrations (Cτ) were reduced by 11%, 13% and 8% at days 1, 7 and 14 after discontinuing efavirenz (Table 1). For all time points, CAB Cτ was above the 4-fold PA-IC90. Similarly, efavirenz was predicted to have a modest effect on IM RPV concentrations with the lowest reduction being 10% and occurring 7 days after the last dose of efavirenz. Residual efavirenz concentrations were predicted to have a less pronounced effect on IM RPV compared to the observed switch data with oral RPV (e.g., IM RPV reduced by 8% vs 28% for oral RPV at day 14 post efavirenz) (Crauwels et al. Antiviral Therapy 2012).
Conclusions:
The PBPK model demonstrates that switching from an efavirenz-containing regimen to IM CAB/RPV does not put at risk of having a time window with suboptimal drug levels.
Table 1: Predictions of IM cabotegravir and rilpivirine concentrations at days 1, 7, 14, and 28 after stopping efavirenz. 