Abstract Body

Cabotegravir (CAB) is an integrase strand transfer inhibitor being investigated for the treatment and prevention of HIV-infection. It is being developed as a long acting (LA) intra-muscular injection to facilitate every 1 or 2-month dosing. It is necessary to evaluate the impact of CAB on the exposure and clearance of co-medications. In vitro studies indicated that CAB inhibits renal transporters OAT1 and OAT3 with half maximal inhibitory concentrations of 0.81 and 0.41 µM, respectively. The objective of the present analysis was to build a physiologically based pharmacokinetic (PBPK) model of CAB to predict the clinical implications of renal OAT1/OAT3 inhibition on co-medications.

A mechanistic PBPK model of CAB in the adult population was built using the Simcyp® v17.1 simulator by incorporating physico-chemical properties, in vitro clearance mechanisms, and in vivo data and validated as per regulatory specifications. The CAB PBPK model was validated through comparison with available clinical PK data following oral CAB 30mg administration in healthy volunteers. The simulator was qualified for predicting observed OAT1 and/or OAT3 inhibition based DDIs. DDI simulations were performed to evaluate the effect of CAB oral doses on the exposure of OAT1/OAT3 substrates (methotrexate, tenofovir, ciprofloxacin, cidofovir, cefuroxime, oseltamivir carboxylate, baricitinib, and S44121).

Simulated DDIs for above mentioned OAT1/OAT3 substrates and inhibitors (probenecid, diclofenac) were within two-fold of the observed clinical DDIs. This qualified the Simcyp® v17.1 simulator and related files as appropriately sensitive for predicting OAT1/OAT3 inhibition-mediated clinical DDIs. CAB PBPK model accurately predicted CAB PK parameters (all within acceptable bioequivalence criteria (0.80-1.25) for single as well as repeat dose studies). DDI simulations predicted a mean change in systemic exposure for tested OAT1/OAT3 substrates of <25% after co-administration with CAB at steady state.

A PBPK model of CAB was developed and validated that accurately predicted human pharmacokinetics observed in healthy volunteers. OAT1/OAT3 substrate drugs such as tenofovir, cidofovir, methotrexate were predicted to have a minimal risk of DDIs when administered with CAB. Similar CAB concentrations following oral and LA administration suggest that these results would apply to CAB LA. The predicted lack of interactions supports co-administration with OAT1/OAT3 substrates without dose adjustments.