Session: 162. PK/PD and Susceptability Testing, Friday, 12:15-1:30 p.m.
CAB is an integrase strand transfer inhibitor under investigation as an injectable LA formulation for the treatment and prevention of HIV, and as a tablet formulation as an oral lead-in (OLI) and bridging treatment for dose interruptions. The monthly injection regimen of CAB LA and rilpivirine (RPV) LA was noninferior to standard oral therapy in maintaining HIV-1 suppression in Phase 3 trials. PPK modeling and simulation was used to inform strategies for managing dosing interruptions.
A 2-compartment model with first-order oral and LA absorption and elimination adequately described the data from 1647 healthy (28%) and HIV infected (72%) adult subjects in 16 studies. Gender was a significant covariate on LA absorption; therefore, simulations of 5000 virtual subjects were performed using a 4:1 male:female ratio to ensure 1000 representative females and covariate sampling with replacement from the analysis dataset. One- to 12-week delays in dosing of the second, third, and fourth injection were simulated, and predicted troughs were compared to the 5th percentile (0.65μg/mL) of trough concentrations following the first injection in Phase 3. Simulations of 1-2 months of oral bridging with CAB 30mg once daily from time of a missed injection until CAB LA dosing resumed were performed, with the median Cmax (13.1μg/mL) observed following oral CAB 60mg once daily in Phase 2b as an upper reference.
Proportions of subjects predicted to achieve target plasma CAB trough concentrations are shown by length of delay and injection visit in Table 1. Oral bridging with CAB 30mg once daily starting at the time of a planned missed injection is predicted to provide exposures within ranges observed in clinical studies (Figure 1).
Dosing delays of up to one week appear to have minimal impact, but the effect is more likely to become problematic with longer delays, particularly in the first few months of dosing. Oral bridging provides therapeutic and safe exposures for planned interruptions in LA dosing. Regardless of use of oral bridging, simulations support resuming CAB LA dosing for interruptions < 1 month (< 2 months between injections) and reinitiating CAB LA with a loading dose and subsequent monthly injections for interruptions ≥ 1 month (≥ 2 months between injections).
Kelong Han– Director, GlaxoSmithKline, Collegeville, PA
Mark Baker– Director, Clinical Pharmacology, ViiV Healthcare, Nyon, Vaud, Switzerland
Parul Patel– Director, Clinical Pharmacology, ViiV Healthcare, Research Triangle Park, NC
David Margolis– Director of HIV Drug Development, ViiV Healthcare, Research Triangle Park, NC
William Spreen– R&D, Medicine Development Leader, ViiV Healthcare, Research Triangle Park, NC
Katy Moore– Head, Clinical Pharmacology, ViiV Healthcare, Research Triangle Park, NC
Susan Ford– Director, GlaxoSmithKline, Research Triangle Park, NC