Rifamycins with cabotegravir
Pharmacokinetic studies have shown that rifampicin reduces oral cabotegravir exposures, potentially leading to treatment failure and risking emergence of drug resistance . The study by Ford et al., revealed that rifampicin dosed at 600mg daily increased the apparent clearance of oral cabotegravir by 2.4-fold, effectively decreasing systemic exposure (area under the plasma concentration-time curve, AUCinf) by 59% .
No in-human pharmacokinetic studies of rifampicin with IM cabotegravir have been conducted due to the reasons described above. However, PBPK models, developed and validated using clinical data from oral cabotegravir studies, have predicted similar reductions in exposure with the LAI formulation. A decrease of 41% in both AUC0-28days and Cmin, 0-28days was observed following simulations of interaction between IM cabotegravir 400mg monthly maintenance dose and 600 mg daily oral rifampicin . Bettonte et al. predicted a similar decrease in AUC and Cmin of 60% and 63% respectively .
In silico simulations of dose adjustment scenarios aimed at maintaining effective target therapeutic cabotegravir exposure (concentrations above 4×PA-IC90 target) suggested that the interaction with rifampicin cannot be overcome with dose-adjustment . The current evidence supports the recommendation that coadministration of rifampicin with oral or LAI cabotegravir should be avoided due to significant reduction in cabotegravir exposure. Rifampicin, and by extension strong CYP inducers e.g., rifapentine, are expected to substantially reduce exposure to IM cabotegravir and increase the risk of treatment failure thus co administration is contraindicated .
Rifabutin, a moderate inducer of CYPs compared to rifampicin, is reported to result in a more modest reduction in systemic exposure to oral cabotegravir. The oral clearance of cabotegravir is increased by 27% when coadministered with rifabutin resulting in a decrease of 21%, 17% and 26% in AUC0-τ, Cmax and Cmin, respectively . These findings are reinforced by PBPK modelling of the interaction between rifabutin 300 mg and LAI cabotegravir 600 mg that predicted similar reductions of 16% and 18% in AUC and Cmin of LAI cabotegravir respectively . However, the overall cabotegravir trough concentration and AUC0-t (2.5 mg/ml and 81.7 mg*h/ml respectively) were observed to be above 1.35 mg/ml and 45.7 mg*h/ml respectively, exposures achieved with administration of oral cabotegravir 10mg once daily . Oral cabotegravir 10mg once daily was previously shown to be safe and efficacious in combination with rilpivirine at maintaining viral suppression in HIV patients, thus the reduction in cabotegravir exposure by rifabutin is not clinically important .