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 .