Drug-Drug Interactions
At clinically relevant concentrations, cabotegravir and rilpivirine
exhibit low risk of affecting the concentrations of other
co-administered drugs as they do not cause any major induction or
inhibition of transporters or enzymes. However, they are susceptible to
DDIs when co-administered with medications that are inducers/inhibitors
of CYP3A4 or UGT1A1 . A summary of potential DDIs with LAI CAB/RPV and
their mechanisms are summarized in Figure 1 and Table 2.
When considering impacts of co-administered medications on CAB/RPV, it
is crucial to define a concentration target to aim for, to avoid
treatment failure of ART. Many definitions have been used, including
Ctrough, inhibitory concentration (IC)
IC50, IC90, PA-IC90, and
Inhibitory Quotient. Ctrough is often used because, for
most drugs with linear pharmacokinetics, it can be a reasonable
surrogate for AUC (or exposure over the dosing interval). While
Ctrough may be an appropriate endpoint to quantify
changes in drug exposure, it does not inherently link to drug efficacy.
Protein-adjusted IC50 or IC90(PA-IC90) are typically determined from in vitro
studies, while appropriately adjusting for differences in protein
binding between culture media and blood. When interpreting these, it is
important to consider the viral isolate(s) used to obtain the values;
frequently these assays are performed early in the drug development
process using wild type virus which may not be representative of the
true clinical situation. Testing a range of clinical HIV isolates will
often lead to a range of IC90s. Inhibitory quotients,
the ratio between drug concentration and IC50 or
IC90, have also been used. Importantly, for
antiretrovirals, the risk of selection of drug-resistant mutants and
therapeutic failure is associated with low Ctroughconcentrations, and the minimum acceptable target concentration is
usually defined in relation to the Ctrough, either as an
X-fold increase, or as a ‘minimum effective concentration’. Another
commonly used target is 4x-PAIC90. In this paper, change
in these drug exposure parameters are assessed in determining the
potential clinical significance of a DDI.