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.