The DDIs arise because many antiretroviral medications inhibit, or in some cases, induce, these CYP enzymes, thereby altering substrate-drug metabolism. Inhibiting a CYP enzyme pathway can decrease substrate-drug clearance and lead to increased levels of that drug. This, in turn, can cause an increased risk of adverse effects, such as extrapyramidal symptoms (EPS) or QTc prolongation, which are both types of pharmacodynamic DDIs.4-28 However, because antipsychotics often have more than one pathway of metabolism, it can be challenging to understand the full effect of CYP-related DDIs. Furthermore, CYP enzyme inducers can decrease drug levels, and in the case of antipsychotics, lead to subtherapeutic responses.
Table 1,6-14,19-28 Table 2,15-28 Table 3,6-14,19-28 and Table 415-28 list many of the known CYP enzyme-related DDIs that may occur with combination antipsychotic and antiretroviral medication therapy and aim to predict CYP induction or inhibition based on a particular combination. The following antiretroviral medications do not have any CYP-related interactions and therefore are not included in the Tables: abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil, zidovudine, enfuvirtide, maraviroc, and raltegravir.
These Tables include the risk ratings for all D-rated (consider alternative therapy) and X-rated (avoid therapy) combinations. The majority of D-rated interactions are caused by CYP inhibition or induction that could potentially lead to altered antipsychotic levels. The majority of X-rated interactions are caused by increased QTc prolongation that may or may not be due to CYP-related DDIs. For example, paliperidone is not believed to be affected by the CYP enzyme system, but it does present a high risk of QTc prolongation on its own. When combined with an antiretroviral that also has a high risk of QTc prolongation, such as lopinavir, then the risk further increases.
Non-nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) are the antiretroviral medications most likely to cause DDIs with antipsychotics. Other antiretroviral classes, such as nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), fusion inhibitors, chemokine receptor 5 inhibitors, and integrase inhibitors, are not associated with CYP-related DDIs.19-28 For the most part, the severity of the CYP-related DDIs have not been well studied; therefore, most recommendations call for closer patient monitoring when combining antiretroviral medications and antipsychotics.6-18 The goal is to monitor for any changes in medication efficacy or adverse effects.
Continue to: Consider adverse effect profiles