Short‐Term Exposure to Low‐Dose Ritonavir Impairs Clearance and Enhances Adverse Effects of Trazodone

Antiretroviral agents may participate in drug interactions that influence the efficacy and toxicity of other antiretrovirals, as well as pharmacologic treatments of coincident or complicating diseases. The viral protease inhibitor, ritonavir, may cause drug interactions by inhibiting the activity of cytochrome P450-3A (CYP3A) isoforms. In a single-dose, blinded, four-way crossover study, 10 healthy volunteer subjects received 50 mg of trazodone hydrochloride or matching placebo concurrent with low-dose ritonavir (four doses of 200 mg each) or with placebo. Compared to the control condition, ritonavir significantly reduced apparent oral clearance of trazodone (155 ± 23 vs. 75 ± 12 ml/min, p < 0.001), prolonged elimination half-life (6.7 ± 0.7 vs. 14.9 ± 3.9 h, p < 0.05), and increased peak plasma concentrations (842 ± 64 vs. 1125 ± 111 ng/ml, p < 0.05) (mean ± SE). Coadministration of trazodone with ritonavir increased sedation, fatigue, and performance impairment compared to trazodone plus placebo; differences reached significance only for the digit-symbol substitution test. Three subjects experienced nausea, dizziness, or hypotension when trazodone was given with ritonavir; 1 of these subjects also experienced syncope. Thus short-term low-dose administration of ritonavir impairs oral clearance of trazodone and increases the occurrence of adverse reactions. The findings are consistent with impairment of CYP3A-mediated trazodone metabolism by ritonavir.