Drug Interactions between darunavir and macitentan / tadalafil

ADJUST DOSE: Coadministration with protease inhibitors (PIs) may increase the plasma concentrations of tadalafil. The mechanism is PI inhibition of tadalafil metabolism via CYP450 3A4. In study subjects, administration of a single 20 mg dose of tadalafil during treatment with ritonavir 500 mg or 600 mg twice daily at steady state resulted in a 30% reduction in tadalafil peak plasma concentration (Cmax) and 32% increase in systemic exposure (AUC) compared to tadalafil administered alone. Administration of the same dose of tadalafil in combination with ritonavir 200 mg twice a day was associated with a 124% increase in tadalafil AUC and no change in Cmax. The pharmacokinetics of tadalafil in the treatment of pulmonary arterial hypertension (PAH) have been studied in the presence of tipranavir/ritonavir. Tadalafil concentrations increased when coadministered with the first dose of tipranavir/ritonavir, but not with tipranavir/ritonavir at steady-state. This would suggest that the initial inhibitory effect of ritonavir on CYP450 3A4 may be mitigated by a more slowly evolving induction effect so that after about one week of ritonavir administered twice daily, the exposure to tadalafil is similar in the presence and absence of ritonavir. Although not specifically studied, other HIV protease inhibitors are expected to increase tadalafil exposure.

MANAGEMENT: Caution is advised if tadalafil is administered in combination with protease inhibitors. For the treatment of erectile dysfunction, the dosage of tadalafil should not exceed 10 mg once every 72 hours when used on an as-needed basis in patients receiving PI therapy. When given for once-daily use in the treatment of erectile dysfunction or benign prostatic hyperplasia, the maximum recommended dose is 2.5 mg. For the treatment of pulmonary arterial hypertension, tadalafil should be started at 20 mg once daily in patients who have been receiving ritonavir-boosted PI therapy for at least one week. The dosage may be increased to 40 mg once daily based upon individual tolerability. The use of tadalafil for PAH should be avoided during the initiation of ritonavir-boosted PI therapy. The manufacturers recommend that tadalafil be discontinued at least 24 hours prior to initiating the PIs. After at least one week, tadalafil may be resumed at 20 mg once daily, and the dosage increased to 40 mg once daily based upon individual tolerability. There is no need to discontinue tadalafil when initiating PI therapy that does not contain ritonavir as a pharmacokinetic booster, nor wait at least one week after PI therapy to start tadalafil. The tadalafil dosage should be initiated at or adjusted to 20 mg once daily when coadministered with nonritonavir-boosted PI regimens, then increased to 40 mg as tolerated. The prescribing information for individual products should be consulted for specific guidance. All patients treated with tadalafil should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4 or moderate dual or combined inhibitors of CYP450 3A4 and CYP450 2C9 may increase the plasma concentrations of macitentan. Macitentan is primarily metabolized by CYP450 3A4 and to a minor extent by CYP450 2C8, CYP450 2C9 and CYP450 2C19. In ten healthy subjects, administration of a single 10 mg oral dose of macitentan on day 5 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure (AUC) compared to administration alone. Additionally, there was a 26% reduction in the AUC of the active metabolite, which has been reported to be approximately 5-fold less potent than macitentan in vitro, but whose systemic exposure in human is 2.5-fold higher than that of macitentan. The clinical significance of these changes has not been established. Macitentan was well tolerated with or without ketoconazole in the study, and there were no relevant differences in safety parameters between the treatments. In addition, physiologically based pharmacokinetic modeling in poor metabolizers of CYP450 2C9 showed that a 400 mg daily dose of fluconazole, a moderate dual CYP450 3A4 and CYP450 2C9 inhibitor, may increase macitentan exposure by approximately 3.8-fold. However, there was no clinically relevant change in exposure to the active metabolite of macitentan. The clinical significance of these findings is not known.

MANAGEMENT: Caution is advisable if macitentan is used with inhibitors of CYP450 3A4 and/or moderate dual or combined inhibitors of CYP450 3A4 and CYP450 2C9. The product labeling recommends avoiding concomitant use with potent inhibitors (e.g., protease inhibitors, clarithromycin, cobicistat, conivaptan, delavirdine, itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole). The manufacturer of macitentan also recommends avoiding concomitant use with moderate dual inhibitors of CYP450 3A4 and 2C9 (e.g., fluconazole, amiodarone) or in combination with both a moderate CYP450 3A4 inhibitor and a moderate CYP450 2C9 inhibitor.

Based on their pharmacology, phosphodiesterase-5 (PDE5) inhibitors may conceivably potentiate the hypotensive effect of antihypertensive medications or effects of agents with hypotensive properties. These agents inhibit PDE5-mediated degradation of cyclic guanosine monophosphate (cGMP), which in vascular smooth muscles can cause peripheral vasodilation. However, clinical pharmacology studies of tadalafil (administered as a 10 mg dose except in studies with angiotensin II receptor (AR) blockers and amlodipine, which used a dose of 20 mg) have demonstrated no clinically significant interaction with various antihypertensive drugs from major classes including calcium channel blockers, ACE inhibitors, beta blockers, thiazide diuretics, and AR blockers. Tadalafil 10 mg and 20 mg also had no clinically significant effect on blood pressure changes due to tamsulosin, an alpha-1a blocker. In addition, analysis of data from Phase 3 clinical trials showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medications. In patients receiving concomitant antihypertensive medications, tadalafil 20 mg may induce a blood pressure decrease that is, in general, minor and not likely to be clinically relevant. In a clinical study of healthy male subjects 45 to 78 years of age, administration of silodosin with a single 20 mg dose of tadalafil resulted in increased frequency of positive orthostatic test results during a 12-hour period following concomitant dosing compared to administration with placebo. No events of symptomatic orthostasis or dizziness were reported in subjects receiving silodosin with tadalafil. Nevertheless, patients should be advised of the potential for interaction and to contact their doctor if they experience symptoms of hypotension such as dizziness, lightheadedness, or fainting.