Drug Interactions between macitentan / tadalafil and pirtobrutinib

MONITOR: Coadministration with pirtobrutinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C8, 2C19, 3A4, P-glycoprotein (P-gp), and/or breast cancer resistance protein (BCRP). The peak plasma concentration (Cmax) and systemic exposure (AUC) of repaglinide, a CYP450 2C8 substrate, increased by 98% and 130%, respectively, and the Cmax and AUC of omeprazole, a CYP450 2C19 substrate, increased by 49% and 56%, respectively, when administered with pirtobrutinib. The Cmax and AUC of oral midazolam, a CYP450 3A4 substrate, increased by 58% and 70%, respectively, while exposure to IV midazolam was not significantly affected, when administered with pirtobrutinib. The Cmax and AUC of digoxin, a P-gp substrate, increased by 51% and 17%, respectively, when administered with a single pirtobrutinib dose (200 mg), and 55% and 35%, respectively, when administered with multiple pirtobrutinib doses (200 mg daily). The Cmax and AUC of rosuvastatin, a BCRP substrate, increased by 146% and 140%, respectively, when administered with pirtobrutinib. The risk of adverse reactions related to these substrates may be increased.

MANAGEMENT: Caution is advised if pirtobrutinib is used concomitantly with substrates of CYP450 2C8, 2C19, 3A4, P-gp, and/or BCRP, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

MONITOR: Coadministration with pirtobrutinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C8, 2C19, 3A4, P-glycoprotein (P-gp), and/or breast cancer resistance protein (BCRP). The peak plasma concentration (Cmax) and systemic exposure (AUC) of repaglinide, a CYP450 2C8 substrate, increased by 98% and 130%, respectively, and the Cmax and AUC of omeprazole, a CYP450 2C19 substrate, increased by 49% and 56%, respectively, when administered with pirtobrutinib. The Cmax and AUC of oral midazolam, a CYP450 3A4 substrate, increased by 58% and 70%, respectively, while exposure to IV midazolam was not significantly affected, when administered with pirtobrutinib. The Cmax and AUC of digoxin, a P-gp substrate, increased by 51% and 17%, respectively, when administered with a single pirtobrutinib dose (200 mg), and 55% and 35%, respectively, when administered with multiple pirtobrutinib doses (200 mg daily). The Cmax and AUC of rosuvastatin, a BCRP substrate, increased by 146% and 140%, respectively, when administered with pirtobrutinib. The risk of adverse reactions related to these substrates may be increased.

MANAGEMENT: Caution is advised if pirtobrutinib is used concomitantly with substrates of CYP450 2C8, 2C19, 3A4, P-gp, and/or BCRP, particularly sensitive substrates or those with a narrow therapeutic range. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.

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.