Drug-Drug Interactions in the Management of Patients With Pulmonary Arterial Hypertension

Abstract

The management of pulmonary arterial hypertension (PAH) has become more complex in recent years because of increased pharmacotherapy options and longer patient survival with increasing numbers of comorbidities. As such, more opportunities exist for drug-drug interactions between PAH-targeted medications and medications potentially used to treat comorbid conditions. In this review, we provide an overview of pharmaceutical metabolism by cytochrome P450 and discuss important drug-drug interactions for the 14 Food and Drug Administration-approved medications for PAH in the nitric oxide (NO), endothelin, and prostacyclin pathways. Among the targets in the NO pathway (sildenafil, tadalafil, and riociguat), important interactions with nitrates, protease inhibitors, and other phosphodiesterase inhibitors can cause profound hypotension. In the endothelin pathway, bosentan is associated with more drug interactions via CYP3A4 inhibition; macitentan and ambrisentan have fewer interactions of note. Although the parenteral therapies in the prostacyclin pathway bypass significant liver metabolism and avoid drug interactions, selexipag and oral treprostinil may exhibit interactions with CYP2C8 inhibitors such as gemfibrozil and clopidogrel, which can raise drug levels. Finally, we provide a framework for identifying potential drug-drug interactions and avoiding errors. The management of pulmonary arterial hypertension (PAH) has become more complex in recent years because of increased pharmacotherapy options and longer patient survival with increasing numbers of comorbidities. As such, more opportunities exist for drug-drug interactions between PAH-targeted medications and medications potentially used to treat comorbid conditions. In this review, we provide an overview of pharmaceutical metabolism by cytochrome P450 and discuss important drug-drug interactions for the 14 Food and Drug Administration-approved medications for PAH in the nitric oxide (NO), endothelin, and prostacyclin pathways. Among the targets in the NO pathway (sildenafil, tadalafil, and riociguat), important interactions with nitrates, protease inhibitors, and other phosphodiesterase inhibitors can cause profound hypotension. In the endothelin pathway, bosentan is associated with more drug interactions via CYP3A4 inhibition; macitentan and ambrisentan have fewer interactions of note. Although the parenteral therapies in the prostacyclin pathway bypass significant liver metabolism and avoid drug interactions, selexipag and oral treprostinil may exhibit interactions with CYP2C8 inhibitors such as gemfibrozil and clopidogrel, which can raise drug levels. Finally, we provide a framework for identifying potential drug-drug interactions and avoiding errors. In the 1980s, before the advent of pulmonary arterial hypertension (PAH)-targeted medical therapies, PAH (then referred to as primary pulmonary hypertension) carried a terrible long-term prognosis, with only a 68% 1-year patient survival rate and a 34% 5-year patient survival rate.1Rich S. Dantzker D.R. Ayres S.M. et al.Primary pulmonary hypertension. A national prospective study.Ann Intern Med. 1987; 107: 216-223Crossref PubMed Scopus (1780) Google Scholar At that time, PAH was a disease of the young (mean age, 36 years) and women (1.7:1 female to male ratio) with few comorbidities. Over the past 25 years, PAH has evolved from a disease with no specific treatments and a dismal prognosis to a disease with three main treatment pathways and significantly improved life expectancy. In the more contemporaneous Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL), the mean age at PAH diagnosis increased to 50.1 years and more comorbidities were seen among patients living with PAH.2Badesch D.B. Raskob G.E. Elliott C.G. et al.Pulmonary arterial hypertension: baseline characteristics from the REVEAL registry.Chest. 2010; 137: 376-387Abstract Full Text Full Text PDF PubMed Scopus (916) Google Scholar Today, more than two-thirds of all patients with idiopathic PAH have significant comorbidities (with one in seven having four or more comorbid conditions), making this patient population more complex to treat than in the past.3Hjalmarsson C. Rådegran G. Kylhammar D. et al.Impact of age and comorbidity on risk stratification in idiopathic pulmonary arterial hypertension.Eur Respir J. 2018; 511702310Crossref PubMed Scopus (70) Google Scholar Not only have patients become more complicated, but the options for medical management of PAH also have increased. Fourteen medications are now approved by the Food and Drug Administration for PAH used in multiple combinations.4Hassoun P.M. Pulmonary arterial hypertension.N Engl J Med. 2021; 385: 2361-2376Crossref PubMed Scopus (144) Google Scholar The currently approved PAH-targeted therapies act on three main pathways: the nitric oxide (NO) pathway (including the phosphodiesterase 5 [PDE5] inhibitors tadalafil and sildenafil and the soluble guanylate cyclase [sGC] stimulator riociguat), the endothelin pathway (bosentan, ambrisentan, and macitentan), and the prostacyclin pathway (including the various formulations of the prostacyclin analogs epoprostenol, iloprost, and treprostinil and a prostacylin-receptor agonist, selexipag). Given the increasing complexity of patients with PAH in terms of comorbidities and disease-specific management, numerous opportunities exist for drug-drug interactions between PAH medications and other drugs or supplements for comorbid conditions. Cytochrome P450 (CYP450) is an enzyme that plays a fundamental role in the metabolism of medications.5Estabrook R.W. A passion for P450s (remembrances of the early history of research on cytochrome P450).Drug Metab Dispos Biol Fate Chem. 2003; 31: 1461-1473Crossref PubMed Scopus (131) Google Scholar Drugs with CYP450 activity may be inhibitors, inducers, substrates, or a combination thereof for a specific CYP450 enzymatic pathway that can change the metabolism of concurrently administered medications. Inhibitors are substances that reduce an enzymatic pathway of CYP450 and may cause increased concentrations of other drugs metabolized by the same pathway, resulting in drug toxicity. Inducers are substances that induce an enzymatic pathway of CYP450, which may increase metabolism of other drugs by the same pathway, leading to subtherapeutic drug levels and treatment failure.6McDonnell A.M. Dang C.H. Basic review of the Cytochrome P450 system.J Adv Pract Oncol. 2013; 4: 263-268PubMed Google Scholar Although more than 50 isoforms of CYP450 have been discovered, six of them (CYP3A4, CYP2D6, CYP1A2, CYP2C9, and CYP2C19) metabolize 90% of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6.7Martin J. Fay M. Cytochrome P450 drug interactions: are they clinically relevant?.Aust Prescr. 2001; 24: 10-12Crossref Scopus (16) Google Scholar As our understanding of CYP450 metabolism continues to grow, new agents undergo extensive drug interaction studies performed before becoming available. However, not all agents have been tested in combination, and at times drug interactions are hypothesized based on known metabolic pathways. As a result, drug-drug interactions may include the magnification of known potential adverse effects. Not all cytochrome P450-mediated drug interactions are clinically significant, and thus may or may not require dosage adjustments. Active drug transporters, P-glycoprotein, and human organic anion-transporting polypeptides (OATPs), also play an important role in drug elimination and affect the bioavailability of a number of drugs by controlling their movement into and out of cells.8DuBuske L.M. The role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions.Drug Saf. 2005; 28: 789-801Crossref PubMed Scopus (75) Google Scholar Refer to Table 1 for commonly used medications with known CYP450, P-glycoprotein, and OATP activity. Knowledge of the drugs metabolized by CYP450 enzymes, active drug transporters, and the most potent inhibiting and inducing drugs can help to minimize the possibility of adverse drug reactions and interactions or therapeutic failures.9Lynch T. Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects.Am Fam Physician. 2007; 76: 391-396PubMed Google ScholarTable 1Common Sites of Drug Metabolism and InteractionsCYP3A4 InhibitorsAzole antifungals, cobicistat, ritonavir, amiodarone, macrolide antibiotics (erythromycin), cyclosporine, diltiazem, verapamil InducersCarbamazepine, phenytoin, rifampin, St. John’s wort, smoking SubstratesaMore than 1,000 medications are metabolized by CYP3A4. This list identifies drugs commonly affected by PAH medications.Hormonal contraceptives, HmG-CoA reductase inhibitors (primarily simvastatin), colchicineCYP2C8 InhibitorsStrong: gemfibrozil; moderate: clopidogrel, deferasirox, leflunomide, teriflunomide; weak: abiraterone, montelukast, trimethoprim InducerRifampin SubstratesChloroquine, paclitaxel, repaglinide, rosiglitazoneCYP2C9 InhibitorsRitonavir, amiodarone, fluconazole, sulfamethoxazole-trimethoprim InducerRifampin SubstrateWarfarin, bosentan, losartan, naproxenCYP2C19 InhibitorsOmeprazole, fluconazole, ketoconazole, isoniazid InducersCarbamazepine, phenytoin, rifampin SubstratesClopidogrel, omeprazole, citalopramCYP1A1 InducerSmokingP-glycoprotein efflux pump InhibitorsCyclosporine, ketoconazole, ritonavir, amiodarone, clarithromycin, propafenone, quinidine, ranolazine, verapamil InducerSt. John’s wort SubstrateDigoxinOATP hepatic transporter InhibitorsGemfibrozil, cyclosporineInhibitors: Expect increase in substrate plasma concentration; Inducers: Expect decrease in substrate plasma concentration; Substrates: Metabolism will be affected by inhibitors or inducers, resulting in increase or decrease in plasma concentrations, respectively. OATP = organic anion-transporting polypeptidea More than 1,000 medications are metabolized by CYP3A4. This list identifies drugs commonly affected by PAH medications. Open table in a new tab Table 2Clinically Established and Other Potentially Significant Drug Interactions: Endothelin Receptor AntagonistsPAH DrugInteracting DrugMechanismEffectRecommendationBosentanGlyburideAdditive hepatotoxicityIncreased incidence of elevated aminotransferasesContraindicatedHormonal contraceptivesCYP3A4 induction by bosentan, reducing plasma concentration of hormonal contraceptivesUnreliable contraceptionCounsel patients to use additional of reductase induction by bosentan, reductase levels reduce and OATP by cyclosporine, increasing bosentan induction by bosentan, levels increased and increasing bosentan not in the increasing bosentan administered with increased bosentan plasma concentration by for increased (including for increasing bosentan increase in bosentan bosentan at 36 before of may bosentan at at the of and bosentan bosentan concentrations by more than that liver be for the liver may be and P-glycoprotein increasing ambrisentan increase in ambrisentan reduce ambrisentan to 5 and increasing macitentan to increase macitentan increase not clinically use with and for increased increasing macitentan clinically not macitentan by with rifampin because of not = pulmonary arterial hypertension. Open table in a new tab Table Established and Other Potentially Significant Drug Interactions: NO DrugInteracting potent at of between the of sildenafil and is sildenafil sildenafil is a substrate of with metabolism of bosentan CYP3A4 resulting in increased bosentan in the concentration of sildenafil and increase in bosentan no on used (including for sildenafil increased to CYP3A4 sildenafil to John’s sildenafil increase in sildenafil may be may increase of sildenafil sildenafil significant in sildenafil may in of potent at of between the of sildenafil and is tadalafil with a tadalafil increased the tadalafil by increased tadalafil by (including for tadalafil tadalafil in a use of tadalafil of at before tadalafil at 1 of by in patients long-term potent leading to not to of of to not use 1 of and P-glycoprotein increased by of times (including for effect to concentrations of in are by with than three times may be = nitric PAH = pulmonary arterial hypertension. Open table in a new tab Table Established and Other Potentially Significant Drug Interactions: DrugInteracting treprostinil increase in treprostinil the of treprostinil to and increase by not more than CYP2C8 selexipag increase in selexipag of selexipag to CYP2C8 active selexipag effect to reduce selexipag to CYP2C8 selexipag effect to reduce selexipag to CYP2C8 selexipag increase in selexipag inhibitors are selexipag in active of selexipag by of selexipag be rifampin and rifampin is = pulmonary arterial hypertension. Open table in a new tab Expect increase in substrate plasma concentration; Inducers: Expect decrease in substrate plasma concentration; Substrates: Metabolism will be affected by inhibitors or inducers, resulting in increase or decrease in plasma concentrations, respectively. OATP = organic anion-transporting PAH = pulmonary arterial hypertension. NO = nitric PAH = pulmonary arterial hypertension. PAH = pulmonary arterial hypertension. drugs may of the three pathways for PAH and not all the medications in a the same drug-drug be of the potential drug-drug interactions that may affect patient we review of the three PAH treatment pathways and the drug-drug interactions commonly Endothelin endothelin 1 to decrease pulmonary Endothelin 1 is a potent that also and Endothelin 1 to endothelin A which to pulmonary and and endothelin which endothelin 1 and via NO and prostacyclin A. A. for pulmonary arterial PubMed Scopus Google Scholar in between and times for than and macitentan are for the and with bosentan being times more for than and macitentan being 50 times more for than the of and on or and the and by endothelin of endothelin and in 2007; PubMed Scopus Google Scholar the three bosentan has the most potential for adverse resulting from drug-drug interactions because of effect and multiple metabolism via CYP450 in liver levels more than three times the of have been with bosentan use because of active into the liver via OATP Other drugs with known be used with which is with bosentan because of an increased risk of liver enzyme A. M. J. In and in studies the interaction between bosentan, a endothelin and PubMed Scopus Google Scholar is metabolized by CYP3A4 and other medications that affect enzymes or induction will affect bosentan levels. a and OATP bosentan plasma concentrations, and use is of a potent CYP3A4 a or with bosentan will cause a significant increase in plasma bosentan levels and are not bosentan also is an of CYP3A4 and and can reduce plasma concentrations of drugs metabolized by oral hormonal contraceptives, which commonly are CYP3A4 substrates, be of the of J. J. M. J. C. and drug-drug interactions of endothelin in pulmonary arterial PubMed Scopus Google Scholar is a therapeutic of bosentan not cause clinically in used Scholar the risk for drug-drug interactions among the because metabolism is the pathway of hepatic J. J. M. J. C. and drug-drug interactions of endothelin in pulmonary arterial PubMed Scopus Google Scholar also is a substrate of CYP2C9, and P-glycoprotein efflux However, a significant clinically drug-drug interaction with Scholar ambrisentan by which a of ambrisentan to 5 administered A that the of ambrisentan was in the and of rifampin, and no of ambrisentan was A. et of on the and of ambrisentan in a Drug 2010; PubMed Scopus Google Scholar The potential for interactions with other drugs that have activity on CYP2C9, and P-glycoprotein and be in patients with and use of drugs with therapeutic M. on the use of ambrisentan in pulmonary arterial Adv Respir PubMed Scopus Google Scholar is a adverse effect by most commonly J. M. D. M. M. Endothelin and for Med. PubMed Scopus Google Scholar Although may treat patients to avoid such that will PAH via A. and J 2021; PubMed Scopus Google Scholar is metabolized by CYP3A4 with metabolism by CYP2C9, and the with CYP3A4 inhibitors be with also avoiding use of macitentan with CYP3A4 and inhibitors because of an increase in macitentan Scholar In the of ketoconazole, a potent CYP3A4 to macitentan However, the increase in macitentan levels was to be clinically because the levels were the in the and studies and were J. J. D. of the of on the of a endothelin in 2013; PubMed Scopus Google Scholar This that of macitentan may not be with CYP3A4 inhibitors to ketoconazole, such as on with and no clinically change in to the active of and be used is with a of CYP3A4 and and Scholar bosentan and ambrisentan, macitentan is not with OATP for hepatic or P-glycoprotein efflux which the possibility of drug interactions at J. and of macitentan in to other endothelin in the treatment of pulmonary arterial Drug Saf. PubMed Scopus Google Scholar As a result, no clinically are macitentan is used concurrently with The of with OATP and P-glycoprotein also macitentan to have fewer than the other In CYP3A4 such as rifampin or have clinically significant in macitentan medications be to ambrisentan, which not significantly with rifampin or be an is by with macitentan has a for drug-drug S. et of and rifampin on the of a endothelin J. PubMed Scopus Google Scholar NO in and the of and the increase in of D. A. T. a for the treatment of pulmonary arterial hypertension and pulmonary Scholar The of NO is in patients with J. J. D. of the of on the of a endothelin in 2013; PubMed Scopus Google Scholar agents that act on the NO pathway increase concentrations of the pulmonary and PAH is for of in pulmonary and also is in S. nitric oxide human to 1987; PubMed Scopus Google Scholar inhibitors, such as sildenafil and tadalafil, the of and activity. a guanylate cyclase to NO and leading to an increase in of use of NO agents with medications that have or may have adverse have that inhibitors are with most and from and M. of tadalafil in patients on J 2003; Full Text Full Text PDF PubMed Scopus Google M. L.M. M. of sildenafil in patients with J 2001; PubMed Scopus Google Drug interactions with inhibitors used for the treatment of or pulmonary 2010; PubMed Scopus Google Scholar such as and are associated with significant risk of with a or guanylate cyclase and are use of an organic is at of between the of and at the of Given the use of and the potential for patients with PAH to is important to all patients tadalafil, or to in medical to avoid such as have significant used with with in of to and S. nitric oxide human to 1987; PubMed Scopus Google Scholar of patients with NO agents is Although the inhibitors sildenafil and tadalafil have and they in drug-drug interactions because of is metabolized by the cytochrome P450 with metabolism by to a M. A. The of inhibitors for 2005; PubMed Scopus Google Scholar of sildenafil is used concurrently with other CYP3A4 inhibitors, leading to plasma concentrations and increased of adverse such as and Drug interactions with inhibitors used for the treatment of or pulmonary 2010; PubMed Scopus Google Scholar of sildenafil for PAH with potent inhibitors such as and is of sildenafil metabolism at CYP3A4 and CYP2C9, resulting in a increase of sildenafil A. J. J. but important PubMed Scopus Google Scholar A of sildenafil with increased sildenafil by and are potent CYP3A4 inhibitors to with no activity at CYP2C9, for increase in sildenafil C. S. S. D. and in the drug-drug interaction with PubMed Scopus Google In of sildenafil of human and potential drug interactions.Drug Metab Dispos Biol Fate Chem. 28: Google Scholar is important to interactions because and are used as inhibitors in combination medications for and cobicistat, and Other inhibitors not have clinically on sildenafil M. A. The of inhibitors for 2005; PubMed Scopus Google Scholar also is to CYP3A4 inducers, which decrease of sildenafil increase in of sildenafil was with St. John’s wort, a CYP3A4 rifampin and phenytoin, potent CYP3A4 inducers, are to cause extensive in sildenafil concentrations that a change in combination in PAH treatment is the use of bosentan CYP3A4 and with which a in the concentration of sildenafil and a increase in bosentan concentration via Although this in concentration of sildenafil is not clinically significant, the sildenafil bosentan combination to the primary in the of of and on and in Pulmonary A and this interaction may have to this et to sildenafil in patients with pulmonary arterial hypertension.Eur Respir J. PubMed Scopus Google Scholar bosentan and sildenafil are used patients may to be for increased bosentan adverse such as and with tadalafil has a longer and is a CYP3A4 S. et of isoforms to of a between sildenafil and tadalafil PubMed Scopus Google Scholar be is to tadalafil at before because of the risk of at concentrations of As as is at a 1 tadalafil may be at a of to for before increasing to long-term use of tadalafil with potent CYP3A4 such as rifampin is not with rifampin was by and Drug drug Food and Drug Administration Scholar also is not metabolized by In to used in combination with bosentan, tadalafil has no effect on plasma concentrations of tadalafil is to be to drug-drug interactions than use with other NO inhibitors inhibitors and other phosphodiesterase inhibitors such as or soluble guanylate cyclase and nitrates, is because of significant effects. between a and between sildenafil and or between tadalafil and be a and of sildenafil in PAH of Respir J. Scholar and are of G. of and for pulmonary hypertension.N Engl J Med. 2013; PubMed Scopus Google Scholar However, is soluble at pump inhibitors and such as or for treatment decrease and be by at 1 and Drug Food and Drug Administration Scholar is metabolized by and can reduce plasma concentrations by to which may in than three times in patients to et of the soluble guanylate cyclase stimulator in young male and of a PubMed Scopus Google Scholar is also a substrate of CYP3A4 and transporter P-glycoprotein and Drugs with activity at multiple such as and P-glycoprotein will increase plasma concentration and may require a at of or is a of with potent and A. A. for pulmonary arterial PubMed Scopus Google Scholar In patients with the decrease of prostacyclin in or and of et of prostacyclin in pulmonary Google Scholar The Food and Drug Administration-approved therapies that the prostacyclin pathway include three or analogs iloprost, and and one prostacyclin and are not to drug-drug interactions because of the of and is at in and is to enzymatic is metabolized via to a use of or with prostacyclin agents may to increased risk of drugs, inhibitors, inhibitors, therapies as or and may increase risk of because of the prostacyclin pathway treprostinil and selexipag are to potential drug-drug interactions by hepatic CYP450 enzymes, of drugs for of cytochrome P450 2005; PubMed Scopus Google Scholar has not been and treprostinil also are to CYP450 enzyme the from the oral have been to the is metabolized by CYP2C8 to a by a potent CYP2C8 treprostinil concentrations is to reduce the of treprostinil to and to increase by not more than to Scholar is a more substrate of CYP2C8 than treprostinil and metabolism via CYP3A4. a CYP2C8 increased the selexipag by S. a CYP2C8 a clinically increase in the to the active of selexipag in J 2021; PubMed Scopus Google Scholar The of selexipag be to in patients a CYP2C8 clopidogrel, leflunomide, and increased the S. M. M. T. A. J. of gemfibrozil and on the of selexipag and active in J PubMed Scopus Google Scholar of selexipag with inhibitors of CYP2C8 is Scholar with an of CYP2C8 and enzymes the active by selexipag and rifampin, the of selexipag be and rifampin is S. M. M. T. A. J. of gemfibrozil and on the of selexipag and active in J PubMed Scopus Google Scholar CYP2C8 is one of the as more or inhibitors are the therapeutic as as adverse of treprostinil and selexipag be A.M. M. of cytochrome P450 in drug metabolism and PubMed Scopus Google Scholar of patients with idiopathic or PAH are This is by a in mean pulmonary of more than to an of with or improved to a active pulmonary NO or M. et for the diagnosis and treatment of pulmonary hypertension: the for the and of Pulmonary of the of and the for and for and J. PubMed Scopus Google Scholar of PAH to of oral such as or are metabolized by which for significant drug interactions with other CYP3A4 inhibitors or T. 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