Pulmonary Arterial Hypertension

Transcription

1 Pulmonary Arterial Hypertension Drug Interactions in Pulmonary Arterial Hypertension and Their Implications Hossein-Ardeschir Ghofrani, Ralph Schermuly, Norbert Weissmann, Robert Voswinckel, Henning Gall, Werner Seeger and Friedrich Grimminger Medical Clinic II/V, University Hospital Giessen and Marburg GmbH Abstract Medical intervention is necessary in the treatment of pulmonary arterial hypertension (PAH) in order to prevent chronic disease progression and clinical deterioration. Recent years have seen the development of new disease-specific drugs, such as endothelin receptor antagonists (ERAs). However, there remains the potential for drug drug interactions (DDIs), which can adversely affect drug metabolism and therefore treatment efficacy, an especially significant factor to consider in light of the increasing use of combination therapy in PAH and the ageing patient population who may also suffer age-related diseases requiring concomitant drug therapy. The ERA ambrisentan has demonstrated lower liver toxicity and fewer DDIs than other ERAs. The lack of any significant drug interactions with commonly used adjunct therapies such as warfarin or sildenafil could potentially improve treatment efficacy as well as patient safety. Keywords Pulmonary arterial hypertension, drug drug interactions, endothelin receptor antagonist, bosentan, sitaxentan, ambrisentan Disclosure: Hossein-Ardeschir Ghofrani has received educational and research grants from Bayer Schering, Pfizer, Encysive (until June 2009) and Ergonex and has provided consulting services for Bayer Schering, Pfizer, Actelion, Encysive, Nycomed, Ergonex and GlaxoSmithKline. In addition, he has performed lectures supported by Bayer Schering, Pfizer, Actelion and Encysive. Ralph Schermuly has received either educational or research grants or speaker honoraria or performed consulting services for Bayer Schering, Pfizer, Actelion, Encysive, Nycomed, Ergonex, GlaxoSmithKline, Novartis and Solvay Pharmaceuticals. Werner Seegar has received educational and research grants from Gilead Colorado, Lung Rx, Myogen Inc. Westminster and Schering Deutschland and has provided consultancy services to Altana Pharma, Bayer Schering, Lung Rx and Schering AG. In addition, he has received speaker honoraria from Bayer Shering, Encysive and Lung Rx. The remaining authors have no conflicts of interest to declare. Received: 1 June 2009 Accepted: 30 June 2009 Correspondence: Hossein-Ardeschir Ghofrani, Medical Clinic II/V, University Hospital Giessen and Marburg GmbH, Klinikstrasse 36, Giessen, Germany. E: Ardeschir.Ghofrani@innere.med.uni-giessen.de Pulmonary arterial hypertension (PAH) has an estimated prevalence of cases/million population. 1 This chronic, progressive disease is defined by a mean pulmonary arterial pressure >25mmHg in conjunction with normal pulmonary capillary wedge pressure <15mmHg. 2 The disease is characterised by increased vascular resistance of the pulmonary microvasculature, ultimately resulting in right ventricular overload, right heart failure and death. 3 Severity of PAH is graded by the New York Heart Association (NYHA) functional classifications (see Table 1), a modification of the original classification by the World Health Organization (WHO); 4 symptomatic severity has long since been recognised to be related to prognosis. 5 Not only is PAH a rapidly evolving disease, but it is also asymptomatic in the early stages. As such, approximately 75% of patients present with NYHA functional class (FC) III and marked functional impairment at diagnosis. 1 PAH is classified as idiopathic (IPAH), familial (FPAH) or occurring in association with other conditions or risk factors. 6 These subgroups share similar clinical and pathological features, but the precise aetiology of PAH remains unknown. This article will consider the treatments available in PAH, the increasing use of combination therapies and the implications of resulting drug drug interactions (DDIs) in PAH, with a special focus on endothelin receptor antagonists (ERAs). Current Management of Pulmonary Arterial Hypertension Treatment of PAH can be non-specific or disease-specific (see Table 2). Anticoagulants are commonly used as conventional therapy in PAH, despite the fact that there has been no evidence from prospective, randomised, placebo-controlled studies in support of this approach. Studies that support the use of anticoagulants have largely been retrospective or non-randomised, with small study numbers of patients with IPAH. 7,8 A target international normalised ratio (INR) between 1.5 and 2.5 for oral anticoagulation is recommended. 9 Diuretics and low-sodium diets are able to relieve hypervolaemia and the associated symptoms, but it is not known whether this approach reduces the burden of right ventricular overload and improves prognosis. Digoxin has also been used as PAH therapy due to its ability to increase cardiac output, but doubts regarding its long-term efficacy have restricted its use to cases of PAH associated with atrial fibrillation. 10 The vasodilatory activity of calcium-channel blockers can be used in a minority of PAH patients to counteract vasoconstriction, which was originally assumed to be the underlying cause of PAH. Favourable response rates to an acute vasodilator are achieved in fewer than 10% of patients, only half of whom are able to main long-term responses TOUCH BRIEFINGS 2009

2 Drug Interactions in Pulmonary Arterial Hypertension and Their Implications Studies of the underlying molecular mechanism in PAH have allowed the development of disease-specific therapies in the three established molecular pathways of PAH pathophysiology: the prostacyclin pathway, the nitric oxide (NO) pathway and the endothelin (ET) pathway. Prostacyclin Pathway and Prostanoids Prostacyclin is a metabolite of arachidonic acid produced by the vascular endothelium, and acts as a potent pulmonary and systemic vasodilator through the effects of the secondary messenger cyclic adenosine monophosphate (camp). 12,13 Prostacyclin also has antiproliferative properties and inhibitory effects on platelet aggregation. Deficiencies of prostacyclin due to reduced expression of prostacyclin synthase in PAH led to the development of prostanoid replacement therapy, of which there are three prostacyclin analogues available on the market (see Table 2). Although effective in improving exercise capacity, cardiopulmonary haemodynamics and symptoms, the short half-lives of these drugs mean that drug delivery is via continuous intravenous (IV) or subcutaneous (SC) administration, which can cause infection from venous catheters and site pain, respectively, or frequent inhalation therapy. 19 Nitric Oxide Pathway and Phosphodiesterase Inhibitors NO has potent pulmonary vasodilatory effects and inhibits platelet activation and vascular smooth-muscle cell proliferation; vasodilation is achieved by activation of the soluble guanylate cyclase by NO and production of the second messenger cyclic guanosine monophosphate (cgmp). 20 However, increased expression of phosphodiesterase-5 (PDE5) in the lungs in PAH leads to enhanced cgmp degradation. Therefore, selective inhibition of PDE5 by sildenafil blocks cgmp degradation in the pulmonary vasculature, leading to increased vasodilatory activity of endogenous NO. 21 Sildenafil has also been shown to improve the six-minute walk distance (6MWD), haemodynamic variables and NYHA FC. 21 Endothelin Pathway and Endothelin Receptor Antagonists Levels of ET-1, a potent vasoconstrictor and smooth-muscle mitogen, are elevated in the plasma and lung tissue of patients with PAH. 22 The effects of ET are mediated by two ET receptor isoforms: ET type A (ET A ) and ET type B (ET B ). Activation of ET A receptors mediates vasoconstriction and cellular proliferation of pulmonary vascular smooth-muscle cells; in normal pulmonary vasculature, ET B receptors mediate vasodilation primarily through clearance of ET-1 circulating in the vascular beds of the lungs and kidneys, and increased production of prostacyclin and NO. 23 Bosentan is a nonselective (dual) ERA; ambrisentan and sitaxentan are specific antagonists of the ET A receptor. Currently, there is no clear evidence suggesting that receptor selectivity confers any advantage in terms of the clinical efficacy of these drugs. Large-scale clinical studies have shown that ERAs have proven efficacy in mediating vasoconstriction in PAH. In the Bosentan Randomized Trial of Endothelin Antagonised Therapy (BREATHE-1), patients receiving bosentan exhibited improvements in FC and exercise capacity as measured by 6MWD and prolonged time to clinical worsening compared with patients receiving placebo. 24 The Sitaxentan to Relieve Impaired Exercise (STRIDE-1) trial showed that patients receiving sitaxentan benefited in terms of improvements Table 1: Functional Classification of Pulmonary Arterial Hypertension* Class I III III IV Description Patients with pulmonary arterial hypertension without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain or near syncope. Patients with pulmonary arterial hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope. Patients with pulmonary arterial hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain or near syncope. Patients with pulmonary arterial hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity. *Modified from the New York Heart Association (NYHA) classification of patients with cardiac disease. Adapted from the pulmonary arterial hypertension (PAH) functional classification according to the World Health Organization, Table 2: Medicines in the Management of Pulmonary Arterial Hypertension Non-specific Therapies Anticoagulants Diuretics Digoxin Calcium-channel blockers Oxygen PAH-specific Therapies Prostacyclin Analogues Epoprostenol (Flolan) Treprostinil (Remodulin) Iloprost (Ventavis) Phosphodiesterase Type-5 Inhibitors Sildenafil (Revatio) Tadalafil (Adcirca) Bosentan (Tracleer) Sitaxentan (Thelin) Ambrisentan (Volibris) Mode of Administration Intravenous infusion Subcutaneous and intravenous infusion/inhalation Inhalation of 6MWD, NYHA FC and pulmonary haemodynamics. 25 The Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) found that patients who were randomised to the ambrisentan groups had significant improvements in increased 6MWD, time to clinical worsening, FC, Borg dyspnoea score and quality of life score. 26 The ERAs are associated with hepatoxicity requiring monthly liver function testing; bosentan and sitaxentan have both been found to induce a dose-dependent increase in hepatic transaminase levels to more than three times the upper limit of normal (ULN) in 11 and 5% of patients, respectively. 24,27 Clinical trials have found a lower incidence of acute hepatotoxicity with ambrisentan, with fewer than 3% of patients experiencing elevations in hepatic aminotransferases more than The pulmonary arterial hypertension (PAH)-specific therapies are European Medicines Agency (EMEA)- and US Food and Drug Administration (FDA)-approved for use in PAH; FDA approval for sitaxentan is currently under way. EUROPEAN CARDIOLOGY 47

3 Pulmonary Arterial Hypertension Table 3: Effect of Commonly Used Pulmonary Arterial Hypertension Medicines on Cytochrome P450 Pathways Cytochrome P450 Subtype Drug CYP3A4 CYP2C9 CYP2C19 CYP3A5 CYP2D6 CYP1A2 CYP2E1 CYP2C8 Met Ind Inh Met Ind Inh Met Ind Inh Met Ind Inh Met Ind Inh Met Ind Inh Met Ind Inh Met Ind Inh Prostacyclin Analogues Epoprostenol 75 Treprostinil 76 Iloprost 78 Phosphodiesterase Type-5 Inhibitors Sildenafil 77 X X X X X X X X Bosentan 62 X X X X X Sitaxentan 63 X X X X X X X X Ambrisentan 31 X X X Some of the drug effects on the cytochrome P450 pathways shown may be weak interactions, which may not be clinically significant. Met = metabolised by; Ind = inducer of; Inh = inhibitor of; X = known interaction; = no known interaction. Table 4: Potential Interactions Between Pulmonary Arterial Hypertension-specific Medications for Intercurrent Illnesses Antiplatelets Statins Digoxin NSAIDs SSRIs/ Sulph. Pioglit. Barb. RTIs Protease Af Cyclos. Hormonal Anticoagulants TCAs Inhibitors Contraceptives Prostacyclin Analogues Epoprostenol 75 X Treprostinil 78 X X Iloprost 76 X Phosphodiesterase Type-5 Inhibitors Sildenafil 77 X X X Bosentan 62 X X X X X X X X X Sitaxentan 63 X X X X X X Ambrisentan 31 NSAID = non-steroidal anti-inflammatory drug; SSRI = serotonin-selective re-uptake inhibitor; TCA = tricyclic acid; RTI = reverse transcriptase inhibitor; X = known interaction; = no known interaction or not clinically significant interaction; Cyclos. = cyclosporine A; Pioglit = pioglitazone; Barb. = barbituates; Af = antifungals. three times ULN This lower incidence of liver function abnormalities has been attributed to the fact that, unlike the other ERAs, ambrisentan does not inhibit the bile salt export pump (BSEP) in the liver Combination Therapy and Drug Drug Interactions With disease-specific therapeutic strategies targeting the multiple pathophysiological pathways and mechanisms of PAH, it is possible that the addition of one agent to another could confer additive or synergistic benefits. Patients can receive disease-specific agents alongside general background therapies, but continued disease progression may eventually lead patients to require a combination of disease-specific therapies in order to effectively manage the disease. The European Society of Cardiology (ESC) advocates such an approach for patients with advanced disease who are not responsive to or exhibit deterioration with first-line treatment. 34 The Registry to EValuate Early And Long-term PAH Disease Management (REVEAL) showed that combination therapy is frequently used to treat PAH in the US, with 36% of patients undergoing dual combination and 9% receiving triple combination. 35 Combination therapy can provide benefits for patients with PAH, addressing more than one of the disease mechanisms and perhaps even allowing for dose reductions and lowered risk of side effects due to enhanced efficacy. 36 However, combination therapy also presents the risk of DDIs, which can compromise disease efficacy or increase the incidence or severity of adverse effects, thereby negatively affecting the health of the patient. Furthermore, the ageing population means an increase in the proportion of elderly patients with PAH, 1,37 many of whom will also require concomitant drug therapy for the prevention or treatment of other age-related diseases, such as diabetes and hypertension. 38 PAH is also frequently associated with other co-morbidities that require concomitant medical treatments, such as scleroderma, HIV and congenital heart disease Studies have shown favourable outcomes in patients receiving combination therapy; sildenafil plus IV epoprostenol conferred improvements in 6MWD and haemodynamic parameters over placebo, with a significant reduction in the number of patients exhibiting clinical worsening, and improved survival. 42 Significant improvements were achieved in 6MWD, NYHA FC and postinhalation haemodynamic parameters in patients with IPAH or associated PAH with NYHA FC III who received the combination of bosentan and iloprost over those who received bosentan and placebo, 43 although another study found no significant change in 6MWD upon addition of iloprost to bosentan. 44 Other studies have documented encouraging results with additional benefits upon sequential addition of bosentan or sildenafil to prostanoids The combination of the orally available 48 EUROPEAN CARDIOLOGY

4 Drug Interactions in Pulmonary Arterial Hypertension and Their Implications Table 5: Significant Drug Interactions Pulmonary Arterial Hypertension Drug Interacting Drug Interaction Bosentan Sildenafil Sildenafil levels fall by 50%; bosentan levels increase by 50% Cyclosporine Contraindicated. Cyclosporin levels fall by 50%; bosentan levels increase 4-fold Erythromycin Bosentan levels increase Ketoconazole, itraconazole Bosentan levels increase HMG-CoA reductase inhibitors Simvastatin levels fall 50%; effects likely to be similar with atorvastatin Warfarin Warfarin metabolism increases, dosage may need re-adjustment Hormonal contraceptives Hormone levels decrease contraception is unreliable Sitaxentan Warfarin Warfarin metabolism inhibited, dosage needs reduction Cyclosporine Contraindicated. Sitaxentan levels increase 6-fold Sildenafil Bosentan Sildenafil levels fall by 50%; bosentan levels increase by 50% HMG-CoA reductase inhibitors Simvastatin/atorvastatin levels may increase HIV protease inhibitors Sildenafil levels increase with ritonavir and saquinovir Erythromycin Sildenafil levels increase Ketoconazole Sildenafil levels increase Cimetidine Sildenafil levels increase Nitrates, nicorandil Profound systemic hypotension HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A. Adapted from Gibbs et al., bosentan and sildenafil has also provided an interesting outcome; patients with mild PAH (WHO FC II) who received this combination were shown to experience decreased pulmonary vascular resistance, but no improvements in 6MWD. 49 Other studies have reported improved 6MWD and NYHA FC in patients with IPAH. 50,51 However, there are pharmacological interactions affecting the metabolism and efficacy of these drugs. Currently, there are no long-term data available concerning combination therapy. DDIs are a result of one medicine altering the pharmacokinetics or pharmacodynamics of another. The most notable DDI is that involving the cytochrome (CYP) P450 oxidases, where modulation of the various CYP isozymes of this enzyme system by one drug can invariably effect the metabolism of another. A number of P450 isozymes with important roles in drug metabolism have been identified; approximately 90% of drug metabolisms by the CYP system can be accounted for by CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP2E1 and CYP3A CYP3A4, of the highly expressed CYP3A family, is the most abundant isoform expressed in the liver and gut, 55 while CYP2D6 and the CYP2C family are also responsible for metabolising a majority of other clinically relevant drugs. 56 Drug Drug Interactions with A number of cytochrome P450 pathways are involved in the metabolism of the ERAs and PDE-5 inhibitor sildenafil (see Table 3). However, ambrisentan, a non-sulphonamide, propanoic-acid-based ERA, is principally metabolised through hepatic glucuronidation, with a minor route through the cytochrome P450 system. These characteristics confer a low risk of DDIs with ambrisentan. 31 Druginduced inhibition of cytochrome isozymes can potentially increase the plasma concentration of the drug, whereas induction would decrease the plasma concentration. The DDIs associated with ERAs are of special interest because many of these interactions are with medications that are taken alongside intercurrent illnesses or conditions (see Table 4). 36 The use of some of these drugs is associated with potential DDIS: bosentan is an inducer of hepatic CYP isozymes, and sitaxentan inhibits hepatic CYP isozymes. 36 Some of these potential clinically significant DDIs are identified in Table 5. Bosentan and sitaxentan are known to compromise the level and therefore the efficacy of CYP3A4 substrates, including cyclosporin, oral oestrogens and simvastatin. Strong CYP3A4 inhibitors such as Drug pharmacokinetics can be influenced by the rate of absorption, the distribution into bodily areas, biotransformation and clearance rates; additional variables of age, genetics and disease mean that DDIs can present in myriad ways in clinical practice. These DDIs can be subtle and go unnoticed unless there is reason to suspect a DDI. Therapeutic ranges of drugs are generally designated such that the lower spectrum is approximately equal to the concentration at which half of the greatest possible therapeutic effect is achieved, while the higher end of the spectrum will limit the number of toxicities to 5 10% of patients. 57 DDIs can then be problematic if the affected drug has a narrow therapeutic window as in the case of warfarin 58 minute changes in plasma concentration could lead to sub-therapeutic effects or toxicity. Furthermore, DDIs are associated with substantial financial effects on healthcare resources; investigations into potential DDIs can prolong the duration and rate of hospitalisation, increase the need for therapeutic monitoring and require extensive laboratory and clinical testing. 59,60 With disease-specific therapeutic strategies targeting the multiple pathophysiological pathways and mechanisms of pulmonary arterial hypertension, it is possible that the addition of one agent to another could confer additive or synergistic benefits. ketoconazole and cyclosporine increase plasma levels of bosentan; the combination of cyclosporine with bosentan or sitaxentan is contraindicated and cautioned with ambrisentan. 31,61,62 Although metabolised by CYP3A4, studies suggest a lack of inductive effect for ambrisentan on the CYP3A4 isozyme. 31 Furthermore, ambrisentan EUROPEAN CARDIOLOGY 49

5 Pulmonary Arterial Hypertension does not appear to interact with the commonly used PAH therapies of sildenafil, a CYP3A4 substrate, and warfarin, a CYP2C9 substrate. 28,63,64 Co-administration of bosentan and sildenafil induces a two-fold increase in sildenafil clearance, 65 while increasing bosentan levels by about 50%. 36,65,66 The resultant decreased dose of sildenafil could lead The use of combination therapy is on the rise, and there is a need for pulmonary arterial hypertension therapies that produce minimal drug drug interactions. inhibitors ritonavir and saquinovir are known inhibitors of CYP3A4, which could interfere with the metabolism of CYP450 isozymes and, thus, bosentan, sitaxentan and ambrisentan. However, DDI studies with antiviral drugs have not been performed. 73 The Outlook for Pulmonary Arterial Hypertension Management The ageing PAH patient population presents a number of complications. Not only are patients older at diagnosis, but they are also more likely to suffer from both disease- and age-related comorbidities, necessitating the use of safe and effective PAH therapies in addition to medications that are required for intercurrent illnesses. Indeed, the use of combination therapy is on the rise, and there is a need for PAH therapies that produce minimal DDIs. to a lack of effect (especially in the indicated dose of 20mg twice a day), while increased bosentan plasma concentration can cause hepatic toxicity. Small but not clinically significant elevations of sildenafil have been observed when co-administered with sitaxentan and ambrisentan separately Induction of CYP2C9 by bosentan or inhibition by sitaxentan can modify warfarin metabolism and alter the bioavailability of the drug, 25,27,36,70,71 which has considerable implications for patients with PAH who use warfarin as background therapy. Indeed, an up to 80% reduction of warfarin was necessary in clinical trials with sitaxentan to prevent over-anticoagulation and account for potential bleeding. 27 Close INR monitoring is recommended when introducing these ERAs. The combination of ambrisentan and warfarin in healthy volunteers and PAH patients did not cause any clinically relevant changes in coagulation, INR or pharmacokinetics of either drug. 64 Pregnancy in women with PAH is associated with an increased risk of maternal mortality of 30 50%. 72 Therefore, women of child-bearing age are encouraged to use both hormonal and mechanical contraception. 34 However, co-administration of PAH drugs can compromise the reliability of hormonal contraceptives. Failure of contraception is possible with bosentan co-administration owing to partial metabolism of oestrogens and progestogens by CYP3A4 and CYP2C9. Conversely, sitaxentan increases oestrogen levels, and can increase contraceptive-associated side effects, such as the risk of thromboembolism, particularly in women who smoke. The combination of ambrisentan and the combined oral contraceptive pill did not cause any clinically relevant changes in either component of the combined oral contraceptive pill (COCP). 31 All three ERAs are contraindicated in pregnancy owing to their teratogenic profiles. 31,61,62 To control hypercholesterolaemia and prevent cardiovascular disease, simvastatin is commonly prescribed. Co-morbidities present in the ageing PAH patient population mean that many of these patients may also require simvastatin therapy. However, co-administration of bosentan and simvastatin significantly reduces the plasma concentration of simvastatin; there was no effect on the plasma concentration of bosentan. 71 Patients receiving bosentan in addition to simvastatin therefore need careful monitoring of cholesterol levels and subsequent dose adjustments. Antiviral drugs used in the treatment of HIV also present potential problems if co-administered with PAH therapies. The HIV protease It is important to address the matter of DDIs, and their potential to perturb the achievement of therapeutic goals. There are various benefits of reducing DDIs: increased treatment efficacy, enhanced ability to implement combination therapies and reductions in complications and investigations to allow healthcare resources to be better spent. Although monotherapy in PAH has undergone great medical advances in recent years, patients with PAH still experience poor quality of life and survival, attempt combination therapies. prompting physicians to The limited data available concerning combinations of bosentan or sildenafil plus prostanoids are encouraging, but there is clearly a need for further studies in order to evaluate the role of other combinations of classes of therapies targeting different pathways of PAH: it is necessary to conduct such studies to ascertain which combinations are beneficial and which have the potential for adverse DDIs. Current data have shown that each of the ERAs has different safety profiles and DDIs. Although each of the ERAs requires monthly liver test monitoring, ambrisentan has demonstrated the least liver toxicity. Head-to-head studies comparing ambrisentan directly with Although monotherapy in pulmonary arterial hypertension has undergone great medical advances in recent years, patients with pulmonary arterial hypertension still experience poor quality of life and survival. other standard therapies would help to define the role of this drug in treating PAH. As yet, there are no such studies that directly compare the efficacy and side-effect profile and incidence between ERAs; any conferred advantage of one agent over the other in PAH is only speculative. However, ambrisentan offers a clinically important advantage compared with other ERAs in that there is a lack of any significant drug interactions with warfarin and sildenafil, thus potentially improving patient safety for the population of PAH patients requiring multiple therapies. 50 EUROPEAN CARDIOLOGY

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