Pharmacologic Treatments for Pulmonary Hypertension

Exploring Pharmacogenomics

Julio D Duarte; Rebekah L Hanson; Roberto F Machado

Disclosures

Future Cardiol. 2013;9(3):335-349. 

In This Article

PDE5 Inhibitors

Pharmacology

Two important features of PAH are increased expression of the vasoconstrictor PDE5 and decreased production of the vasodilator nitric oxide in the pulmonary vasculature.[93] PDE5 is an enzyme abundantly expressed in the lungs that hydrolyzes cGMP, a second messenger of the NO pathway within the lungs. PDE5 inhibitors prevent the hydrolysis of cGMP, which has vasodilatory and antiproliferative effects on the pulmonary vasculature.[93] The two PDE5 inhibitors FDA-approved for treatment of PAH in the USA are sildenafil and tadalafil.

Sildenafil has high selectivity for PDE5 versus PDE2, 3 and 4.[94] However, selectivity is decreased towards PDE6 and 1, which can increase cAMP, and may explain some of sildenafil's antiproliferative effects.[95] Sildenafil has a half-life of approximately 4 h, requiring dosing three-times daily. Limited food interactions exist with sildenafil; however, absorption and extent of systemic exposure (area under the curve [AUC]) is reduced when given with a high-fat meal.[96] Sildenafil is somewhat metabolized by CYP2C9, but is predominantly metabolized by CYP3A4 into an N-desmethyl metabolite that also has some PDE5 inhibitory activity.[97] Thus, drug interactions can occur with CYP3A4 inhibitors such as erythromycin, saquinavir or ritonavir.[98,99] Importantly, pharmacokinetic studies have shown that sildenafil AUC decreases approximately 50% when coadministered with bosentan, a known inducer of CYP3A4.[100]

Similar to sildenafil, tadalafil is highly selective for PDE5 compared with 1–4 and 7–10. Because of its long half-life (17 h), tadalafil is usually dosed once daily. Tadalafil pharmacokinetics are not affected by food or alcohol consumption, and it is primarily metabolized by CYP3A4 to inactive metabolites. Thus, known inducers of CYP3A4 such as rifampin, phenytoin and carbamazepine, and inhibitors such as ketoconazole, ritonavir and erythromycin could affect plasma concentrations of tadalafil.[101]

Clinical Use

The pivotal trial that established sildenafil as a treatment for WHO Group 1 PH was the SUPER trial.[102] SUPER enrolled WHO functional class II and III PAH patients, who were randomized to receive placebo or sildenafil 20, 40 or 80 mg three-times daily for 12 weeks. Compared with placebo, sildenafil improved 6MWD, mPAP, and WHO functional class, all in a dose-dependent fashion. However, incidence of clinical worsening did not differ with sildenafil therapy. Based on the results of SUPER, the FDA-recommended dose for treatment of PAH is 20 mg three-times daily.

Sildenafil has also been tested in combination with other PAH medications. In the PACES trial, patients on long-term iv. epoprostenol were randomized to receive either placebo or sildenafil 20 mg three-times daily, which was titrated to 40 or 80 mg three-times daily.[103] An additional improvement in 6MWD and longer time to clinical worsening were observed with the addition of sildenafil treatment. This study suggests that combination therapy may be beneficial in some patients. One recent study investigated sildenafil in patients with PH associated with sickle cell disease, but was halted early due to an increased incidence of hospitalization for pain in the sildenafil group.[104]

Tadalafil showed benefit in PAH in the PHIRST trial.[105] This trial enrolled 405 PAH patients (a majority were WHO functional class II and III) and randomized them to placebo or tadalafil 2.5, 10, 20, or 40 mg daily for 16 weeks. Compared with placebo, tadalafil 10, 20 and 40 mg significantly improved 6MWD in a dose-dependent manner, while improvement in WHO functional class did not significantly differ at any dose. Only the 40-mg dose improved incidence and time to clinical worsening. Of note, approximately half of the enrolled patients were also on bosentan and 6MWD improvement in this subset of patients only trended towards significance. Based on the results of this trial, the FDA-recommended dose for treatment of PAH is 40 mg daily.

While a majority of the research with PDE5 inhibitors has been completed in patients with WHO Group 1 PH, disease improvement has also been observed in WHO Groups 2, 3 and 4. In Group 2 PH, the use of vasodilators could theoretically cause pulmonary edema when administered to patients with elevated LV filling pressures. However, this may be offset if administered with concomitant treatments that reduce LV afterload and filling pressures.[19] A recent clinical pilot study investigated 1 year of sildenafil treatment (50 mg three-times daily) in 44 patients with WHO Group 2 PH associated with left heart diastolic dysfunction.[106] Improvements were found not only in mPAP and pulmonary capillary wedge pressure, but also RV function, pulmonary function and quality of life. Additionally, a retrospective case–control study in patients with PH associated with advanced heart failure awaiting transplant indicated that sildenafil reduced PVR and improved New York Heart Association functional class and post-transplant survival.[107] A large, randomized, placebo-controlled trial is currently underway to more clearly establish the therapeutic benefits of sildenafil treatment in patients with WHO Group 2 PH.[108]

At this point, the data do not support the use of PDE5 inhibitors in patients with WHO Group 3 PH. In patients with COPD, one small clinical study found that a single dose of sildenafil improved mPAP, but also impaired gas exchange, which decreases arterial oxygenation.[109] Impaired gas exchange with sildenafil was confirmed in a recent study of COPD patients without PH.[110] However, other small studies of sildenafil in COPD patients both with and without PH failed to detect any changes in stroke volume, CO or exercise capacity, as well as observing no changes in oxygenation.[111,112] In ILD, small clinical studies indicate that sildenafil causes preferential pulmonary vasodilation, as well as increasing 6MWD.[113,114] However, unlike in COPD, sildenafil may improve gas exchange in this patient population.[114]

In WHO Group 4 patients with inoperable CTEPH, one study found that 3 months of sildenafil treatment (50 mg three-times daily) significantly reduced pulmonary vascular resistance and increased 6MWD.[115] Lastly, in patients with sarcoidosis (WHO Group 5), a small retrospective study showed that sildenafil improved mPAP and PVR.[116]

Compared with prostacyclin analogs and ERAs, PDE5 inhibitors tend to be well tolerated. Adverse effects appear to be similar in sildenafil and tadalafil.[102,105] The most common effects include headache, dyspepsia, flushing, visual impairment and nasal congestion.[117] Due to the concern regarding severe hypotension, PDE5 inhibitors should not be used with nitrates. More serious, but rare adverse effects include retinal vascular disease, myocardial infarction and nonarteritic ischemic optic neuropathy.[118,119]

Pharmacogenomics

While not numerous, more pharmacogenetic studies exist in PDE5 inhibitors than in other PH medications and almost exclusively in sildenafil. Most of the pharmacogenetic research carried out with sildenafil relates to its use in erectile dysfunction (ED). However, some of these data can be extrapolated to sildenafil's use in PH, as its mechanism of vascular smooth muscle vasodilation is similar in both diseases. Thus, many of the genetic associations found in ED response indicate strong candidates for research in PH.

A T-1142G polymorphism in the PDE5 promoter region was not found to be associated with sildenafil response in ED patients.[120] However, because no evidence exists in the literature that other polymorphisms in the gene have been studied, PDE5 cannot be completely ruled out as a candidate gene. A key effector in the NO–cGMP pathway is endothelial NO synthase (eNOS). In two separate studies, the 4a variable number tandem repeat in intron 4 of NOS3 (the gene that encodes eNOS) was associated with better ED response to sildenafil.[121,122] A separate group replicated this variable number tandem repeat association and also found an association between C allele in T-786C and good response to sildenafil.[122] A retrospective study suggests that variation in GNB3, a gene that encodes a key component of intracellular signal transduction in G-protein-coupled receptors, affects sildenafil response in ED.[123] However, the number of patients with the response-affecting variant was small and this finding is yet to be replicated in the literature.

Since CYP2C9 is responsible for approximately 20% of sildenafil metabolism, potential polymorphisms in CYP2C9 could affect sildenafil response. However, when heterozygotes were tested retrospectively in a sildenafil pharmacokinetic study, nonsignificant increases in AUC were observed.[124] It is important to note, however, that none of these subjects were homozygous genetic variants, which is often associated with a much greater decrease in in vivo enzyme activity. Thus, pharmacogenetic effects of CYP2C9 on sildenafil pharmacokinetics cannot be ruled out.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....