Understanding the Pharmacokinetics of Oral Treprostinil in Patients With Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a life-threatening disorder characterized by abnormal elevation in the pulmonary pressures that, if untreated, leads to right heart failure and death. The disease is thought to develop as a consequence of a genetic and environmental injury that triggers progressive small vessel loss and obliterative vascular changes, which impair blood flow and increase pulmonary vascular resistance.1,2 At present, there are 3 classes of therapies approved for the treatment of World Health Organization (WHO) group 1 PAH: phosphodiesterase (PDE) 5 inhibitors, endothelin receptor antagonist (ERAs), and prostacyclin analogs.2 Although PDE5 inhibitors and ERAs are mostly available in pill form, prostacyclin analogs can be administered via inhaled, subcutaneous, and/or intravenous routes.3 As the first of the prostacyclin analogs to receive Food and Drug Administration approval in 1995, epoprostenol remains one of the most potent therapies available to treat patients with moderate to severe idiopathic PAH. Besides being effective in improving functional status, exercise capacity, and quality of life, epoprostenol is the only PAH therapy that has been shown to increase survival.4 However, because of its very short half-life (T1/2 = 2–3 minutes), use of epoprostenol requires that patients have rapid access to medical attention in case of treatment interruption because this can lead to acute cardiopulmonary decompensation and death. The introduction of treprostinil in 2002 marked a new era for the prostacyclin analogs as this class of agents, in contrast to epoprostenol, have a longer half life (T1/2 = 4–6 hours) and can be administered in inhaled, subcutaneous, or intravenous forms with similar therapeutic efficacy. However, despite its apparent advantages over epoprostenol, use of treprostinil still requires that patients undergo intense training on how to prepare the medication and on the appropriate use of the specialized delivery devices required for its administration.2 Furthermore, given the need for permanent tunneled catheter to allow continuous administration of either epoprostenol or the intravenous form of treprostinil, these patients are also at risk of non–PAH-related complications such as line sepsis and thrombosis.5 Therefore, it is no surprise that much effort has been invested in developing oral prostacyclin analogs that demonstrate similar therapeutic efficacy as that of epoprostenol or treprostinil but with a better safety profile. To address the need for an oral prostacyclin analog, treprostinil diethanolamine was introduced as a salt form of treprostinil that, when incorporated within an osmotic capsule, can provide sustained-release of the drug with an absolute bioavailability of 18%.6 To determine the safety and efficacy of treprostinil diethanolamine in PAH, 2 phase 3 trials were started in 2006: the FREEDOM C (which looked at oral treprostinil in patients receiving other oral PAH therapies) and FREEDOM M (which looked at oral treprostinil in treatment-naive patients with PAH). In 2012, the results of FREEDOM C were published and indicated that the study did not meet its primary end point because change in 6-minute walk distance from baseline to week 16 was nonsignificant.6,7 A key observation in this study was that many patients discontinued the test drug prematurely as a result of severe side effects, which were made worse when the dose was increased. This is relevant as the authors state that the high discontinuation rate could have limited the overall potential effect of oral treprostinil and could explain the apparent lack of significant improvement in exercise capacity. In the original experimental design, patients were being initiated with doses of treprostinil diethanolamine of 1.0 mg followed by 1.0 mg increments every 3 days as tolerated. However, after encountering that many patients were not able to tolerate this regime, the investigators decided to amend the protocol to include 0.5 and 0.25 mg tablets, which led to a dramatic decrease in the rate of treatment discontinuation (25% in those who only used 1.0 mg vs. 0% in patients who had access to 0.25, 0.5, and 1.0 mg tablets). However, since the new doses were introduced 1 year before the conclusion of the study, the impact of the protocol amendment may have been missed in the final analysis. Finally, it is worth noting that since these patients were also being treated with other oral therapies such as PDE5 inhibitors and ERAs, it is possible that drug–drug interactions could have reduced the biological activity of the oral treprostinil. Given the potential limitations that dosing of oral treprostinil could have on future use of this therapy in patients with PAH, it is especially important to have a better understanding of the pharmacokinetics of treprostinil diethanolamine in patients with WHO group 1 PAH. The study by White et al7 published in this issue of the journal attempts to characterize the pharmacokinetics of oral treprostinil in patients who participated in both FREEDOM C and M using serum samples to measure drug levels and clearance within 12 hours of administration. The investigators looked at 70 patients, 54% of them were on oral treprostinil monotherapy, and documented that the great majority were taking a dose of either 2.0 or 6.0 mg. They report that the area under the curve covering the time before and after the treprostinil dose (AUC0–12) increased consistently with increases in the dosage ranging from 5244 to 204,086 pg·h−1·mL−1. An interesting find was that with the exception of a few patients, the time to maximum concentration occurred within 8 hours after treprostinil administration. Also, the apparent clearance estimates (CL/F) were found to be similar across all groups supporting that the relationship between dose and AUC0–12 was constant. Using both nonlinear and linear analyses, the authors demonstrate that a linear relationship exist between maximum plasma concentrations and dosing of oral treprostinil if used within a range of 0.5 and 15 mg. Finally, despite reporting no statistically significant variability secondary to factors within the study population, the authors identified trends suggesting possible effects on AUC0–12 by ethnicity and concomitant ERA. The authors conclude that twice-daily treprostinil diolamine administration using the range included in the protocols of FREEDOM C and M should provide adequate treprostinil plasma concentrations in patients with PAH and that increasing doses should result in a proportional increase in treprostinil levels. There are a number of strengths and weaknesses associated with this study that should be taken into account as we prepare to move forward with this therapy into the clinical arena. Overall, the study's main strength is that it provides evidence that the doses of oral treprostinil used in the clinical trials result in proportional increases in plasma treprostinil concentrations. This is important as we look back at FREEDOM C and attempt to understand the difficulties the investigators of that trial faced when attempting to increase oral treprostinil dosage by 1.0 mg every 3 days to their goal of achieving doses of 12–16 mg by the end of week 16. Given the almost linear proportionality between dosage and plasma concentration, it can be predicted that a 1 mg tablet of treprostinil diolamine would produce plasma levels equivalent to those seen with a dose of 8–12 ng·kg−1·min−1 of intravenous treprostinil. Because this dose range is associated with significant side effects in patients being initiated on intravenous therapy, it may explain the high incidence of significant side effects experienced by patients in FREEDOM C and justify the use of smaller doses (0.25 and 0.5 mg) for initiation and titration of oral treprostinil. This strategy has now been used in the recently published FREEDOM M trial in which patients who had access to 0.25 mg tablets managed to tolerate doses of up 3.6 mg by the end of the study (week 12).8 However, despite the availability of smaller doses, the rate of patient discontinuation was 17% raising concerns that despite the dose reduction, the side effects may still remain an issue when attempting to dose titration. The critical weakness of the study is the lack of efficacy and adverse effect data at the time of sampling that could have allowed for a more accurate correlation between a particular dose and its clinical impact. This information is important if we consider that, given the proportional increase in side effect relative to dosage, it would have allowed to determine whether a dose range with the minimum side effects would still have provided acceptable benefits in exercise capacity. Although authors address this serious limitation in their discussion section and promise that future open-label studies will address this issue, the question remains as to what would be the optimal therapeutic dose of oral treprostinil that should be offered to patients. Given that patient compliance with prostacyclin analogs is strongly influenced by the severity of side effects, the success of oral treprostinil will be strongly dependent on how well this therapy can be tolerated by patients. Another unfortunate limitation of this study is the small number of patients included who were using other oral PAH therapies such as PDE5 and ERAs. Although the authors state that no statistically significant variations in oral treprostinil levels were observed in the setting of either PDE5 inhibitors or ERA use, the small numbers of patients in these groups (n = 8 for PDE5 inhibitors, n = 19 for ERAs, and n = 5 for use of both) raise questions as to whether the use of larger numbers could reveal that significant interactions exist between oral treprostinil and either PDE5 or ERAs. This is an important point as most patients with PAH are currently on some form of oral monotherapy or a combination and the addition of oral treprostinil to these patients should take into account whether the therapeutic efficacy of the latter may be adversely affected by the presence of other agents. This is relevant to future trials using oral treprostinil as indicated by the announcement in 2011 that FREEDOM C2 (a 16-week trial of oral treprostinil in patients already on approved oral therapies) failed to meet its primary end point of improvement in exercise capacity despite use of 0.25 mg tablets for dose titration. Despite the disappointing results of FREEDOM C and C2, there is still hope that oral treprostinil may have a role in the management of patients with PAH. The results of the recently published FREEDOM M study showed that patients on oral treprostinil demonstrated a significant increase in their 6 Minute Walk Test from baseline (23.0 m, P = 0.0125) arguing that the use of this agent as monotherapy may prove to be the a better strategy. However, it remains to be seen whether performance of oral treprostinil offers advantage over other Food and Drug Administration–approved oral PH therapies to justify its preferential use in newly diagnosed patients with WHO group 1 PH. Another argument that has been raised to explain the lack of efficacy of oral treprostinil is that patients may not have reached adequate therapeutic levels because of the short duration of the studies. At present, the FREEDOM EV (NCT#01560624) study is recruiting patients who have recently being initiated on approved oral therapies to study the effects of oral treprostinil over a longer time period. In contrast to other FREEDOM studies, the primary end point will be time to clinical worsening rather than change in exercise capacity. Finally, interest in developing oral prostacyclin analogs have extended beyond treprostinil and have motivated investigators to look at both old and new drug candidates to fill this void. Among the available oral prostanoids, beraprost sodium has received significant attention in the past for being one of the first oral prostanoid analogs to be investigated in patients with PH. Published in 2002, the ALPHABET study reported that beraprost led to a significant improvement in exercise capacity, functional status, hemodynamics, and dyspnea in patients suffering from New York Heart Association functional class II and III PAH over a period of 12 weeks.9 Despite this promising result, subsequent studies demonstrated that these benefits are transient given that no differences were seen between patients taking beraprost or placebo by 12 months.10 In light of these findings, beraprost is not currently approved for use in the United States but has found a place in the treatment regime for patients with PH in other countries. Most recently, there has been much interest surrounding selexipag, a novel non-prostanoid prostaglandin receptor agonist that has been shown in phase 2 studies to produce significant improvements in both pulmonary vascular resistance and 6MWT in patients already taking other oral therapies.11 The favorable side effect profile of selexipag has led to the initiation of a phase 3 multicenter, double-blind placebo-controlled trial (GRIPHON, NTC#NCT01112306) designed to determine the safety and efficacy of selexipag in a population of more than 1000 patients with PAH. In conclusion, it remains to be seen how oral treprostinil would fit into the treatment algorithm for PAH or whether it will be compatible with the other oral therapies included in the guidelines. Although the available evidence seems to suggest that patients who are treatment naive may benefit the most from initiation of oral treprostinil, it is important to ask whether the expected clinical benefit will justify using this therapy in lieu of PDE5 inhibitors or ERAs and the potential side effects associated with the drug. However, as it appears that the field is poised to answer these questions over the next 3 years, it is possible that we may yet see these agents being incorporated in the treatment armamentarium to provide more options to clinicians who care for patients afflicted with this devastating disease.