Substrate‐specific pharmacokinetic interaction between endothelin receptor antagonists and phosphodiesterase‐5 inhibitors – assembling the clues

While the cure for pulmonary arterial hypertension (PAH) has been elusive, it has been managed by the use of prostanoids, endothelin receptor antagonists (ERA) and the phosphodiesterase-5 (PDE5) inhibitors [1–7]. Recently, the combination of ERA (e.g. bosentan) and PDE5 inhibitors (e.g. sildenafil) has been explored with encouraging outcome [6, 8–10]. The clinical pharmacology of bosentan, the first approved ERA, has been reviewed by Dingemanse and van Giersbergen [11]. Bosentan apparently undergoes complete elimination via hepatic metabolism, followed by biliary excretion of the metabolites with an elimination half-life of 4–5 h. Apart from mild hepatic dysfunction, other conditions of hepatic dysfunction of increasing severity substantially altered the pharmacokinetic disposition of bosentan. The involvement of both cytochrome P450 (CYP) 3A4 and CYP2C9 has been implicated in bosentan's metabolism to form three oxidative metabolites. Interestingly, bosentan decreases the exposure of both CYP3A4 and CYP2C9 substrates due to induction phenomena, whereas a CYP3A4 inhibitor has the propensity to increase dramatically the exposure to bosentan. The pharmacokinetics and clinical pharmacology attributes of sildenafil have been described [12–15]. The metabolic pathways of sildenafil comprise N-demethylation, aliphatic hydroxylation and oxidation, with major involvement of CYP3A4 (70%) and minor involvement of CYP2C9 (20%) isozymes; upon co-administration, both CYP3A4 and CYP2C9 inhibitors can increase exposure of sildenafil, whereas the inducers of these isozymes drastically reduce exposure to sildenafil. The clearance of sildenafil was described to be moderate in humans and the elimination half-life value is about 3 h. The clinical pharmacology and pharmacokinetic characteristics of tadalafil have been reported [15–18]. Tadalafil's metabolism, controlled by CYP3A4, showed formation of an inactive catechol metabolite. A large portion of the catechol metabolite undergoes Phase II metabolism after methylation step to form a glucuronide conjugate. Tadalafil has been documented not to inhibit or induce important CYP isozymes. However, co-administration of tadalafil with CYP3A4 inducer or inhibitor can decrease or increase the exposure of tadalafil. Clearance of tadalafil is slower compared with sildenafil, with an elimination half-life of 17 h. Recently a systematic pharmacokinetic investigation was published that evaluated the interaction potential of both agents when co-administered vs. single agent treatments [19]. There was a 60% reduction in the exposure of sildenafil, which confirmed the earlier findings of decreased exposure of sildenafil when co-administered with bosentan [19, 20]. However, interestingly, an opposite effect was observed in the exposure of bosentan, which showed about 50% increased exposure as a result of co-administration with sildenafil [20]. The authors postulated that sildenafil may play an inhibitory role in the hepatic transporter uptake/biliary clearance of bosentan [20–22]. Since bosentan does not undergo nonhepatic clearance, an inhibitory effect on hepatobiliary clearance mechanisms may lead to the accumulation of the drug. Although sildenafil is an organic anion-transporting polypeptide (OATP) transport inhibitor [22], it was apparent that a greater threshold concentration was necessary to elicit the desired response. It is quite possible that with a dosing of 80 mg sildenafil (t.i.d.), the desired threshold may have been achieved in this study under in vivo conditions [20]. Almost concurrently, another interesting pharmacokinetic interaction report between bosentan and tadalafil in healthy subjects has been published [23]. Whereas, as expected, bosentan reduced the exposure of tadalafil by almost 40%, tadalafil did not appear to increase the exposure of bosentan, in contrast to what was observed previously with that of sildenafil, although numerically the exposure of bosentan (i.e. AUC) was found to increase marginally by 13% [23]. Although it is difficult to rationalize the unique pharmacokinetic interaction observed in the above-cited examples [20, 23], it appears that differential behaviour is exhibited by the two PDE5 inhibitors. It is unknown whether or not tadalafil has a role to play in the OATP transporter uptake inhibition of bosentan. Additionally, a recent study seems to suggest that tadalafil has a tendency to exhibit mechanism-based inhibition of CYP3A4 isozyme with a very low potency [17] and therefore there was a possible opportunity to increase bosentan levels from both speculative counts (CYP3A4 and hepatic uptake inhibition), although it was not supported by study data [23]. These recently reported differential pharmacokinetic interaction data between bosentan vs. PDE5 inhibitors [20, 23] will pave the way for further in vitro and in vivo experiments to understand fully the nature and consequences of such interactions. In this context, another approved ERA agent, ambrisentan, for PAH treatment, may provide an alternative option for co-administration with PDE5 inhibitor [24]. Since ambrisentan is a substrate for both OATP and P-glycoprotein transporter systems as well as CYP3A4 [25], it could be speculated that a similar type of interaction could possibly occur between sildenafil and ambrisentan. However, a single dose of ambrisentan (10 mg recommended dose) did not influence the pharmacokinetic disposition of sildenafil (20 mg t.i.d. dosing) and its active metabolite [25]. Similarly, the pharmacokinetics of ambrisentan was not altered by a single dose of sildenafil [25]. Although no reports have been published, it is unlikely that a drug–drug interaction would have occurred under steady-state conditions between the two agents, because ambrisentan is not documented to be a CYP3A4 inducer or inhibitor [24]. Although drug–drug interaction represents a liability, it could be countered by proper dosage adjustments of either one of the two agents. Although it is customary to dose adjust one agent per the propensity of the documented interaction, it may be difficult to dose adjust both agents such as the one observed between bosentan and sildenafil, especially when the effect of the two agents is observed to act in opposite directions. The other key question is: does increased exposure to bosentan adequately compensate for the reduced exposure to both sildenafil and its metabolite in terms of the pharmacodynamic attributes so that the requirement for dosage adjustment would not arise. Therefore, from all data gathered from the literature there appears to be scientific merit in rationalizing combination use in PAH patients of ERA and PDE5 inhibitors by choosing the appropriate agents that present limited potential for any drug–drug interaction, and/or titrating to the desired pharmacodynamic end-points by taking advantage of the observed pharmacokinetic interactions. None declared.