First‐in‐man study of ACT‐453859, a potent CRTH2 antagonist—Is the metabolite formation influenced by a polymorphic enzyme?

Gehin et al (2015) reported an interesting phase 1 investigation of ACT-453859, a new and potent CRTH2 antagonist, where a systematic evaluation of safety, tolerability, pharmacokinetics, and pharmacodynamics was performed in a meticulous manner.1 This has led to nominating the drug for the next phase of clinical investigation to probe the clinical effectiveness of the drug. The work needs to be commended for providing an exemplary early investigation package that could serve as a model to probe clinical pharmacology–related issues for other therapeutic areas. Particularly, some key questions relating to dose selection and dose regimen for a human proof-of-concept study were answered by a careful design of pharmacodynamic measurements in both single- and multiple-dose studies. The inclusion of a comparator drug, setipiprant, which had previously undergone a successful proof-of-mechanism study in humans, further substantiated the intrinsic value of the clinical pharmacology data of ACT-453859.1 The appearance of the dealkyated metabolite (M1) peak at the first pharmacokinetic sampling point as well as the M1 peak almost coinciding with the Tmax of the parent drug suggested that metabolism of ACT-453859 may be occurring presystemically (ie, first-pass metabolism).1 Because the parent/metabolite AUC ratios appeared to be relatively constant across the single or multiple doses, it suggested that first-pass metabolism was not saturated, even at high oral doses and/or the metabolism of ACT-453859 may be mediated by multiple CYP enzymes. However, at the top single dose, there appeared to be a suggestion of a lowered metabolism (parent/metabolite ratio of 2.53 compared with an average of 2 for all other doses combined).1 The contribution of M1 appears to be important for total drug pharmacodynamic activity, as enumerated by a sustained pharmacodynamic effect under steady-state conditions.1 For instance, if M1 pharmacodynamic effects were to be removed, the pharmacodynamic profile of ACT-453859 would be similar to the comparator profile, and this would have necessitated every-12-hour dosing. Therefore, understanding the M1 formation and disposition may further benefit the design of future clinical studies. The noninclusion of a phenotyping strategy using midazolam as a probe substrate for CYP3A or a cocktail approach to probe various CYPs in the first-in-man study suggested that there was no particular concern for the involvement of any particular CYP enzyme(s) in the metabolism of ACT-453859. Given this background, a few questions that need introspection would be the following: (1) Is the formation of M1 metabolite mediated by a single CYP or multiple CYP enzymes? (2) Is there involvement of any polymorphic CYP in the metabolism of ACT-453859? (3) Because a substantial amount of M1 is formed, is there any particular concern of CYP enzyme inhibition? Although some of the developmental issues will get sorted out, ACT-453859 represents an interesting drug that appears to have the right attributes of pharmacokinetics/pharmacodynamics and is well differentiated from its predecessor, setipiprant.