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The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP3652 in First-in-Human and Ascending Multiple Oral Dose Studies in Healthy Subjects



Inhibitors of fatty acid amide hydrolase (FAAH) increase the levels of endocannabinoids and have shown analgesic and anti-inflammatory activity in animal models. ASP3652 is a peripherally acting FAAH inhibitor in development for the treatment of chronic bladder and pelvic pain disorders. Here we describe the safety, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of ASP3652 administered in healthy non-elderly and elderly male and female volunteers.


Study 1 was a combined single-ascending dose and food-effect study in which ASP3652 was given as single doses (1–600 mg) or matching placebo in healthy subjects. Study 2 was a multiple ascending dose study in which ASP3652 or matching placebo was administered in multiple oral doses (10–300 mg bid and 600 mg qd for 14 days) to healthy subjects. In both studies, the levels of ASP3652, FAAH, endocannabinoids (eCBs) and safety were evaluated.


ASP3652 was readily absorbed to reach Cmax at 1 h after a single dose. Steady state was reached within 3 days after the start of multiple dosing. The Cmax and AUC of ASP3652 increased in a slightly more than dose-proportional manner after a single dose of ASP3652 at 30–600 mg. There was some accumulation (15–38%) based on Cmax and AUC12h upon multiple doses. Cmax was 47% lower in combination with food. There was no significant effect of gender or age on the pharmacokinetics of ASP3652. FAAH activity was inhibited in a dose-dependent manner in all dose groups after single and multiple doses of ASP3652, paralleled by an increase in plasma levels of anandamide (AEA). The incidence of adverse events following multiple doses was similar across all treatment groups including the placebo group.


Single and multiple doses of ASP3652 were safe and well tolerated and increased endogenous cannabinoid plasma levels.

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The authors would like to thank all the participants of these studies.


Both studies were funded by Astellas Pharma Europe B. V. and journal’s Rapid Service Fee was funded by Astellas Pharma Inc.


All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.


Dr. Dirk Cerneus, Dr. Ingrid Michon, MSc. Sanne Rijnders, MSc. Desiree van der Heide; MSc. John Meijer were employees of Astellas Pharma Europe B. V. at the time of the conduct of the work. Dr. Yuichiro Sato, MSc. Masaomi Takizawa and Dr. Matthias Stoelzel are employees of Astellas Pharma Inc. The authors have indicated that they have no other conflicts of interest with regard to the contents of this article.

Compliance with Ethics Guidelines

Both studies were conducted in accordance with ethical principles that have their origin in the Helsinki Declaration of 1964 and its later amendments, Good Clinical Practice, International Conference on Harmonization guidelines, and applicable laws and regulations. Protocols and informed consent forms of both studies were approved by the Independent Ethics Committee (Medisch Ethische ToetsingsCommissie). Study 1 was conducted at a clinical center of PRA International (Zuidlaren, the Netherlands) from July 2008 to May 2009 and study 2 at a clinical center of PRA International (Groningen, the Netherlands) from May 2009 to May 2010. All subjects provided written informed consent before screening.

Data Availability

The datasets generated or analyzed during the both studies are available at For the Astellas criteria on data sharing, see

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Correspondence to Masaomi Takizawa.

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Supplementary file1 (DOCX 60 kb)


Supplementary Fig. 1 Individual Cmax adjusted for dose by body weight for ASP3652 after single oral administration (PKAS) (TIF 28 kb)


Supplementary Fig. 2 Individual AUC adjusted for dose by body weight for ASP3652 after single oral administration (PKAS) (TIF 25 kb)

Supplementary Fig. 3 Individual Cmax values for plasma AEA in steady state (PDAS) (TIF 22 kb)

Supplementary Fig. 4 Individual AUC12h values for plasma AEA in steady state (PDAS) (TIF 22 kb)

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Takizawa, M., Cerneus, D., Michon, I. et al. The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP3652 in First-in-Human and Ascending Multiple Oral Dose Studies in Healthy Subjects. Adv Ther 37, 3878–3900 (2020).

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  • Anandamide
  • Fatty acid amide hydrolase
  • First-in-human study
  • Pharmacokinetics
  • Safety
  • Tolerability