José MartÃn Pastor(1), Victor Mangas Sanjuan(2), Roberta Bursi(3), Jens Rengelshausen(4), Iñaki F. Trocóniz(1)
(1) Pharmacometrics & Systems Pharmacology; Department of Pharmacy and Pharmaceutical Technology; School of Pharmacy; University of Navarra; Pamplona 31080; Spain; Area of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University Miguel Hernández, Alicante, Spain ; (3) Pharmacometrics and (4) Translational Science; Grünenthal GmbH; Aachen; Germany
Objectives: To characterize the PKPD properties of the active components of axomadol (GRT0151Y) quantifying their contribution to the analgesic and pupillometry effects.
Racemic axomadol is a centrally active analgesic agent with opioid agonistic properties and inhibitory effects on the monoamines reuptake. The opioid action is related to the (+)-enantiomer of the O-demethyl metabolite, whereas the monoamine reuptake inhibition is exerted by the (-) enantiomers.
Methods: Data from two clinical trials were used to perfom the analysis. Healthy volunteers (n=74) received either placebo or axomadol orally at doses of ranging from 75 to 225 mg following multiple dosing regimens. Blood samples were withdrawn at selected times to quantify the plasma concentrations of the two enantiomers of axomadol and its metabolite. Pharmacodynamic responses (initial pupil diameter and cold pressor test) were also measured at specific times during the trials.The population analysis was performed with NONMEM 7.2.
Results: The kinetics of the parent drug and its metabolite could be simultaneously described using a PK model including an extra compartment resembling the liver, from which the metabolite is formed, and from which the drug distributes to the central compartment. The current analysis confirms that within the dose range studied axomadol and its O-demethyl metabolite show linear pharmacokinetic characteristics.
Administration of axomadol elicited significant effects on both pharmacodynamic endpoints with respect to placebo. (-)-parent compound elicited a plasma concentration dependent increase in pupil diameter that could be characterize by an EMAX model, on the contrary the (+)-O-demethyl metabolite decreased the pupil diameter as a linear function of the predicted effect site concentrations. An additive model integrating both type of response described adequately the net effects. For the case of the Cold pressor test, the use of the plasma concentration of the (+)-metabolite provided an adequate description of the response data.
Conclusions: The PKPD analysis performed in the current evaluation based on plasma concentration and biomarker data after oral administration of racemic axomadol has allowed to extract and quantified the PKPD properties of the active compounds. Those properties were in accordance with the known mechanisms of action, namely opioid agonism and inhibitory effects on the reuptake of NA and 5-HT monoamines norepinephrine (NA) and serotonin (5-HT).
Reference: PAGE 23 () Abstr 3278 [www.page-meeting.org/?abstract=3278]
Poster: Drug/Disease modeling - CNS