title: Population pharmacokinetic/pharmacodynamic modelling of the effects of axomadol and its O-demethyl metabolite on pupil diameter and nociception in healthy subjects.
abstract: The aim of the present study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) properties of the active components of axomadol and to quantify their contribution to observed the pupillometric and analgesic (measured through the cold pressor test) effects linking the PD engagement biomarker with clinical response.
  
  
  
  Healthy subjects (n = 74) received either placebo or axomadol orally at doses ranging from 66 mg to 225 mg following multiple dosing regimens in two separate clinical trials. Plasma concentrations of the two enantiomers of axomadol and their metabolites, and PD responses were measured at specific times. The population analysis was performed using NONMEM 7.2.
  
  
  
  The kinetics of the parent drug and its metabolite could be described simultaneously using an extra compartment mimicking the liver, where the metabolite is formed. The SS parent compound elicited a plasma concentration-dependent increase in pupil diameter, with estimates (percentage relative standard errors) of maximal effect (Emax ) and plasma concentration exerting a half-maximal effect (C50 ) of 0.79 (17.4) mm, and 90.7 (27) ng ml(-1) , respectively. The predicted effect site concentrations of the RR O-demethyl metabolite decreased the pupil diameter linearly, with an estimate of the slope of 0.00967 (18.7) mm·ml ng(-1) . An additive model, integrating the net effect on pupil diameter, described adequately the reduction in pain with a linear function. The PK/PD model revealed that each 0.5 mm change in pupil diameter is associated with a 10% decrease in cold pressor area under the concentration-time curve effects.
  
  
  
  The PK/PD analysis performed enabled the individual contributions of the active compounds to the observed effects to be identified and quantified. These effects were in accordance with the known mechanisms of action - namely, opioid agonism and noradrenaline reuptake inhibition.
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.|Area of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University Miguel Hernández, Alicante, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Mangas-Sanjuan
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: José Martín
authors.initials: JM
authors.lastname: Pastor
authors.affiliation: Early Clinical Science, Grünenthal GmbH, Aachen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Rengelshausen
authors.affiliation: Pharmacometrics, Grünenthal GmbH, Aachen, Germany.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bursi
authors.affiliation: Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Troconiz
mesh_terms: D000328:Adult; D000368:Aged; D000700:Analgesics / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D018592:Cross-Over Studies; D003511:Cyclohexanols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011680:Pupil / Q000187:drug effects*; D013237:Stereoisomerism
chemical_list: D000700:Analgesics; D003511:Cyclohexanols; C000624574:axomadol
keywords: analgesia; axomadol; pharmacokinetic/pharmacodynamic; pupil diameter