title: Population pharmacokinetics of morphine and morphine-6-glucuronide following rectal administration--a dose escalation study.
abstract: BACKGROUND
  To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety.
  
  
  METHODS
  This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction.
  
  
  RESULTS
  A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6h, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed.
  
  
  CONCLUSIONS
  A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated.
authors.affiliation: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark. Electronic address: anne.brokjaer@rn.dk.
authors.forename: Anne
authors.initials: A
authors.lastname: Brokjær
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: mads.kreilgaard@sund.ku.dk.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
authors.affiliation: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: aneso@rn.dk.
authors.forename: Anne Estrup
authors.initials: AE
authors.lastname: Olesen
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. Electronic address: Ulrika.Simonsson@farmbio.uu.se.
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: llc@sund.ku.dk.
authors.forename: Lona Louring
authors.initials: LL
authors.lastname: Christrup
authors.affiliation: Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: A.Dahan@lumc.nl.
authors.forename: Albert
authors.initials: A
authors.lastname: Dahan
authors.affiliation: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark. Electronic address: amd@rn.dk.
authors.forename: Asbjørn Mohr
authors.initials: AM
authors.lastname: Drewes
mesh_terms: D000285:Administration, Rectal; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D009022:Morphine Derivatives / Q000097:blood; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine
keywords: Dose escalation; Morphine; Morphine-6-glucuronide; Population pharmacokinetics; Rectal administration