Eva Sverrisdóttir (1) Mads Kreilgaard (2) Anne Brokjær (3) Katja Kjeldgaard Miltersen (4) Anne Estrup Olesen (1,3) Lona Louring Christrup (1) Asbjørn Drewes (3,5)
(1) Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark (2) Novo Nordisk, Måløv, Denmark (3) Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mølleparkvej 4, DK-9000 Aalborg, Denmark (4) 4Klinisk Biokemisk Afdeling, Aarhus Universitetshospital, Palle Juul-Jensens Boulevard 99, DK-8200 Aarhus N, Denmark, (5) Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 11, DK-9000 Aalborg, Denmark
Objectives: To establish the population PKPD relationship of morphine after rectal administration using pupillometry as a central biomarker. Furthermore, to evaluate if a peripheral opioid receptor antagonist, methylnaltrexone, can be assumed not to influence morphine’s PKPD properties within the central nervous system.
Methods: Morphine hydrochloride (HCl) was administered to healthy male participants in a randomized, placebo controlled, double-blinded, four-way cross-over study, where 15 volunteers received placebo or 30 mg rectally administered morphine HCl in combination with either placebo or 12 mg methylnaltrexone administered subcutaneously. PK and PD assessment was carried out over 3 h. PK data from a previous study was included in the PK analysis [1]. Plasma concentrations and pupil diameter were fitted to PK and PD models using non-linear mixed-effects modelling implemented in NONMEM V 7.3.0 [2]. The absorption of morphine after rectal administration was tested as first-order with or without absorption lag or as transit-compartment absorption with or without a first order absorption rate constant [3]. Pupil diameter was fitted to linear and E-max models. The influence of age, weight, height, and co-administration of methylnaltrexone was tested for PK and PD, as well as any interoccasion variability. Stepwise covariate modelling in Perl speaks NONMEM was used to search for categorical and continuous exponential, linear, hockey-stick, and power covariate relationships. The residual error models tested were proportional, additive, or a combination.
Results: Morphine distribution was best described with a two-compartment model and the absorption of morphine after rectal administration was described with two transit-compartment absorption with a first-order absorption between last absorption compartment and central compartment. Body weight correlated linearly to morphine clearance, and mean transit time varied between occasions. Preliminary results suggest that central effect evaluated by pupil constriction was best described with a linear model with effect delay, and that methylnaltrexone had no influence on morphine PK or PD.
Conclusions: Co-administration of methylneltrexone did not affect morphine PK or central PD effect.
References:
[1] Brokjaer A, Kreilgaard M, Olesen AE, et al. Population pharmacokinetics of morphine and morphine-6-glucuronide following rectal administration–a dose escalation study. Eur J Pharm Sci. 2015;68:78-86. doi: 10.1016/j.ejps.2014.12.004 [doi]
[2] Bauer R. NONMEM users guide introduction to NONMEM 7.3.0. ICON Development Solutions Ellicott City, MD. 2013.
[3] Savic RM, Jonker DM, Kerbusch T, Karlsson MO. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J Pharmacokinet Pharmacodyn. 2007;34(5):711-726.
Reference: PAGE 24 (2015) Abstr 3587 [www.page-meeting.org/?abstract=3587]
Poster: Drug/Disease modeling - CNS