Eva Sverrisdóttir (1), David John Richard Foster (2), Anne Estrup Olesen (1,3), Trine Meldgaard Lund (1), Asbjørn Mohr Drewes (3,4), Lona Louring Christrup (1), Mads Kreilgaard (1) & Richard Neil Upton (2)
(1) Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark, (2) Australian Centre for Pharmacometrics, School of Pharmaceutical and Medical Sciences, City East Campus, North Terrace, University of South Australia, Adelaide SA 5000, Australia, (3) Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mølleparkvej 4, DK-9000 Aalborg, Denmark, (4) Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 11, DK-9000 Aalborg, Denmark,
Objectives: Morphine is the gold standard opioid to treat moderate to severe pain. Morphine-6-glucuronide (M6G) is an active metabolite and contributes to the effect of morphine [1]. The pharmacokinetics (PK) of morphine and M6G are associated with large inter-individual variability, which makes optimal dose selection challenging, especially in populations such as neonates and patients with renal impairment [2]. The aims of this study were to develop a combined morphine and M6G PK metamodel in neonates and adults, identify covariates that explain some of the large variability, and describe the formation of M6G after administration of morphine through different routes.
Methods: Morphine and M6G data from 22 studies in diverse populations were fitted to PK models using NONMEM 7.3 [3]. Morphine was administered through the intravenous, oral, intramuscular, rectal, and subcutaneous route. M6G was administered intravenously in four studies, and metabolite M6G concentrations were available in 15 studies. Study populations included healthy volunteers, preterm neonates, and patients with renal impairment. Model development of the combined PK metamodel consisted of three stages. First, morphine concentration-time data was fitted to PK models and optimised regarding random effects and covariates. Second, M6G data was included in the model and the M6G PK model was developed, with the morphine model fixed. Lastly, the formation of M6G after administration of morphine was estimated and covariates were tested for the M6G model.
Results: Morphine and M6G PK were described with two-compartment PK models. Absorption of morphine after oral, rectal, and subcutaneous administration was described with transit compartment absorption models. A sigmoidal maturation model defined as a function of postmenstrual age described the maturation of morphine clearance in neonates. In adults, morphine clearance was shown to decrease with age. M6G formation constituted 17% of morphine clearance. In addition, 26% of an oral or rectal dose was formed to M6G (first-pass metabolism). Creatinine clearance was included as a covariate for M6G clearance.
Conclusions: Some of the large inter-individual variability in morphine and M6G PK was explained with weight, age, creatinine clearance, and postmenstrual age. The formation of M6G was described after administration of morphine, with additional first-pass metabolism for the oral and rectal route.
Acknowledgements: Data was kindly provided by Albert Dahan, Camilla Staahl, Hanne Villesen, Pernille Ravn, Anne Brokjær, Felix Bochner, Mark Dershwitz, Richard Osborne, Magdi Hanna, Ola Dale, Thor Bjelland, Ingolf Meineke, John van den Anker, Brian Anderson
References:
[1] Binning, A.R., Przesmycki, K., Sowinski, P., Morrison, L.M., Smith, T.W., Marcus, P., Lees, J.P., Dahan, A., 2011. A randomised controlled trial on the efficacy and side-effect profile (nausea/vomiting/sedation) of morphine-6-glucuronide versus morphine for post-operative pain relief after major abdominal surgery. Eur. J. Pain 15, 402-408.
[2] Somogyi, A.A., Barratt, D.T., Coller, J.K., 2007. Pharmacogenetics of opioids. Clin. Pharmacol. Ther. 81, 429-444.
[3] Beal, S.L., Sheiner, L.B., Boeckmann, A.J., Bauer, R.J., 1989-2013. NONMEM 7.3.0 Users Guides. 7.3.0.
Reference: PAGE 25 () Abstr 5808 [www.page-meeting.org/?abstract=5808]
Poster: Drug/Disease modeling - CNS