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A Prospective Population Pharmacokinetic Study on Morphine Metabolism in Cancer Patients.
Erasmus MC Canc Inst, Dept Med Oncol, Groene Hilledijk 301, NL-3075 EA Rotterdam, Netherlands.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometric Research Group)ORCID iD: 0000-0001-8240-0865
Erasmus MC, Dept Clin Chem, Rotterdam, Netherlands.; Sophia Childrens Univ Hosp, Erasmus MC, Dept Pediat Surg, Rotterdam, Netherlands.
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2017 (English)In: Clinical Pharmacokinetics, ISSN 0312-5963, E-ISSN 1179-1926, Vol. 56, no 7, 733-746 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Oral and subcutaneous morphine is widely used for the treatment of cancer-related pain; however, solid pharmacokinetic data on this practice are lacking. Furthermore, it is largely unknown which factors contribute to the variability in clearances of morphine and its metabolites and whether morphine clearance is related to treatment outcome.

METHODS: Blood samples from 49 cancer patients treated with oral and/or subcutaneous morphine were prospectively collected and were used to develop a population pharmacokinetic model for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). The influence of age, gender, renal function and several polymorphisms possibly related to the pharmacokinetics of the three compounds was investigated. In addition, the relation between treatment failure and morphine and metabolite clearances was explored.

RESULTS: A one-compartment model including an extensive first-pass effect adequately described the data of morphine and its metabolites. Estimated mean area under the plasma concentration-time curve (AUC) ratios following oral versus subcutaneous administration were: M3G/morphine 29.7:1 vs. 11.1:1; M6G/morphine 5.26:1 vs. 1.95:1; and M3G/M6G 5.65:1 vs. 5.70:1. Renal function was significantly correlated with clearance of the metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m(2) increase of estimated glomerular filtration rate (eGFR), reaching a plateau for eGFR >90 mL/min/1.73 m(2). The clearance of morphine or its metabolites was not found to be correlated with treatment failure.

CONCLUSION: The influence of age-, gender- and pharmacokinetic-related polymorphisms was not identified on the pharmacokinetics of morphine. Clearance of morphine or its metabolites was not found to explain treatment outcome; however, large variations in plasma concentrations of morphine, M3G and M6G support further studies on the relation between plasma concentrations and treatment outcome. Dutch Trial Register ID: NTR4369.

Place, publisher, year, edition, pages
2017. Vol. 56, no 7, 733-746 p.
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Clinical Medicine
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URN: urn:nbn:se:uu:diva-318992DOI: 10.1007/s40262-016-0471-7ISI: 000403686200005PubMedID: 27815868OAI: oai:DiVA.org:uu-318992DiVA: diva2:1085772
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Available from: 2017-03-30 Created: 2017-03-30 Last updated: 2017-09-14Bibliographically approved

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Abrantes, João A.Jönsson, Siv

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