Pharmacokinetic modeling of morphine and its glucuronides: Comparison of nebulization versus intravenous route in healthy volunteers

Autor: M.-P. Tavolacci, Tony Pereira, Thomas Duflot, Fabien Lamoureux, Frédéric Aubrun, Virginie Lvovschi, Robinson Joannides
Přispěvatelé: Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), douville, sabine, Hôpital Charles Nicolle [Rouen]-CHU Rouen
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Adult
Male
[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Metabolite
Pharmacokinetic modeling
RM1-950
Absorption (skin)
Pharmacology
030226 pharmacology & pharmacy
Models
Biological
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Sex Factors
Pharmacokinetics
Healthy volunteers
Administration
Inhalation
[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]
Medicine
Distribution (pharmacology)
Humans
Pharmacology (medical)
Computer Simulation
ComputingMilieux_MISCELLANEOUS
Morphine Derivatives
Dose-Response Relationship
Drug
Morphine
business.industry
Research
Nebulizers and Vaporizers
Articles
Middle Aged
Healthy Volunteers
3. Good health
Bioavailability
Analgesics
Opioid
chemistry
Modeling and Simulation
Injections
Intravenous
Female
Therapeutics. Pharmacology
business
030217 neurology & neurosurgery
medicine.drug
Zdroj: CPT: Pharmacometrics and Systems Pharmacology
CPT: Pharmacometrics and Systems Pharmacology, 2021, ⟨10.1002/psp4.12735⟩
CPT: Pharmacometrics & Systems Pharmacology
CPT: Pharmacometrics & Systems Pharmacology, Vol 11, Iss 1, Pp 82-93 (2022)
CPT: Pharmacometrics and Systems Pharmacology, American Society for Clinical Pharmacology and Therapeutics ; International Society of Pharmacometrics, 2021, ⟨10.1002/psp4.12735⟩
ISSN: 2163-8306
Popis: Intravenous (i.v.) morphine is a safe, robust, and recommended treatment for severe pain using the titration principle. Despite its high efficacy, it is impacted by organizational constraints related to venous access. Nebulized (NEB) morphine may represent an alternative for titration but pharmacokinetic (PK) properties of short nebulization using routine devices need evaluation. Twenty‐seven healthy volunteers were included to receive NEB or i.v. morphine administration using increasing amounts according to Dixon’s reference method. Plasma morphine, morphine‐3‐glucuronide (M3G), and morphine‐6‐glucuronide (M6G) were quantified. PK modeling and simulations were performed using Monolix. Dixon’s method exhibited a significantly higher morphine dose regimen in the NEB group versus the i.v. group (6.2 [5.3–7.1] vs. 3.0 [2.0–4.0] mg, p < 0.001). Morphine, M3G, and M6G dose‐normalized exposure were significantly lower in the NEB group versus the i.v. group: morphine (19 [13–23] vs. 1044 [702–1266] µg min/L, p < 0.001), M3G (245 [162–287] vs. 3752 [2487–5165] µg min/L, p < 0.001) and M6G (28 [21–43] vs. 466 [370–723] µg min/L, p < 0.001). The model that best fitted the data consisted in a transit compartment for morphine absorption, three compartments for morphine distribution followed by multiple transit compartments (8.2 and 57.5‐min transit time for M3G and M6G, respectively) and a first order elimination for M3G and M6G. Morphine bioavailability in the NEB group was 3.5% using the i.v. group as reference. Administration route and sex significantly influenced morphine and metabolite PKs. This work aimed to evaluate the PKs of NEB morphine compared with the i.v. route. Despite a bioavailability to improve, NEB morphine administration using a routine device is suitable to plan morphine titration.
Databáze: OpenAIRE
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