Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ‐opioid receptor occupancy

Kyhl, Lars-Erik Broksoe; Shen, Li; Faerch, Kirstine Ullitz; Soegaard, B; Larsen, Frank; Areberg, Johan

doi:10.1111/bcp.12805

Cited by 18 publications

(16 citation statements)

References 16 publications

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“…and p.o. Phase 1 studies of nalmefene [36]. In dogs, the oral bioavailability of 1.3% is low and contrasts with the value of 40% reported in man [7].…”

Section: Pharmacokinetics Of Nalmefene In Dogs Following Bolus Dosingmentioning

confidence: 88%

“…Our approach was based on the successful strategy employed for antipsychotics, for example haloperidol decanoate [29,30] and paliperidone palmitate [31,32], in which a lipophilic prodrug in an oil depot formulation is administered intramuscularly [33,34]. Our target plasma concentrations of 0.5-1.0 ng/ml since were based upon the observation that a plasma nalmefene concentration of 0.34 ng/ml occupies 50% of human brain μ opioid receptors [35,36] and that 60-90% levels of occupancy required for efficacy [36].…”

Section: Graphical Abstractmentioning

confidence: 99%

“…In summary, these data show that alkyl ester prodrugs of nalmefene can produce sustained plasma concentrations of nalmefene in the region of 0.5-1.0 ng/mL for several weeks in dogs and mini-pigs, with the kinetics being dictated by the length of the alkyl group. Moreover, a dose of 5 mg/kg equivalent of the dodecanoate single-ester prodrug produces plasma nalmefene concentrations (0.5-1.0 ng/ml) sufficient to achieve the 60-90% levels of μ opioid receptor occupancy required for clinical efficacy [36] in alcohol dependence [4] and potentially other disorders [58,59]. Figure S1.…”

Section: Development Of Long-acting Nalmefenementioning

confidence: 99%

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Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Gaekens

Guillaume

Borghys

et al. 2016

Journal of Controlled Release

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Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5-1.0ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2-0.3ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5-1.0ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene prodrugs and that the pharmacokinetic profile of nalmefene can be tuned by varying the length of the alkyl group.

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“…and p.o. Phase 1 studies of nalmefene [36]. In dogs, the oral bioavailability of 1.3% is low and contrasts with the value of 40% reported in man [7].…”

Section: Pharmacokinetics Of Nalmefene In Dogs Following Bolus Dosingmentioning

confidence: 88%

Section: Graphical Abstractmentioning

confidence: 99%

Section: Development Of Long-acting Nalmefenementioning

confidence: 99%

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Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Gaekens

Guillaume

Borghys

et al. 2016

Journal of Controlled Release

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“…It is known that both κ-agonism and μ-antagonism can cause activation of the HPA axis in humans and nonhuman primates (Maqueda et al, 2016;Pascoe et al, 2008;Schluger et al, 1998). The IV dose of both naltrexone and nalmefene administered here (10 mg) is expected to cause maximal occupancy of μ-receptor populations (Broksoe Kyhl et al, 2016;Ingman et al, 2005;Webster, Johnson, Stauffer, Setnik, & Ciric, 2011). The pharmacokinetic half-life of IV nalmefene in humans is thought to be longer than that of naltrexone (Dixon et al, 1986;Webster et al, 2011), although they have never been compared in the same study, to our knowledge.…”

Section: Acth and Cortisolmentioning

confidence: 92%

“…The use of the IV route allowed for a comparison of the pharmacodynamic effects of naltrexone and nalmefene, decreasing the potential impact of different oral pharmacokinetics and bioavailability of these two compounds. Oral or IV pharmacokinetics and bioavailability of naltrexone and nalmefene have never been directly compared, to our knowledge (Broksoe Kyhl et al, 2016;Kogan, Verebey, & Mule, 1977). The selection of the 10-mg IV dose was guided by the goal of achieving comparability with prior studies (Bart et al, 2005;Schluger et al, 1998) and is substantially greater than IV doses of either naltrexone or nalmefene, which are needed to cause μ-receptor antagonism in humans (Moore, Bikhazi, Tuttle, & Weidler, 1990;Webster et al, 2011).…”

Section: Design Considerations and Limitationsmentioning

confidence: 99%

Neuroendocrine effects of naltrexone versus nalmefene in humans

Butelman

Fry

Kimani

et al. 2020

Human Psychopharmacology

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Objective Naltrexone and nalmefene are approved for the treatment of alcohol use disorders, in different countries. Naltrexone is also approved for the treatment for opioid use disorders, most recently in a depot formulation. These compounds target primarily μ(mu)‐ and κ(kappa)‐opioid receptor systems, which are involved in the downstream neurobiological effects of alcohol and in the modulation of neuroendocrine stress systems. The study objective was to compare the neuroendocrine effects of naltrexone and nalmefene on adrenocorticotropic hormone (ACTH), cortisol, and prolactin, in normal volunteers. Method Adult normal volunteers (n = 11 male and n = 9 female) were studied in a stress‐minimized inpatient setting on three consecutive days, after intravenous saline, naltrexone HCl (10 mg), or nalmefene HCl (10 mg), in fixed order. ACTH, cortisol, and prolactin were analyzed pre‐injection and up to 180 min post‐injection. Results Naltrexone and nalmefene caused elevations in ACTH and cortisol compared with saline. Nalmefene had a greater effect on ACTH and cortisol, compared with naltrexone. Both compounds also caused elevations in prolactin in males (females were not examined, due to the influence of menstrual cycle on prolactin). Conclusions This study suggests that both nalmefene and naltrexone have effects potentially due to κ‐partial agonism in humans, as well as antagonist effects at μ‐receptors.

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Pharmacokinetic Properties of an FDA‐approved Intranasal Nalmefene Formulation for the Treatment of Opioid Overdose

Crystal

Ellison

Purdon

et al. 2023

Clinical Pharm in Drug Dev

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Nalmefene is a high‐affinity, long‐duration opioid antagonist that was approved in 1995 as an injection for the treatment of opiate overdose, but subsequently withdrawn (2008) for reasons other than safety or effectiveness. The dramatic rise in opioid overdose deaths over the past 7‐8 years catalyzed the development of an intranasal (IN) formulation of nalmefene for the emergency treatment of opioid overdose. The studies described here compare the pharmacokinetic properties and safety profiles of an IN formulation containing nalmefene (2.7 mg in 0.1 mL) to an approved 1 mg intramuscular (IM) dose. IN nalmefene produced maximum plasma concentrations that were significantly higher than observed following the IM dose (12.2 and 1.77 ng/mL, respectively). The time to reach maximum plasma concentrations was also faster following IN administration (0.25 and 0.33 hours, respectively) with significant differences in plasma concentrations manifested as early as 2.5 minutes after administration (NCT04759768). The plasma half‐life of nalmefene was similar following IM and IN administration (10.6‐11.4 hours). Furthermore, dose‐normalized nalmefene exposure was similar for both 1 spray in each nostril and 2 sprays in the same nostril compared to a single spray in each nostril (NCT05219669). There were no sex differences in the pharmacokinetic properties of either IN or IM nalmefene. In an era when almost 90% of opioid overdose deaths have been linked to high‐potency synthetic opioids, the ability to rapidly deliver high concentrations of nalmefene could represent an important tool for reducing both morbidity and mortality.

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Population pharmacokinetics of nalmefene in healthy subjects and its relation to μ‐opioid receptor occupancy

Cited by 18 publications

References 16 publications

Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Neuroendocrine effects of naltrexone versus nalmefene in humans

Pharmacokinetic Properties of an FDA‐approved Intranasal Nalmefene Formulation for the Treatment of Opioid Overdose

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