Lipophilic nalmefene prodrugs to achieve a one-month sustained release.
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.
API Small Molecule Development, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Tim
T
Gaekens
API Small Molecule Development, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Michel
M
Guillaume
Neuroscience, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Herman
H
Borghys
Drug Metabolism and Pharmacokinetics, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Loeckie L
LL
De Zwart
Drug Metabolism and Pharmacokinetics, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Ronald
R
de Vries
Drug Product Development, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Roger C A
RC
Embrechts
Clinical Pharmacology, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium.
An
A
Vermeulen
Neuroscience, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Anton A H P
AA
Megens
Neuroscience, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium; Department of Nuclear Medicine and PET Research, VU University Medical Centre, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
Josée E
JE
Leysen
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Box 1030, B-3000 Leuven, Belgium.
Piet
P
Herdewijn
Laboratory for Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, O&N2, Herestraat 49-Box 921, B-3000 Leuven, Belgium.
Pieter P
PP
Annaert
Neuroscience, Janssen Pharmaceuticals, Turnhoutseweg 30, B-2340 Beerse, Belgium. Electronic address: J.Atack@Sussex.ac.uk.
John R
JR
Atack
D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D005227:Fatty Acids / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D005977:Glutarates / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics; D013552:Swine; D013556:Swine, Miniature
D002219:Carbamates; D003692:Delayed-Action Preparations; D005227:Fatty Acids; D005977:Glutarates; D009292:Narcotic Antagonists; D011355:Prodrugs; D009271:Naltrexone; C038981:nalmefene
Extended-release; Nalmefene; Nalmefene (PubChem CID: 5284594); Opioid; Pharmacokinetics; Prodrug