III. Nonclinical findings Introduction The range of studies submitted was adequate, and relevant studies were Good Laboratory Practice (GLP) compliant. A notable feature of the submission which detracted from its overall quality was that a large number of the studies, including many of the pivotal studies, dated back to around the 1980s. The quality of reporting was often poorer than what is expected today, and in some instances the study designs reflected the era, with toxicokinetic data, in particular, being limited. However, several more recent studies were conducted to rectify some of the deficiencies from the earlier studies. These issues are discussed in further detail under the relevant sections below. In many of the study reports, the exact nature of the test compound (base, hydrochloride salt or hydrochloride dihydrate) and how the dose/concentration was expressed was not clear. The molecular weight (MW) difference between the base and hydrochloride salt is ~11% and between the base and the hydrochloride dihydrate is ~21%. Where available, the missing information was provided in the Section 31 response; the remaining gaps in the data were considered to have little/no impact on study interpretation/conclusions. Pharmacology Primary pharmacology Table 6 shows binding affinity for nalmefene and its metabolites at the µ, and opioid δ κ receptors. 6a: Binding affinity: Ki values (nM) for nalmefene and its metabolites at the µ, and opioid receptors. δ κ Study 054-884-2011 (cloned 12 (guinea pig brain) (receptor receptors, human source) unless noted) Compound Nalmefene Nalmefene Nalmefene Nornalmefene glucuronide µ receptor 0.2 0.73 810 18.7 1.3 receptor 16 9.3 5,064 279 δ 53 receptor 0.31 (rat receptor) 4.7 ~10,000 917 κ 1.1 0.64 Table 6b: Binding affinity: Ki values (nM) for nalmefene and its metabolites at the µ, and opioid receptors. δ κ Study 056-884-2011 (cloned receptors, 053-884-2011 (cloned receptors, human (receptor human unless noted) unless noted) source)
III. Nonclinical findings Introduction The range of studies submitted was adequate, and relevant studies were Good Laboratory Practice (GLP) compliant. A notable feature of the submission which detracted from its overall quality was that a large number of the studies, including many of the pivotal studies, dated back to around the 1980s. The quality of reporting was often poorer than what is expected today, and in some instances the study designs reflected the era, with toxicokinetic data, in particular, being limited. However, several more recent studies were conducted to rectify some of the deficiencies from the earlier studies. These issues are discussed in further detail under the relevant sections below. In many of the study reports, the exact nature of the test compound (base, hydrochloride salt or hydrochloride dihydrate) and how the dose/concentration was expressed was not clear. The molecular weight (MW) difference between the base and hydrochloride salt is ~11% and between the base and the hydrochloride dihydrate is ~21%. Where available, the missing information was provided in the Section 31 response; the remaining gaps in the data were considered to have little/no impact on study interpretation/conclusions. Pharmacology Primary pharmacology Table 6 shows binding affinity for nalmefene and its metabolites at the µ, δ and κ opioid receptors. 6a: Binding affinity: Ki values (nM) for nalmefene and its metabolites at the µ, δ and κ opioid receptors. Study (receptor source) 054-884-2011 (cloned receptors, human unless noted) 12 (guinea pig brain) Compound Nalmefene Nalmefene Nalmefene glucuronide Nornalmefene µ receptor 0.2 1.3 0.73 810 18.7 δ receptor 16 53 9.3 5,064 279 κ receptor 0.31 (rat receptor) 1.1 0.64 4.7 ~10,000 917 Table 6b: Binding affinity: Ki values (nM) for nalmefene and its metabolites at the µ, δ and κ opioid receptors. Study (receptor source) 056-884-2011 (cloned receptors, human unless noted) 053-884-2011 (cloned receptors, human unless noted)
auspar-nalmefene-as-hydrochloride-dihydrate-160809_0.docx