The Pfizer mRNA vaccines contain
(4-hydroxybutyl) azanediyl) bis(hexane-6,1-diyl) bis(2-hexyldecanoate) ALC-0315
also known as 6-[N-6-(2-hexyldecanoyloxy)hexyl-N-(4-hydroxybutyl)amino]hexyl 2-hexyldecanoate, sold as a yellow oil.
It has 2 chiral centres so potentially the different optical isomers will have different toxic properties in Humans as found for Thalidomide.
Has any effort been made to separate isomers?
ALC-0315 has not had detailed toxicology studies, however in rats the half-life for transfer from blood to other organs was 139 hours, indicating it is very strongly bound inside the bodies of mammals. Would there be any difference in binding and metabolism of the isomers?
Which enzymes or other essential biological molecules might be expected to interact with ALC-0315?
Hi,
What we know from available documents ALC-0315 is 1:1 racemate, and a statement from the document below explains that racemate was used:
"This excipient contains two chiral centres, but the excipient is a 1:1 racemic mixture of the diastereomers. The excipient is not optically active."
In regards to impurities of ALC-0315 looks like additional data was collected a year ago. But I'm not sure the data are publicly available:
"5) The sponsor to provide a discussion regarding process development for ALC-0315 with emphasis on the identification and purge of impurities. Due date: July 2021.
6) The sponsor will notify Medsafe of any changes to the ALC-0315 manufacturing process and/or suppliers/manufacturers/testing sites using Changed Medicine Notifications.
7) Specified impurities should be further evaluated and appropriate specification limits for individual impurities should be included when more data are available. Acceptance criteria for specified and un-specified impurities should be added to the specification for ALC-0315 and should also be evaluated during stability studies. Due date: July 2021; Interim report: April 2021 (...)
9) The sponsor to update the ALC-0315 assay and impurities limits when additional supporting data is available. Due date: July 2021."
Ref:
One comment related to the long half-life. It could be possible in cases when the specific molecule is present in the bile that enterohepatic recirculation of the substance is possible. It can explain extremely long half-lives sometimes. Of course in some optically active substances, the process could be enantioselective (chiral inversion).
Article Enantioselectivity in Drug Pharmacokinetics and Toxicity: Ph...
As we know ALC-0315 is a mixture of the diastereomers: "Diastereomers are any molecules which have two or more chiral centers. A diastereomer with two chiral carbon has four isomers. Unlike enantiomers, the physical and chemical properties of diastereomers can differ and consequently, their chemical characterization is easy and their biological activities are often different."
Article Chiral Drugs: An Overview
Hope could be helpful for future discussions,
Best regards,
Tomasz
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