Pre-absorption physicochemical compatibility assessment of 8-drug metabolic cocktail.
A comprehensive 8-drug metabolic cocktail was designed to simultaneously target 6 Cytochrome P450 enzymes and 2 membrane transporters. This study aimed to assess the pre-absorption risk of this new metabolic cocktail which contained metoprolol, caffeine, midazolam, pravastatin, flurbiprofen, omeprazole, digoxin and montelukast. This paper describes a systematic approach to understand whether the co-administration of the 8 selected drug products, i.e., the physical mixing of these products in the human gastro-intestinal environment, will create any issue that may interfere with the individual drug dissolution which in turns modify the total amount or timing of their availability for absorption. The evaluation consisted of two steps. An initial evaluation was based on theoretical understanding of the physicochemical properties of the drugs and the gastro intestinal environment, followed by in vitro dissolution tests. The results indicated that the designer 8-drug cocktail has acceptable pre-absorption compatibility when dosed simultaneously, and recommended the progression of the cocktail into clinical validation study.
Discovery Pharmaceutics, Bristol-Myers Squibb, Princeton, NJ, USA. Electronic address: chingkim@gmail.com.
Ching Kim
CK
Tye
Discovery Pharmaceutics, Bristol-Myers Squibb, Princeton, NJ, USA.
Zhanbin
Z
Wang
Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, NJ, USA.
Randy C
RC
Dockens
Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, Princeton, NJ, USA.
Blisse
B
Vakkalagadda
Bioanalytical and Discovery Analytical Sciences, Bristol-Myers Squibb, Princeton, NJ, USA.
Chunlei
C
Wang
Bioanalytical and Discovery Analytical Sciences, Bristol-Myers Squibb, Princeton, NJ, USA.
Yingru
Y
Zhang
Discovery Pharmaceutics, Bristol-Myers Squibb, Princeton, NJ, USA.
Ching Chiang
CC
Su
Discovery Pharmaceutics, Bristol-Myers Squibb, Princeton, NJ, USA.
Michael J
MJ
Hageman
D055598:Chemical Phenomena; D004338:Drug Combinations; D004339:Drug Compounding / Q000379:methods; D004347:Drug Interactions; D065546:Drug Liberation; D006863:Hydrogen-Ion Concentration
D004338:Drug Combinations
Caffeine (PubChem CID: 2519); Co-administration; Digoxin (PubChem CID: 2724385); Flurbiprofen (PubChem CID: 3394); Metabolic cocktail; Metoprolol (PubChem CID: 11957594); Midazolam (PubChem CID: 4192); Montelukast (PubChem CID: 5281040); Omeprazole (PubChem CID: 4594); Physicochemical interaction; Pravastatin (PubChem CID: 16759173)