The Irrelevance of In Vitro Dissolution in Setting Product Specifications for Drugs Like Dextromethorphan That are Subject to Lysosomal Trapping

The purpose of the present study was to develop a physiologically based pharmacokinetic model for dextromethorphan (DEX) and its metabolites in extensive and poor metabolizers. The model was used to study the influence of dissolution rates on the sensitivity of maximum plasma concentration and area...

Celý popis

Uloženo v:
Podrobná bibliografie
Vydáno v:Journal of pharmaceutical sciences Ročník 108; číslo 1; s. 268
Hlavní autoři: Bolger, Michael B, Macwan, Joyce S, Sarfraz, Muhammad, Almukainzi, May, Löbenberg, Raimar
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.01.2019
Témata:
Absorption, Physiological
Area Under Curve
Caco-2 Cells
Computer Simulation
Cytochrome P-450 CYP3A - genetics
Dextromethorphan - blood
Dextromethorphan - chemistry
Enterocytes - metabolism
Humans
Lysosomes - metabolism
Metabolic Clearance Rate - genetics
Models, Biological
Permeability
Polymorphism, Genetic
Solubility
Therapeutic Equivalency
dissolution rate
absorption
computational ADME
CYP enzymes
pharmacokinetics
metabolite kinetics
metabolism
genetic polymorphisms
bioequivalence
ISSN:1520-6017, 1520-6017
On-line přístup:Zjistit podrobnosti o přístupu
Tagy: Přidat tag
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
Popis
Shrnutí:The purpose of the present study was to develop a physiologically based pharmacokinetic model for dextromethorphan (DEX) and its metabolites in extensive and poor metabolizers. The model was used to study the influence of dissolution rates on the sensitivity of maximum plasma concentration and area under the concentration-time curve for immediate release formulations. Simulation of in vitro cellular transwell permeability was used to confirm lysosomal trapping. GastroPlus™ was used to build a mechanistic absorption and physiologically based pharmacokinetic model of DEX. The model simulations were conducted with and without lysosomal trapping. The simulated results matched well with observed data only when lysosomal trapping was included. The model shows that DEX is rapidly absorbed into the enterocytes, but DEX and its metabolites only appear slowly in the portal vein and plasma, presumably due to lysosomal trapping. For this class of drug, the rate of in vitro and in vivo dissolution is not a sensitive factor in determining bioequivalence. This study shows that dissolution and the rate of absorption into the enterocytes are clinically irrelevant for the performance of DEX immediate release product. An understanding of the entire underlying mechanistic processes of drug disposition is needed to define clinically relevant product specifications for DEX.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1520-6017
1520-6017
DOI:10.1016/j.xphs.2018.09.036