The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective.
Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.
Wyeth, Collegeville, Pennsylvania, USA.
Thorir D
TD
Bjornsson
John T
JT
Callaghan
Heidi J
HJ
Einolf
Volker
V
Fischer
Lawrence
L
Gan
Scott
S
Grimm
John
J
Kao
S Peter
SP
King
Gerald
G
Miwa
Lan
L
Ni
Gondi
G
Kumar
James
J
McLeod
Scott R
SR
Obach
Stanley
S
Roberts
Amy
A
Roe
Anita
A
Shah
Fred
F
Snikeris
John T
JT
Sullivan
Donald
D
Tweedie
Jose M
JM
Vega
John
J
Walsh
Steven A
SA
Wrighton
D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D004364:Pharmaceutical Preparations / Q000378:metabolism; D010641:Phenotype; D012107:Research Design; D013379:Substrate Specificity
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D020719:Glucuronides; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System