Hepatic drug-metabolizing enzyme induction and implications for preclinical and clinical risk assessment.
Hepatic drug metabolizing enzyme (DME) induction complicates the development of new drugs owing to altered efficacy of concomitant treatments, reduction in exposure resulting from autoinduction, and potential generation of toxic metabolites. Risk assessment of DME induction during clinical evaluation is confounded by several uncertainties pertaining to hazard identification and dose response analysis. Hepatic DME induction rarely leads to clinical evidence of altered metabolism and toxicity in the patient, which typically occur only if the DME induction is relatively severe. High drug doses are associated with a greater likelihood of hepatic DME induction and downstream effects; therefore, drugs of low potency requiring higher dosing tend to lead to a greater risk of drug-drug interactions. Vigilance in clinical trials for increased or diminished drug effect and, specifically, pharmacokinetic studies in the presence of other drugs and concomitant diseases are necessary for a drug risk assessment profile. Efforts to remove hepatic DME-inducing drugs from development can be facilitated with current in vitro and in vivo assessments and will improve with the development of newer technologies. A carefully tailored case-by-case approach will lead to the development of efficacious drugs with an acceptable risk/benefit profile available to patients.
Mohutsky
Michael A
MA
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
Romeike
Annette
A
Meador
Vince
V
Lee
William M
WM
Fowler
John
J
Francke-Carroll
Sabine
S
D000818:Animals; D002986:Clinical Trials as Topic; D004790:Enzyme Induction / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D018570:Risk Assessment; D018675:Toxicity Tests / Q000379:methods*; D015262:Xenobiotics / Q000378:metabolism*
D015262:Xenobiotics