Ketoconazole-Associated Liver Injury in Drug-Drug Interaction Studies in Healthy Volunteers

Journal of Clinical Pharmacology
Peymaan S BanankhahDavid J Greenblatt

Abstract

Ketoconazole is a potent CYP3A inhibitor in vivo, and frequently serves as an index CYP3A inhibitor in drug-drug interaction (DDI) studies with healthy volunteers. Limitations restricting the use of systemic ketoconazole in such studies have been recently imposed by regulatory agencies in the United States, the European Union, and elsewhere. A risk of ketoconazole-associated liver injury in the context of DDI studies was cited as the primary justification for these measures. To evaluate the basis for these restrictions, we analyzed a series of published DDI studies identified from a review of existing literature. The study set consisted of 53 DDI studies, and included 971 healthy volunteers with systemic ketoconazole exposure in addition to the victim drug under study. Ketoconazole-associated abnormalities in serum chemistry values indicative of liver injury were observed in 4 subjects, representing a prevalence of 0.41% within the study population. There were no major adverse reactions or instances of hepatic failure. All abnormalities indicative of liver injury resolved upon discontinuation of ketoconazole treatment. The findings from this review do not support restriction of ketoconazole as an index CYP3A inhibitor in DDI st...Continue Reading

References

Jun 26, 1998·The Annals of Pharmacotherapy·C C Rheney, C M Saddler
Mar 10, 2000·Clinical Pharmacokinetics·K VenkatakrishnanD J Greenblatt
Oct 21, 2005·British Journal of Clinical Pharmacology·Abhijeet S JakateRam Kapil
Jul 27, 2006·Basic & Clinical Pharmacology & Toxicology·Pieter J SwartNeila N Smith
Apr 18, 2007·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Marta RobertGeorg Golor
May 24, 2007·Clinical Pharmacokinetics·Robert Z HarrisDesmond Padhi
Nov 21, 2007·Journal of Clinical Pharmacy and Therapeutics·W RidtitidM Wongnawa
Mar 5, 2008·Antimicrobial Agents and Chemotherapy·D Ronald GoldwaterStephen A Villano
Mar 26, 2008·British Journal of Clinical Pharmacology·Samantha AbelGary J Muirhead
May 2, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Masakatsu KotsumaKenji Nishimura
Nov 19, 2008·Antimicrobial Agents and Chemotherapy·Benoite KaeserXiaoping Zhang
Apr 25, 2009·Journal of Clinical Pharmacology·Duncan B RichardsLinda S Henderson
Sep 11, 2009·British Journal of Clinical Pharmacology·John M KovarikPatricia A Chandler
Mar 18, 2010·British Journal of Clinical Pharmacology·Kwang-Hee ShinKyung-Sang Yu
Aug 13, 2010·Journal of Clinical Pharmacology·Chiaki TanakaHorst Schran
Dec 15, 2010·Journal of Clinical Pharmacology·Richat AbbasDaryl Sonnichsen
Mar 15, 2011·British Journal of Clinical Pharmacology·Richat AbbasDaryl Sonnichsen
Apr 2, 2011·Clinical and Experimental Dermatology·A H Schmitt-HoffmannI Meyer
Apr 27, 2011·Journal of Clinical Pharmacy and Therapeutics·W MahatthanatrakulW Pipatrattanaseree
Jan 12, 2013·British Journal of Clinical Pharmacology·Wolfgang MueckMichael Becka
Feb 23, 2013·BMJ Case Reports·Peter Ng
Jun 27, 2013·Journal of Clinical Pharmacology·Narayana I NarasimhanDaryl Sonnichsen
Oct 3, 2013·Cancer Chemotherapy and Pharmacology·Catherine DutreixYanfeng Wang
Apr 22, 2014·Clinical Pharmacology and Therapeutics·A B KeS D Hall
Sep 13, 2014·Journal of Clinical Pharmacology·H Karl Greenblatt, David J Greenblatt
Sep 23, 2014·Clinical Therapeutics·Ramesh BoinpallyAntonia Periclou
Nov 8, 2014·British Journal of Clinical Pharmacology·Charles E FrostFrank LaCreta

❮ Previous
Next ❯

Citations

Jul 14, 2016·Journal of Clinical Pharmacology·Noémi OuteiroGerd Mikus
Oct 25, 2016·The Journal of Nutritional Biochemistry·Srinivasan PeriasamyMing-Yie Liu
Jan 2, 2019·Clinical Pharmacology in Drug Development·David J Greenblatt, Gerd Mikus
May 22, 2020·Journal of Clinical Pharmacology·Brit Silja Rohr, Gerd Mikus
Apr 3, 2020·Clinical Pharmacology in Drug Development·Anna ElgartOfer Spiegelstein
Jan 28, 2020·Molecular Pharmaceutics·Flavia MartinIoana Bâldea

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.