Liver injury associated with ketoconazole: Review of the published evidence

Greenblatt, H. Karl; Greenblatt, David J.

doi:10.1002/jcph.400

Cited by 71 publications

(78 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Ketoconazole's side-effect profile (Table 1) is relatively benign, except for idiosyncratic severe hepatic dyscrasia, which is estimated to occur in one in 15 000 exposed individuals (115,(122)(123)(124). The FDA issued a black box warning for this in 2013, and the European Medicines Agency has restricted access to the agent to physicians specialized in treating CS (125).…”

Section: Evidence Ketoconazolementioning

confidence: 97%

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline

Nieman

Biller

Findling

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

1,016

959

View full text Add to dashboard Cite

Treatment of Cushing's syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushing's syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient.

show abstract

Section: Evidence Ketoconazolementioning

confidence: 97%

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline

Nieman

Biller

Findling

et al. 2015

The Journal of Clinical Endocrinology & Metabolism

1,016

959

View full text Add to dashboard Cite

show abstract

“…Greenblatt et al demonstrated that approximately 1 in 500 patients were at risk of liver injury after ketoconazole administration. 14 In the early 1990s, when the triazoles became available for systemic use, they rapidly supplanted ketoconazole.…”

Section: Azolesmentioning

confidence: 99%

“…14 Unlike mammalian membranes, which are rich in cholesterol, ergosterol is the predominant sterol in the cell membrane of fungi. Thus, targeting ergosterol synthesis results in selectivity against fungi.…”

Section: Azolesmentioning

confidence: 99%

New facets of antifungal therapy

et al. 2016

View full text Add to dashboard Cite

Invasive fungal infections remain a major cause of morbidity and mortality in immunocompromised patients, and such infections are a substantial burden to healthcare systems around the world. However, the clinically available armamentarium for invasive fungal diseases is limited to 3 main classes (i.e., polyenes, triazoles, and echinocandins), and each has defined limitations related to spectrum of activity, development of resistance, and toxicity. Further, current antifungal therapies are hampered by limited clinical efficacy, high rates of toxicity, and significant variability in pharmacokinetic properties. New antifungal agents, new formulations, and novel combination regimens may improve the care of patients in the future by providing improved strategies to combat challenges associated with currently available antifungal agents. Likewise, therapeutic drug monitoring may be helpful, but its present use remains controversial due to the lack of available data. This article discusses new facets of antifungal therapy with a focus on new antifungal formulations and the synergistic effects between drugs used in combination therapy.

show abstract

“…The FDA specifically recommended the use of clarithromycin or itraconazole as alternative strong CYP3A4/5 inhibitors for use in clinical DDI studies, but further noted that investigators may suggest other CYP3A4/5 inhibitors (FDA, 2013a). In addition to itraconazole and clarithromycin, ritonavir has also been suggested by some authors as a possible alternative to ketoconazole (Greenblatt and Greenblatt, 2014;Greenblatt, 2015;Greenblatt and Harmatz, 2015), but excluded by others on the basis of nonspecific CYP inhibition or induction (Ke et al, 2014;Liu et al, 2015).…”

mentioning

confidence: 99%

Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin, and Itraconazole on 13 Clinically-Relevant Drug Transporters

Vermeer

Isringhausen

Ogilvie

et al. 2015

Drug Metabolism and Disposition

105

View full text Add to dashboard Cite

Ketoconazole is a potent CYP3A4/5 inhibitor and, until recently, recommended by the Food and Drug Administration (FDA) and the European Medicines Agency as a strong CYP3A4/5 inhibitor in clinical drug-drug interaction (DDI) studies. Ketoconazole sporadically causes liver injury or adrenal insufficiency. Because of this, the FDA and European Medicines Agency recommended suspension of ketoconazole use in DDI studies in 2013. The FDA specifically recommended use of clarithromycin or itraconazole as alternative strong CYP3A4/5 inhibitors in clinical DDI studies, but many investigators have also used ritonavir as an alternative. Although the effects of these clinical CYP3A4/5 inhibitors on other CYPs are largely established, reports on the effects on the broad range of drug transporter activities are sparse. In this study, the inhibitory effects of ketoconazole, clarithromycin, ritonavir, and itraconazole (and its CYP3A4-inhibitory metabolites, hydroxy-, keto-, and N-desalkyl itraconazole) toward 13 drug transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, MATE2-K, P-gp, BCRP, MRP2, MRP3, and BSEP) were systematically assessed in transporterexpressing HEK-293 cell lines or membrane vesicles. In vitro findings were translated into clinical context with the basic static model approaches outlined by the FDA in its 2012 draft guidance on DDIs. The results indicate that, like ketoconazole, the alternative clinical CYP3A4/5 inhibitors ritonavir, clarithromycin, and itraconazole each have unique transporter inhibition profiles. None of the alternatives to ketoconazole provided a clean inhibition profile toward the 13 drug transporters evaluated. The results provide guidance for the selection of clinical CYP3A4/5 inhibitors when transporters are potentially involved in a victim drug's pharmacokinetics.

show abstract

Liver injury associated with ketoconazole: Review of the published evidence

Cited by 71 publications

References 89 publications

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline

Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline

New facets of antifungal therapy

Evaluation of Ketoconazole and Its Alternative Clinical CYP3A4/5 Inhibitors as Inhibitors of Drug Transporters: The In Vitro Effects of Ketoconazole, Ritonavir, Clarithromycin, and Itraconazole on 13 Clinically-Relevant Drug Transporters

Contact Info

Product

Resources

About