Ketoconazole and Liver Injury: A Five‐Year Update

Proposal of a Safe and Effective Study Design for CYP3A‐Mediated Drug‐Drug Interactions

“…However, despite this recommendation, in clinical drug interaction trials, a different length of preexposure of itraconazole in comparison with ketoconazole has to be used to generate maximum inhibition, which has already been discussed in the literature. 3 In addition, itraconazole is not as strong as ketoconazole regarding inhibition of CYP3A, with an average area under the concentration-time curve (AUC) ratio (AUCR) of 7.3 compared with an average of 11.5 for oral midazolam when ketoconazole is used. 4 The safety of healthy volunteers taking part in DDI trials is of paramount importance.…”

The Effect of CYP3A Induction and Inhibition on the Pharmacokinetics of Laquinimod, a Novel Neuroimmunomodulator

“…It is important to note that ketoconazole is no longer recommended by the FDA for use in drug‐drug interaction (DDI) studies, 15 although it was recommended at the time the present study was conducted 16 and had been safely used as the index strong inhibitor of CYP3A metabolism in DDI studies for many years 17,18 . Previous studies demonstrate that maximal inhibition of CYP3A activity is achieved using customary oral doses of ketoconazole as were administered in the present study 19–21 . Evaluation of biochemical evidence of liver injury associated with ketoconazole use in DDI studies done in healthy volunteers indicates no evidence of meaningful hepatotoxicity in this context 21–23 …”

“…17,18 Previous studies demonstrate that maximal inhibition of CYP3A activity is achieved using customary oral doses of ketoconazole as were administered in the present study. [19][20][21] Evaluation of biochemical evidence of liver injury associated with ketoconazole use in DDI studies done in healthy volunteers indicates no evidence of meaningful hepatotoxicity in this context. [21][22][23]…”

“…[19][20][21] Evaluation of biochemical evidence of liver injury associated with ketoconazole use in DDI studies done in healthy volunteers indicates no evidence of meaningful hepatotoxicity in this context. [21][22][23]…”

Utility of Cytochrome P450 4F2 Genotyping to Assess Drug Interaction Risk for Brincidovovir, a Cytochrome P450 4F2 Substrate

“…Drug interaction studies with ketoconazole, a known inhibitor of CYP4F2, 7,8 have been discouraged by US and European regulatory authorities due to hepatic safety concerns in healthy volunteers. While recent reviews have questioned the hepatic safety risk for ketoconazole use in drug interaction studies, 9,10 due to the regulatory concerns on ketoconazole use and no other established CYP4F2 inhibitor available, drug-drug interaction (DDI) studies evaluating CYP4F2 substrates as victims are challenging.…”