The impact of co‐administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers

Liu, Yong; Zhou, Simon; Wan, Yuntao; Wu, Aibin; Palmisano, Maria

doi:10.1111/bcp.12448

Cited by 25 publications

(31 citation statements)

References 16 publications

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“…The selected study set consisted of 53 separate DDI studies taken from 46 publications between 2005 and 2015, which included 971 subjects with systemic ketoconazole exposure (Table ). A majority of the studies were conducted at study centers in the United States and Germany (Table ).…”

Section: Resultsmentioning

confidence: 99%

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

Banankhah

Garnick

Greenblatt

2016

The Journal of Clinical Pharma

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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 studies involving healthy volunteers.

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Section: Resultsmentioning

confidence: 99%

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

Banankhah

Garnick

Greenblatt

2016

The Journal of Clinical Pharma

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“…Rifampin (oral capsule) was used as a CYP3A4 perpetrator because it is a well‐documented strong CYP3A4 inducer . Rifampin, when administered as a dose of 600 mg QD for 10 days, was anticipated to induce CYP3A4 and used to evaluate the effect of strong CYP3A4 induction on the PK of avadomide.…”

Section: Discussionmentioning

confidence: 99%

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

Ogasawara¹,

MacGorman²,

Liu³

et al. 2019

The Journal of Clinical Pharma

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Avadomide (CC‐122) is a novel immunomodulatory drug that binds to cereblon, a member of the Cullin 4‐RING E3 ubiquitin ligase complex. Avadomide has multiple pharmacologic activities including potent immune modulation, antiangiogenic, antitumor, and antiproliferative activity and is being evaluated as an oncology treatment for hematologic malignancies and advanced solid tumors. In vitro study has indicated that cytochrome P450 (CYP) 3A and CYP1A2 appear to be the major enzymes involved in the oxidative metabolism of avadomide. The effects of CYP3A inhibition/induction and CYP1A2 inhibition on the pharmacokinetics of avadomide in healthy adult subjects were assessed in 3 parts of an open‐label, nonrandomized, 2‐period, single‐sequence crossover study. Following a single oral dose of 3 mg, avadomide exposure when coadministered with the CYP1A2 inhibitor fluvoxamine was 154.81% and 107.59% of that when administered alone, for area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐inf) and maximum observed plasma concentration (Cmax), respectively. Avadomide exposures, when coadministered with the CYP3A inhibitor itraconazole, were 100.0% and 93.64% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide exposures when coadministered with the CYP3A inducer rifampin were 62.83% and 88.17% of that when administered alone, for AUC0‐inf and Cmax, respectively. Avadomide was well tolerated when administered as a single oral dose of 3 mg alone or coadministered with fluvoxamine, itraconazole, or rifampin. These results should serve as the basis for avadomide dose recommendations when it is coadministered with strong CYP3A and CYP1A2 inhibitors and with rifampin.

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“…16 Therefore, the use of strong CYP3A4 enzyme inducers (Table 4) with apremilast is not recommended. There was no clinically meaningful drug-drug interaction with ketoconazole, methotrexate and oral contraceptives.…”

Section: Drug Interactionsmentioning

confidence: 99%

European S3‐Guideline on the systemic treatment of psoriasis vulgaris – Update Apremilast and Secukinumab – EDF in cooperation with EADV and IPC

Nast

Spuls

Kraaij

et al. 2017

Acad Dermatol Venereol

119

129

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The impact of co‐administration of ketoconazole and rifampicin on the pharmacokinetics of apremilast in healthy volunteers

Cited by 25 publications

References 16 publications

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

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

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

European S3‐Guideline on the systemic treatment of psoriasis vulgaris – Update Apremilast and Secukinumab – EDF in cooperation with EADV and IPC

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