An open-label study to explore the optimal design of CYP3A drug-drug interaction clinical trials in healthy Chinese people.
Pharmacol Res Perspect
; 12(4): e1252, 2024 Aug.
Article
in En
| MEDLINE
| ID: mdl-39073244
ABSTRACT
A drug-drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early-phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three-cycle, self-controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1-hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21-fold based on maximum plasma concentration (Cmax), 8.37-fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC0-t), and 11.22-fold based on area under the curve from zero to infinity (AUC0-∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27-fold based on Cmax, ~0.18-fold based on AUC0-t, and ~0.18-fold based on AUC0-∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near-maximal CYP3A levels.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Midazolam
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Itraconazole
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Asian People
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Drug Interactions
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Cytochrome P-450 CYP3A
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Cytochrome P-450 CYP3A Inhibitors
Limits:
Adult
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Female
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Humans
/
Male
Language:
En
Journal:
Pharmacol Res Perspect
Year:
2024
Document type:
Article
Affiliation country:
China