Intrasubject Variability in Intravenous and Oral Probes for Hepatic and First-Pass CYP3A Activity.

Autor: Kharasch ED; Department of Anesthesiology, Duke University School of Medicine, 905 S. LaSalle St, GSRB1 Room 2031, Box 3094, Durham, NC, 27710, USA. evan.kharasch@duke.edu.; Bermaride LLC, Durham, NC, 27712, USA. evan.kharasch@duke.edu., Hoffer C; Department of Anesthesiology, University of Washington, Seattle, WA, USA., Bedynek P; Department of Anesthesiology, University of Washington, Seattle, WA, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacokinetics [Clin Pharmacokinet] 2024 Aug; Vol. 63 (8), pp. 1121-1135. Date of Electronic Publication: 2024 Jul 29.
DOI: 10.1007/s40262-024-01406-y
Abstrakt: Background and Objectives: Clearances and the area under the plasma concentration-time curve extrapolated to infinity (AUC 0-∞ ) of intravenous (IV) and oral midazolam and alfentanil are probes for hepatic and first-pass cytochrome P450 3A (CYP3A) activity, drug interactions, and phenotyping. Single-time plasma concentrations are also used as a proxy for clearance and AUC 0-∞ . Pupil diameter change is a noninvasive surrogate for plasma alfentanil. An ideal probe should have minimal intrasubject (interday) variability. Despite their widespread use, the intrasubject variability of CYP3A probes is not well characterized. This investigation determined the intrasubject (interday) variability of midazolam and alfentanil metrics of hepatic and first-pass CYP3A.
Methods: Twelve volunteers were studied in a four-period protocol, with each period identical and separated by approximately 2 weeks. In each period, participants received 1 mg IV midazolam then 15 μg/kg IV alfentanil 1 h later. The next day, they received 3 mg oral midazolam then 60 μg/kg oral alfentanil. Plasma drug concentrations were determined by liquid chromatography-mass spectrometry (LCMS). Dark-adapted pupil diameters were measured coincident with blood sampling. Plasma concentrations and pupil effects (miosis) were analyzed using noncompartmental methods. The results were the coefficient of variation (%CV, mean ± SD) across four sessions in 12 participants.
Results: For IV midazolam: AUC 0-∞ , clearance, and 5 h concentration, the %CVs were 12 ± 3, 12 ± 3, and 18 ± 8. For IV alfentanil AUC 0-∞ , clearance, 2 h concentration, and area under the effect curve from time zero to infinity (AUEC 0-∞ ), the %CVs were 16 ± 5, 15 ± 4, 22 ± 7, and 50 ± 28. For oral midazolam AUC 0-∞ , clearance, and 5 h concentration, %CVs were 19 ± 5, 18 ± 4, and 28 ± 11. For oral alfentanil: AUC 0-∞ , clearance, 4 h concentration, and AUEC 0-∞ , %CVs were 20 ± 4, 21 ± 4, 42 ± 26, and 37 ± 14.
Conclusions: Midazolam and alfentanil had comparable intrasubject variabilities of clearance and AUC 0-∞ . Single-time point metrics had greater intrasubject variability than AUC 0-∞ and clearance. Miosis was a surrogate for alfentanil concentrations and provided real-time results, but intrasubject variability was greater than that of clearances and AUC 0-∞ .
(© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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