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Alfentanil-Induced Miosis Clearance as a Liver CYP3A4 and 3A5 Activity Measure in Healthy Volunteers: Improvement of Experimental Conditions

From the Clinical Pharmacology Unit, St Luc University Hospital, Brussels, Belgium (Ms Baririan, Dr Horsmans, Dr Desager); Pharmacokinetics, Metabolism, Nutrition and Toxicology Unit, Université Catholique de Louvain, Brussels, Belgium (Dr Verbeeck); Therapeutic Monitoring and Toxicology Laboratories, St Luc University Hospital Brussels, Belgium (Dr Vanbinst, Dr Wallemacq); and the Anesthesiology Unit, Université Catholique de Louvain, Brussels, Belgium (Dr Van Obbergh).

The aims of this study were to demonstrate the correlation between alfentanil-induced miosis evaluation and alfentanil pharmacokinetics (PK) as a CYP3A4 and 3A5 activity probe in volunteers and to explain the variability in pupilar response and in alfentanil PK. In ambient light, the miosis kinetic parameters were significantly correlated with PK (CLs: r =0.9, P = .00; AUCs: r =0.8, P = .01). In dark, a similar correlation was observed between miosis and alfentanil clearances (r = 0.85, P = .03). In 6 volunteers, the sigmoid E_max model was applicable (average E_max =2.5 ± 0.7 mm, =2.5 ± 1.6 and EC₅₀ = 76.8 ± 22.3 ng/mL), and in 3, the simple E_max model was applicable (average E_max = 2.8 ± 0.3 mm and EC₅₀ = 19.9 ± 8.5 ng/mL). There was a large interindividual variability in PK parameters (coefficient of variation = 19.7%-31.2%). Free drug fraction concentrations were negatively correlated with plasma ₁-AGP (r = -0.9, P = .04) and albumin levels (r = -0.94, P = .02). Alfentanil-induced miosis clearance as a noninvasive CYP3A4 and 3A5 activity measure can be done in both ambient and dark conditions. Drug free fraction may be responsible for large intersubject variability in alfentanil PK.

Key Words: Alfentanil • pharmacokinetics • CYP3A4 • miosis

Address for reprints: Yves Horsmans MD, PhD, Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Avenue Hippocrate, 10, Brussels 1200, Belgium.

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