Abstract:

Objectives: (i) To evaluate the pupillary response to alfentanil as a surrogate measure of alfentanil pharmacokinetics in cirrhotic patients and to compare the data observed in cirrhotic patients with those found in healthy volunteers (historical control group); and (ii) to compare this test with other liver function tests in cirrhotic patients.

Methods: Six patients with mild cirrhosis (Child-Pugh grade A) and six patients with moderate cirrhosis (Child-Pugh grade B) were studied after a single 15 µg/kg bolus of alfentanil. Alfentanil plasma concentrations were measured by liquid chromatography-tandem mass spectrometry, and pupillary responses were measured with a Pupilscan II pupillometer. Alfentanil pharmacokinetics (plasma concentration, area under the plasma concentration-time curve from time zero to infinity [AUC_∞(p)] and from time zero to 2 hours [AUC_2(p)], apparent volume of distribution at steady state, clearance and terminal elimination half-life [t_½(p)]) and miosis pseudo-kinetic parameters [AUC_∞(miosis), AUC_2(miosis), t_½(miosis)] were determined using a noncompartmental analysis method. In six patients (three Child-Pugh grade A and three Child-Pugh grade B), antipyrine (measure of liver intrinsic activity) and D-sorbitol (measure of liver blood flow) tests were performed.

Results: A significant correlation was found between the alfentanil AUC_∞(p) and AUC_∞(miosis) (r = 0.6, p < 0.05) in cirrhotic patients. This correlation was even more significant if AUC determinations were limited to the first 2 hours after alfentanil administration (r = 0.9, p < 0.01). Statistically significant differences in pharmacokinetics and miosis pseudo-kinetic parameters were observed between cirrhotic patients and healthy volunteers from our previous experiment (historical control group). The correlations were significant between alfentanil clearance and antipyrine clearance (n = 6, r = 0.9, p < 0.05), alfentanil clearance and steady-state hepatic blood clearance [CL_H(b)] measured by the D-sorbitol test (n = 6, r = 0.9, p < 0.05).

Conclusion: Alfentanil pharmacokinetic parameters were correlated with miosis pseudo-kinetic parameters in cirrhotic patients. There was a significant decrease in pharmacokinetics and miosis pseudo-kinetics in cirrhotic patients compared with volunteers from the historical control group. Alfentanil-induced miosis has the advantage of being noninvasive and can be limited to miosis measurements during the first 2 hours after alfentanil administration in cirrhotic patients. We thus propose to substitute the AUC_2(miosis) for alfentanil pharmacokinetics in cirrhosis.

Keywords: Alfentanil; Cirrhosis; Miosis

Document Type: Research article

Affiliations: 1: Clinical Pharmacology and Gastroenterology Unit, St Luc University Hospital (Université Catholique de Louvain), Brussels, Belgium