Alfentanil-Induced Miosis as a Surrogate Measure of Alfentanil Pharmacokinetics in Patients with Mild and Moderate Liver Cirrhosis

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’/2(p)]) and miosis pseudo-kinetic parameters [AUC ∞(miosis) , AUC 2(miosis) , t½ (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.