Alfentanil-induced miosis as a surrogate measure of alfentanil pharmacokinetics in patients with mild and moderate liver cirrhosis.
OBJECTIVE
(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 microg/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(infinity(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((1/2)(p))]) and miosis pseudo-kinetic parameters [AUC(infinity)((miosis)), AUC(2)((miosis)), t((1/2))((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(infinity(p)) and AUC(infinity)((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).


CONCLUSIONS
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.
Baririan
Nariné
N
Clinical Pharmacology and Gastroenterology Unit, St Luc University Hospital (Université Catholique de Louvain), Brussels, Belgium.
Van Obbergh
Luc
L
Desager
Jean-Pierre
JP
Verbeeck
Roger K
RK
Wallemacq
Pierre
P
Starkel
Peter
P
Horsmans
Yves
Y
D000328:Adult; D000368:Aged; D015760:Alfentanil / Q000493:pharmacokinetics*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000983:Antipyrine; D015415:Biomarkers; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004232:Diuretics; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D015877:Miosis / Q000139:chemically induced* / Q000503:physiopathology*; D013012:Sorbitol
D000701:Analgesics, Opioid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D004232:Diuretics; D015760:Alfentanil; D013012:Sorbitol; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000983:Antipyrine