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

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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 [AUC2(p)], apparent volume of distribution at steady state, clearance and terminal elimination half-life [t’/2(p)]) and miosis pseudo-kinetic parameters [AUC∞(miosis), AUC2(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 [CLH(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 AUC2(miosis) for alfentanil pharmacokinetics in cirrhosis.

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  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

The authors wish to thank Pr Jean Cumps (UCL, School of Pharmacy) for statistical support. No sources of funding were used to assist in the preparation of this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Clinical Pharmacology and Gastroenterology Unit, St Luc University Hospital (Université Catholique de Louvain), Avenue Hippocrate, 10, MD/GAEN, Brussels, 1200, Belgium

    Nariné Baririan, Luc Van Obbergh, Jean-Pierre Desager, Roger K. Verbeeck, Pierre Wallemacq, Peter Starkel &  Yves Horsmans

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  1. Nariné Baririan
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  2. Luc Van Obbergh
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  3. Jean-Pierre Desager
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  4. Roger K. Verbeeck
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  7. Yves Horsmans
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Correspondence to Yves Horsmans.

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Baririan, N., Van Obbergh, L., Desager, JP. et al. Alfentanil-Induced Miosis as a Surrogate Measure of Alfentanil Pharmacokinetics in Patients with Mild and Moderate Liver Cirrhosis. Clin Pharmacokinet 46, 261–270 (2007). https://doi.org/10.2165/00003088-200746030-00006

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