Aim: Fentanyl is a potent opioid analgesic used for post-operative management of acute pain and breakthrough cancer pain. During the development of a nasal delivery method for fentanyl, several clinical studies were completed. These included a study of fentanyl delivery via i.v. and nasal routes with venous blood sampling and measurement of post-operative pain scores1, and a study showing substantial arterio-venous differences of fentanyl in the 60 min after nasal administration2. Also available were historical data on the kinetics of fentanyl in arterial blood in man, and data on the lung and brain kinetics of fentanyl in sheep. It was postulated that these four studies could be reconciled using a physiologically based recirculatory PK-PD model, with particular emphasis on achieving a model that could simultaneously account for the arterial and venous (arm) concentrations of fentanyl, could relate PD effects to the CNS concentrations of fentanyl, and could account for the effect of body size and age on fentanyl kinetics.
Methods: Allometric scaling was used to convert data on the cerebral and lung uptake of fentanyl in sheep into membrane-limited sub-models of the kinetics of fentanyl in the brain and lungs of a “standard” man. The data of Moksnes et al2 were fitted to determine a sub-model of the kinetics of fentanyl across the arm of a standard man, and this was assumed to be representative of fentanyl kinetics in muscle. The sub-models of fentanyl kinetics in these three organs (brain, lung and muscle) were incorporated into a “whole body” recirculatory model by adding sub-models for a venous mixing compartment, the liver and gut, the kidney and the “rest of the body”. Blood flows and organ volumes were based on values for a standard man. A population model was developed (using NONMEM) by allometric scaling of organ size and blood flows in man, and evidence based assumptions about the effect of weight and age on cardiac output. Population variability was assumed in free fraction in plasma and hepatic extraction of fentanyl.
Results: The final population model could describe the fentanyl concentrations for the three clinical studies. The unknown parameters were estimated with adequate precision, and the range of the prediction errors for the three clinical data sets were between -3.16 and 11.1 % (Median Prediction Error) and between -2.0 and 17.8% (Median Absolute Prediction Error). The nasal absorption characteristics of fentanyl were found to be 98% bioavailability, an absorption rate constant of 0.215 min-1 (95% variability across the population) and an absorption lag of 1.20 min (at 30 years) that decreased with age (64% variability across the population).
Conclusion: A physiological interpretation of clinical data was possible via allometric scaling and the use of key animal data. The model has the potential to critically analyse and develop dose regimens of fentanyl by nasal and other routes, particularly with respect to the effect of altered physiology in the post-operative period.
References
- Christrup LL, Foster D, Popper LD, Troen T, Upton R: Pharmacokinetics, efficacy, and tolerability of fentanyl following intranasal versus intravenous administration in adults undergoing third-molar extraction: A randomized, double-blind, double-dummy, two-way, crossover study. Clin Ther 2008; 30: 469-81.
- Moksnes K, Fredheim OM, Klepstad P, Kaasa S, Angelsen A, Nilsen T, Dale O: Early pharmacokinetics of nasal fentanyl: is there a significant arterio-venous difference? Eur J Clin Pharmacol 2008; 64:497-502.