K. Rowland-Yeo,1 T. Johnson,1 M. Dickins,1 A. Rostami-Hodjegan2; 1Simcyp Ltd, Sheffield, United Kingdom, 2University of Manchester, Manchester, United Kingdom
BACKGROUND: During gestation, neonates may be exposed to various legal and illicit substances which can result in varying degrees of withdrawal after delivery. The partial µ-opioid receptor agonist buprenorphine is recommended for infants requiring treatment for neonatal abstinence syndrome. Buprenorphine is metabolized extensively by CYP3A4 and UGT1A1 and undergoes biliary clearance (CL). A PBPK model incorporating ontogeny data relating to these processes was used to predict the exposure of buprenorphine in neonates.
METHODS: Prior in vitro data on metabolism, protein binding and physicochemical properties of buprenorphine were obtained from the literature and incorporated into a PBPK model within the Simcyp Simulator (Version 13R2). Data on developmental physiology and CYP3A4 and UGT1A1 ontogenies were available (Johnson et al., 2006). Various maturation functions for biliary CL were investigated with the purpose of recovering observed data under the so called “middle-out” modeling framework.
RESULTS: The buprenorphine PBPK model was able to recover the observed plasma exposure and CL (0.77 Lh-1kg-1) following IV administration (1.2 mg) in adults. For simulations in neonates (postnatal age 1-2 days), integration of a moderate maturation function (compared with CYP3A4/UGT1A1) for biliary CL was necessary to obtain predicted Css and CL values of 3.3 ng/ml and 0.25 Lh-1kg-1 which were consistent with observed data (3.6 ng/ml and 0.22 Lh-1kg-1; n=7) (Barrett et al.,1993).
CONCLUSION: Combining bottom-up PBPK modeling with reliable in vitro data allowed elucidation of the disposition of buprenorphine in neonates based on top-down analysis of observed data.
Barrett et al. (1993) Br J Clin Pharmacol 36: 215-9.
Johnson et al. (2006) Clin Pharmacokinet 45(9): 931-56.