Abstract
Buprenorphine plays a crucial role in the therapeutic management of pain in adults, adolescents and pediatric subpopulations. However, only few pharmacokinetic studies of buprenorphine in children, particularly neonates, are available as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling allows the prediction of drug exposure in pediatrics based on age-related physiological differences. The aim of this study was to predict the pharmacokinetics of buprenorphine in pediatrics with PBPK modeling. Moreover, the drug-drug interaction (DDI) potential of buprenorphine with CYP3A4 and P-glycoprotein perpetrator drugs should be elucidated. A PBPK model of buprenorphine and norbuprenorphine in adults has been developed and scaled to children and preterm neonates, accounting for age-related changes. One-hundred-percent of the predicted AUClast values in adults (geometric mean fold error (GMFE): 1.22), 90% of individual AUClast predictions in children (GMFE: 1.54) and 75% in preterm neonates (GMFE: 1.57) met the 2-fold acceptance criterion. Moreover, the adult model was used to simulate DDI scenarios with clarithromycin, itraconazole and rifampicin. We demonstrate the applicability of scaling adult PBPK models to pediatrics for the prediction of individual plasma profiles. The novel PBPK models could be helpful to further investigate buprenorphine pharmacokinetics in various populations, particularly pediatric subgroups.
Highlights
Buprenorphine is a partial agonist of the μ-opioid receptor with an analgesic potency 25 to 100 times greater compared with that of morphine [1,2]
The internal training dataset was complemented with information on the fraction of buprenorphine metabolized to norbuprenorphine, fraction of buprenorphine excreted unchanged in urine, and fraction of dose excreted in urine as norbuprenorphine [35,52,53]
The Physiologically-based pharmacokinetic (PBPK) model predictions for fraction metabolized to norbuprenorphine of ~37% and for fraction of buprenorphine excreted unchanged in urine of ~0.5% perfectly align with these literature reports
Summary
Buprenorphine is a partial agonist of the μ-opioid receptor with an analgesic potency 25 to 100 times greater compared with that of morphine [1,2]. Buprenorphine plays a crucial role in the therapeutic management of pain in adults and adolescents, which is suggested among others in a recent guideline on cancer pain management of the World Health Organization (WHO) [2]. In recent years the use of buprenorphine has become widespread in pediatrics with indications ranging from postoperative analgesia to chronic pain in palliative care [3,4]. Buprenorphine displays a ceiling effect in adults, in which escalating doses do not cause additional respiratory depression [5,6]. This effect does not seem to apply to young children [7,8]. Buprenorphine-related serious adverse reactions (ADR) up to fatal events have been reported, especially in young children, as well as single cases of accidental poisoning due to improperly stored buprenorphine drug products [7,9,10]
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