Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study by Tobechi Brendan Nnanna instant download

Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study by Tobechi Brendan Nnanna instant download

Abstract Plasma levels of sublingual buprenorphine utilized in the therapy of opioid use disorder, has been demonstrated to undergo gestation-associated decline in vivo, to an extent influenced by upheavals physiologically across gestational trimesters. However, based on extant literature, a dearth of knowledge exists in the optimization of buprenorphine therapeutic modalities, pharmacokinetic interactions and posological scrutiny, necessary for successful regimen adherence. A physiologically-based pharmacokinetic modelling methodology in a virtual clinical trial premise was utilized to investigate gestational upheavals in peak plasma buprenorphine concentrations, followed by a pharmacokinetic drug-drug interaction investigation and dose optimization strategy, to maintain buprenorphine levels above proposed thresholds of 1ng/ml and below 22.2ng/ml adjudicated as a fatality limit. A fold decline (> 1.3fold) in buprenorphine mean peak plasma concentration (92% - 74%) was evident for the model predicted buprenorphine metrics across selected gestational weeks to term in line with the model predicted increases in physiological upheavals occurring across gestation which may influence the changes. The rifampicin mediated drug-drug interaction on buprenorphine levels initially resulted in fold decreases (>1.5 fold) over a twenty-four hour duration, in concert with escalating physiological metrics across gestational trimesters. The interaction perpetrated with Clarithromycin dosing resulted in fold increases (> 2-fold) in the plasma concentration as well as an increase in other metrics associated with buprenorphine kinetics. The dose optimization approach maintained majority of subjects (>90%) with the extensive metabolizer (EM) phenotype above 1ng/ml and below 22.2ng/ml in the 8mg – 24mg dose ranges albeit with 1% and 3% in the 28mg and 32mg doses above the fatality limit respectively. This study demonstrates the utility of PBPK modeling.