No abstract

PBPK model-based simulation may be a useful tool to optimize BUP pharmacotherapy during pregnancy, obviating the need to perform pharmacokinetic studies in each trimester and the postpartum period that normally require intensive blood sampling.

Background Dose-adjusted plasma concentrations of buprenorphine are significantly decreased during pregnancy compared to the non-pregnant state. This observation suggests that pregnant women may need a higher dose of buprenorphine than non-pregnant individuals in order to maintain similar drug exposure (plasma concentrations over time after a dose). The current dosing recommendations for buprenorphine during pregnancy address the total daily dose of buprenorphine to be administered but the frequency of dosing is not clearly addressed. Based on buprenorphine’s long terminal half-life, once daily or twice daily dosing has generally been suggested. Objective To assess the impact of dosing frequency on buprenorphine plasma concentration time course during pregnancy. Study Design We have utilized three data sources to determine an optimal frequency for dosing of buprenorphine during pregnancy: data from a pharmacokinetic study of 14 pregnant and post-partum women on maintenance buprenorphine in a supervised clinical setting; data from pregnant women attending a buprenorphine clinic; and data from a physiologically based pharmacokinetic (PBPK) modeling of buprenorphine pharmacokinetics in non-pregnant subjects. Results Among the fourteen women participating in the pharmacokinetic study during and after pregnancy, plasma concentrations of buprenorphine were < 1ng/ml (the theoretical concentration required to prevent withdrawal symptoms) for 50–80% of the 12 hour dosing interval while at steady state. Among 62 women followed in a opioid agonist treatment program, where dosing frequency is determined in part by patient preference, 10 (16 %) were on once daily dosing, 10 (16%) were on twice daily dosing, 28 (45%) were on thrice daily dosing and 14 (23%) were on four times daily dosing. A physiologic based pharmacokinetic (PBPK) model in non- pregnant subjects demonstrated that dosing frequency impacts the duration over which the plasma concentrations are below a specified plasma concentration threshold. Conclusion(s) A more frequent dosing interval i.e. TID or QID dosing may be required in pregnant women to sustain plasma concentrations above the threshold of 1ng/ml to prevent withdrawal symptoms and to improve adherence.

For kidney transplant recipients, immunosuppression commonly consists of combination treatment with a calcineurin inhibitor, an antiproliferative agent and a corticosteroid. Many medical centers use a sequential immunosuppression regimen where an induction agent, either an anti-thymocyte globulin or interleukin-2 receptor antibody, is given at the time of transplantation to prevent early acute rejection which is then followed by a triple immunosuppressive maintenance regimen. Very low rejection rates have been achieved at many transplant centers using combinations of these agents in a variety of protocols. Yet, a large number of recipients suffer chronic allograft injury and adverse events associated with drug therapy. Regimens designed to limit or eliminate calcineurin inhibitors and/or corticosteroid use are actively being pursued. An ideal immunosuppressive regimen limits toxicity and prolongs the functional life of the graft. This article contains a critical analysis of clinical data on currently available immunosuppressive strategies and an overview of therapeutic moieties in development.

The validated PBPK models will be used in future studies to predict BUP plasma and brain concentrations based on the varying demographic, physiological and pathological characteristics of patients.