(53) Adopting a Buprenorphine Precision Dosing Approach Treatment for Hispanic Puerto Ricans

Introduction/Background
High accessibility to fentanyl adulterated heroin in Puerto Rico (PR) promotes drug use practices and resulting opioid tolerance profiles different to those of prescription opioids in the US. We have reasoned that adopting a buprenorphine precision dosing approach to treat Hispanic Puerto Ricans (HPRs) with OUD will significantly improve the efforts towards combating the OUD crisis in PR. The purpose of this study was to develop a buprenorphine pharmacokinetic dosing model as a precision dosing approach by describing the metabolism of buprenorphine in HPRs.

Methods
We conducted an 8-hour PK study that collected buprenorphine and it’s metabolites plasma levels after dosing from 12 buprenorphine maintained OUD HPR (6 males/6 females; 96 total samples); in steady state dose, no dose adjustment in the last 3 months and negative toxicology results for illicit drug use. Non-compartmental and compartmental pharmacokinetic analyses were performed to describe buprenorphine characteristics, metabolism and for the development of a precision dosing model.

Results
The average age and weight of the recruited participants was 46.7 years and 151 lbs (68 kg),respectively. Recruited patients were maintained with an average prescribed buprenorphine dose of 7.6 mg. Pharmacokinetic observed estimates were: tmax=1.5±0.7 h, Co=1.6+1.4 ng/mL, Cmax=7.2±6 ng/mL and AUC0–8h=26.8±17.8 ng·h/mL. Considerable variability in the concentration vs time curves between subject was observed.
A two-compartmental dosing model was developed with 307 buprenorphine and metabolites plasma levels. The model elucidated similar kinetic metabolism of buprenorphine to nor-buprenorphine and buprenorphine glucuronide, with both being metabolized to nor-buprenorphine-glucuronide which is eliminated from the body. The adequacy of the developed model was evidenced with its capability of capturing the observed (collected) plasma levels of buprenorphine and each metabolite. The model was externally validated through the comparison of model-predicted and observed (reported) buprenorphine concentrations across several dose-levels.
The model proposed two optimized dosing schemes to increase the proportion of patients in this population (>80%) having a trough level above 3ng/mL: 24 mg divided three times a day, or 32 mg divided two times a day.

Discussion/Conclusion
Our study was the first to characterize and describe the pharmacokinetics of buprenorphine in a Hispanic population. Plasma samples from recruited buprenorphine-maintained HPR individuals with OUD elucidated unique characteristics important for transforming the current approach to treat OUD in the population group. Recruited patients even though considered to be in maintenance dose, had plasma levels at trough (just before dosing) lower than reported values to clinically suppress withdrawal symptoms. Although the study did not collect withdrawal symptoms, we anecdotally observed some patients showing anxiety, irritability and restlessness just before taking their daily dose. This evidences a need for a different dosing approach to maintain these individuals stable throughout a dosing period (24 hours),and avoid low plasma levels before the next dose. Our model proposed optimized dosing schemes to maintain plasma levels >3ng/mL and as such increase the proportion of patients having significant opioid receptor blockage throughout the dosing period (24 hours). Our proposed dosing schemes deviate from traditional dosing in frequency and dose. We are currently conducting PK studies to refine even more our precision dosing model required before clinical implementation studies and address important limitations of this model.

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