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Background: The aim of this analysis was to characterize the pharmacokinetics (PK) of sublingual buprenorphine (BUP) and its metabolites (buprenorphine glucuronide; BUP-g, norbuprenorphine; Nor-BUP, and norbuprenorphine glucuronide; Nor-BUP-g) in opioid use disorder (OUD) patients in Puerto Rico (PR) as a first step of evidence-based BUP dosing strategies in this population. Methods: BUP and metabolites concentrations were measured from 0 to 8 h after the administration of sublingual buprenorphine/naloxone films in 12 stable OUD subjects. Results: PK non-compartmental characteristics showed considerable variability in parameters between the subjects over the 8-h sampling time (t_max = 1.5 ± 0.7 h, C_o = 1.6 ± 1.4 ng/mL, C_max= 7.1 ± 6 ng/mL, and AUC_0–8h = 26.8 ± 17.8 h·ng/mL). Subjects had a significantly higher tendency towards CYP-mediated N-demethylation, with the AUC_0–8h ratios of the molar concentrations of [Nor-BUP + Nor-BUP-g] to BUP being (3.4 ± 1.9) significantly higher compared with BUP-g to BUP (0.19 ± 0.2). A two-compartment population-PK model with linear absorption (k_a = 2.54 h⁻¹), distribution (k₁₂= 2.34 h⁻¹, k₁₄ = 1.29 h⁻¹), metabolism (k₂₄ = 1.28 × 10⁻¹ h⁻¹, k₂₃ = 6.43 × 10⁻² h⁻¹, k₃₅ = 1.23 × 10⁻¹ h⁻¹, k₄₅ = 8.73 × 10⁻¹ h⁻¹), and elimination (k₃₀ = 3.81 × 10⁻³ h⁻¹, k₅₀ = 1.27 × 10⁻¹ h⁻¹) adequately described the time-course of BUP and its metabolites, which has been externally validated using published data. Conclusions: Although limited in sampling time and number of recruited subjects, this study presents specific BUP PK characteristics that evidenced the need for additional PK studies and subsequent modeling of the data for the development of evidence-based dosing approaches in Puerto Rico. Full article