Pharmacokinetic Characterization and External Evaluation of a Quantitative Framework of Sublingual Buprenorphine in Patients with an Opioid Disorder in Puerto Rico.

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 (tmax = 1.5 ± 0.7 h, Co = 1.6 ± 1.4 ng/mL, Cmax= 7.1 ± 6 ng/mL, and AUC0-8h = 26.8 ± 17.8 h·ng/mL). Subjects had a significantly higher tendency towards CYP-mediated N-demethylation, with the AUC0-8h 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 (ka = 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.

Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression of epidermal growth factor receptor (EGFR). Nimotuzumab is a recombinant humanized monoclonal antibody against human EGFR. The aim of this study was to develop a population pharmacokinetic model for nimotuzumab and to identify demographic and clinical predictive factors of the pharmacokinetic variability. The population pharmacokinetics (PopPK) of nimotuzumab was characterized using a nonlinear mixed-effect modeling approach with NONMEM®. A total of 422 log-transformed concentration-versus-time datapoints from 20 patients enrolled in a single-center phase I clinical trial were used. Quasi steady state approximation of the full TMDD (target-mediated drug disposition) model with constant target concentration best described the concentration-time profiles. A turnover mediator was included which stimulates the non-specific clearance of mAb in the central compartment in order to explain the reduced levels at higher doses. Covariates had no influence on the PK (pharmacokinetics) parameters. The model was able to detect that the maximum effective dose in ADPKD subjects is 100 mg. The developed PopPK model may be used to guide the dose selection for nimotuzumab during routine clinical practice in patients with polycystic kidney disease. The model will further support the ongoing investigations of the PK/PD relationships of nimotuzumab to improve its therapeutic use in other disease areas.