Population Pharmacokinetic Analysis Supports Initiation Treatment and Bridging from Sublingual Buprenorphine to Subcutaneous Administration of a Buprenorphine Depot (CAM2038) in the Treatment of Opioid Use Disorder

Abstract

Background and objective: In treating opioid use disorder (OUD), subcutaneous (SC) extended-release buprenorphine (BPN) depots, e.g., CAM2038, have been shown to provide smaller and less frequent fluctuations in BPN plasma concentrations and pharmacodynamic responses, improve outcomes, reduce treatment burden, and lower risks of misuse and diversion compared to daily sublingual (SL) BPN. This analysis characterized the pharmacokinetics (PK) of BPN following intravenous and SL administration, and administration of SC CAM2038 weekly and monthly.

Methods: Pharmacokinetic data from two Phase 1 and two Phase 2 trials in healthy participants and participants with OUD, respectively, were used to develop a population PK model using non-linear mixed effects modelling. The analysis included data from 252 participants and 10,658 BPN observations.

Results: The disposition of BPN was best described by a three-compartment model with first-order elimination, and absorption of SL BPN and SC CAM2038 weekly and monthly by dual parallel absorption pathways. Model diagnostics indicated good predictive performance of BPN concentrations. Buprenorphine plasma concentration-time profiles were simulated for treatment initiation, switching from SL BPN to CAM2038 weekly and monthly, and tapering after interrupting treatment with CAM2038. Simulations predicted CAM2038 weekly and monthly doses that provided BPN plasma maximum concentration (C_max) and trough concentration (C_trough) values at steady state within those observed following SL BPN administration.

Conclusions: This population PK model supports the use of CAM2038 doses as individualized treatment for OUD across different treatment stages, including initiation, switching from SL BPN according to established dose conversion schedules, and tapering.

Trial registrations: ISRCTN41550730 (05/19/2014), ISRCTN24987553 (07/29/2014), NCT02611752 (11/23/2015), NCT02710526 (03/16/2016).

Fig. 1

Population PK model of BPN. BPN buprenorphine, $\mathit{CL}$ plasma clearance, CMT_q1w1 compartment q1w1, CMT_q1w2 compartment q1w2, CMT_q4w1 compartment q4w1, CMT_q4w2 compartment q4w2, CMT_SL1 compartment SL1, CMT_SL2 compartment SL2, D_SL1 duration of drug input to compartment SL1, D_q1w1 duration of drug input to compartment q1w1, F_SL1 fraction of bioavailable dose going into compartment SL1, F_q1w1 fraction of dose going into compartment q1w1, F_q4w1 fraction of dose going into compartment q4w1, IV intravenous, k_a,q1w1 first-order rate constant from compartment q1w1, k_a,q1w2 first-order rate constant from compartment q1w2, k_a,q4w1 first-order rate constant from compartment q4w1, k_a,q4w2 first-order rate constant from compartment q4w2, k_a,SL1 first-order rate constant from compartment SL1, k_a,SL2 first-order rate constant from compartment SL2, Q1D once daily, Q1W once weekly, Q₂ inter-compartmental clearance to second compartment, Q₃ inter-compartmental clearance to third compartment, Q4W once monthly, SC subcutaneous, SL sublingual, t_lag,SL1 lag-time to compartment SL1, V₂ volume of second compartment, V₃ volume of third compartment, V_c central volume of distribution

Fig. 2

Prediction-corrected visual predictive check of BPN concentrations for the final BPN population PK model. BPN concentrations are displayed versus time after last dose, stratified by treatment. Observations below the LLOQ were included in the calculations of median and percentiles The solid and dashed blue lines represent the median and 5th and 95th percentiles of the observations, the shaded red and blue areas represent the 95 % confidence interval of the median and the 5th and 95th percentiles predicted by the model. BPN buprenorphine, IV intravenous, LLOQ lower limit of quantification, PK pharmacokinetic, Q1W once weekly, Q4W once monthly, SC subcutaneous, SL sublingual

Fig. 3

Simulated median BPN plasma concentration-time profiles based on the final population PK model, during treatment initiation of 16 mg CAM2038 Q1W followed by 8 mg CAM2038 after 3 and 5 days in comparison with initial treatment of 24 mg and 32 mg CAM2038 Q1W. BPN buprenorphine, Q1W once weekly

Fig. 4

Simulated median BPN plasma concentration-time profiles, based on the final population PK model, during the first week after administration of 24 mg CAM2038 Q1W, 96 mg CAM2038 Q4W, and 16 mg SL BPN Q1D. BPN buprenorphine, Q1D once daily, Q1W once weekly, Q4W once monthly, SL sublingual

Fig. 5

Simulated steady-state BPN plasma concentration-time profiles for a daily 16 mg SL BPN and 24 mg CAM2038 Q1W, b daily 16 mg SL BPN and 96 mg CAM2038 Q4W, and c 24 mg CAM2038 Q1W and 96 mg CAM2038 Q4W. BPN buprenorphine, CI confidence interval, Q1D once daily, Q1W once weekly, Q4W once monthly, SL sublingual

Fig. 6

Simulated steady-state BPN PK parameters (C_trough,ss –C_av,ss–C_max,ss), based on the final population PK model, following dosing for a) daily 8 mg SL BPN, 16 mg SC CAM2038 Q1W, and 64 mg SC CAM2038 Q4W, b) daily 16 mg SL BPN, 24 mg SC CAM2038 Q1W, and 96 mg SC CAM2038 Q4W, c) daily 24 mg SL BPN, 32 mg SC CAM2038 Q1W, and 128 mg SC CAM2038 Q4W. BPN buprenorphine, C_av,ss average plasma concentration during the dosing interval at steady state (geometric mean), C_max,ss maximum plasma concentration at steady state, C_trough,ss trough plasma concentration at steady state, PK pharmacokinetic, Q1D once daily, Q1W once weekly, Q4W once monthly, SC subcutaneous, SL sublingual

Fig. 7

Predicted BPN plasma concentrations, based on the final population PK model, after discontinuation of treatment following SC administration of 5 doses of 32 mg CAM2038 Q1W and 5 doses of 128 mg CAM2038 Q4W. BPN buprenorphine, CI confidence interval, PK pharmacokinetic, Q1W once weekly, Q4W once monthly, SC subcutaneous