Pharmacokinetic Characterization and External Evaluation of a Quantitative Framework of Sublingual Buprenorphine in Patients with an Opioid Disorder in Puerto Rico
Abstract
:1. Introduction
2. Materials and Methods
2.1. Participants and Procedures
2.2. Assay Methodology
2.3. Non-Compartmental Pharmacokinetic Analysis
2.4. Population Pharmacokinetic Analysis
3. Results
3.1. Non-Compartmental PK Analysis
3.2. Population PK Analysis
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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BUP PK | Dose 1 (mg) | tmax (h) | Cmax (ng/mL) | AUC2 (ng·h/mL) | Dose Normalized | |
---|---|---|---|---|---|---|
Cmax (ng/mL)/mg | AUC (ng·h/mL)/mg | |||||
Mean | 7.64 | 1.45 | 7.18 | 26.80 | 1.06 | 3.84 |
SD | 3.32 | 0.69 | 5.76 | 17.87 | 0.79 | 2.35 |
RSD | 43% | 47% | 80% | 66% | 74% | 61% |
BUP PK | Cmax (ng/mL) | Cmin2 (ng/mL) | ||||||
---|---|---|---|---|---|---|---|---|
BUP 1 | Nor-BUP | BUP-g | Nor-BUP-g | BUP | Nor-BUP | BUP-g | Nor-BUP-g | |
Mean | 7.18 | 3.56 | 7.58 | 16.32 | 1.67 | 1.60 | 0.72 | 9.11 |
SD | 5.76 | 4.9 | 10.6 | 19.7 | 1.44 | 2.03 | 1.10 | 11.61 |
CYP 1 | UGT 2 | |
---|---|---|
AUCnBup+nBupG/AUCBup | AUCBupG/AUCBup | |
Mean | 3.34 | 0.39 |
SD | 1.87 | 0.26 |
RSD | 55% | 66% |
Parameter | Units | Final PK Model | Bootstrap Analysis (n = 500) | ||||
---|---|---|---|---|---|---|---|
Value | RSE [%] | Median | 2.5th | 97.5th | |||
Fixed-effects | K12 | [1/h] | 2.34 | 34 | 2.41 | 0.77 | 4.11 |
K14 | [1/h] | 1.29 | 61 | 1.27 | 0.84 | 3.98 | |
K24 | [1/h] | 1.28 × 10−1 | 32 | 1.19 × 10−1 | 7.42 × 10−2 | 1.54 × 10−1 | |
K23 | [1/h] | 6.43 × 10−2 | 36 | 6.32 × 10−2 | 2.69 × 10−2 | 1.07 × 10−1 | |
K26 | [1/h] | 2.18 × 10−1 | 23 | 2.11 × 10−1 | 1.12 × 10−1 | 3.41 × 10−1 | |
K62 | [1/h] | 4.10 × 10−2 | 14 | 4.21 × 10−2 | 3.86 × 10−2 | 4.61 × 10−2 | |
K35 | [1/h] | 1.23 × 10−1 | 52 | 1.31 × 10−1 | 7.41 × 10−2 | 2.65 × 10−1 | |
K45 | [1/h] | 8.73 × 10−1 | 43 | 8.81 × 10−1 | 4.55 × 10−1 | 1.31 | |
K30 | [1/h] | 3.81 × 10−4 | 21 | 3.62 × 10−1 | 3.11 × 10−3 | 4.97 × 10−3 | |
K50 | [1/h] | 1.27 × 10−1 | 15 | 1.39 × 10−1 | 9.91 × 10−2 | 1.54 × 10−1 | |
KA | [1/h] | 2.54 | 58 | 2.43 | 1.71 | 4.38 | |
V2/F | [L] | 861 | 11 | 872 | 811 | 965 | |
V3/F | [L] | 702 | 16 | 712 | 623 | 802 | |
Inter-individual variability | K24 | [%] | 41 | 87 | 43 | 15 | 87 |
K23 | [%] | 63 | 78 | 65 | 11 | 76 | |
K35 | [%] | 70 | 69 | 71 | 38 | 134 | |
K45 | [%] | 56 | 121 | 54 | 13 | 159 | |
K50 | [%] | 54 | 38 | 58 | 21 | 64 | |
Residual error | BUP | [%] | 38 | 18 | 35 | 22 | 48 |
Nor-BUP | [%] | 29 | 21 | 26 | 13 | 39 | |
BUP-g | [%] | 80 | 61 | 78 | 42 | 187 | |
Nor-BUP-g | [%] | 26 | 41 | 25 | 12 | 38 |
Doses (mg) | Predicted AUC (ng·h/mL) | Observed AUC (ng·h/mL) | AUC Ratio | Predicted Cmax (ng/mL) | Observed Cmax (ng/mL) | Cmax Ratio | Reference | ||||
---|---|---|---|---|---|---|---|---|---|---|---|
5th | 95th | Mean | Mean | 5th | 95th | Mean | Mean | ||||
16 | 31.56 | 71.84 | 54.13 | 45.64 | 1.19 | 6.15 | 8.27 | 7.47 | 6.25 | 1.20 | M. Jönsson, European Journal of Pharmaceutical Sciences 122 (2018) 125–133; [21] |
4 | 8.54 | 22.87 | 15.86 | 17.84 | 0.89 | 1.91 | 3.54 | 2.71 | 2.44 | 1.11 | |
4 | 8.54 | 22.87 | 15.86 | 12.52 | 1.27 | 1.91 | 3.54 | 2.71 | 1.84 | 1.47 | Harris et al. Healthy females and male non-opioid-dependent users, age range (22–42 years); [22] |
8 | 19.11 | 40.34 | 29.74 | 20.22 | 1.47 | 2.51 | 5.27 | 3.87 | 3 | 1.29 | |
16 | 31.56 | 71.84 | 54.13 | 34.89 | 1.55 | 6.15 | 8.27 | 7.47 | 5.95 | 1.26 | |
16 | 31.56 | 71.84 | 54.13 | 32.63 | 1.66 | 6.15 | 8.27 | 7.47 | 5.47 | 1.37 | |
2 | - | - | - | - | - | 0.89 | 1.72 | 1.12 | 1.06 | 1.06 | McAleer et al. Opioid-naïve healthy male subjects, age range (19–42); [23] |
8 | 19.11 | 40.34 | 29.74 | 31.81 | 0.93 | 2.51 | 5.27 | 3.87 | 4 | 0.97 | |
12 | 29.63 | 54.22 | 42.59 | 41.61 | 1.02 | 4.29 | 7.61 | 5.84 | 5.4 | 1.08 | |
16 | 31.56 | 71.84 | 54.13 | 52 | 1.04 | 6.15 | 8.27 | 7.47 | 6.4 | 1.17 | |
8 | 19.11 | 40.34 | 29.74 | 24.55 | 1.21 | 2.51 | 5.27 | 3.87 | 3.2 | 1.21 | |
8 | 19.11 | 40.34 | 29.74 | 24.6 | 1.21 | 2.51 | 5.27 | 3.87 | 3.2 | 1.21 | |
4 | 8.54 | 22.87 | 15.86 | 9.37 | 1.69 | 1.91 | 3.54 | 2.71 | 2 | 1.36 | Ciraulo et al. Healthy non-opioid-dependent users, age range (21–45); [24] |
8 | 19.11 | 40.34 | 29.74 | 19.92 | 1.49 | 2.51 | 5.27 | 3.87 | 2.65 | 1.46 | |
16 | 31.56 | 71.84 | 54.13 | 34.94 | 1.55 | 6.15 | 8.27 | 7.47 | 4.42 | 1.69 | |
24 | 51.93 | 82.74 | 67.56 | 48.81 | 1.38 | 7.95 | 10.67 | 9.44 | 5.41 | 1.74 | |
4 | 8.54 | 22.87 | 15.86 | 13.09 | 1.21 | 1.91 | 3.54 | 2.71 | 2.33 | 1.16 | Ciraulo et al. Healthy non-opioid-dependent users, age range (21–55); [23] |
8 | 19.11 | 40.34 | 29.74 | 23.23 | 1.28 | 2.51 | 5.27 | 3.87 | 3.53 | 1.10 | |
16 | 31.56 | 71.84 | 54.13 | 39.38 | 1.37 | 6.15 | 8.27 | 7.47 | 5.83 | 1.28 | |
24 | 51.93 | 82.74 | 67.56 | 47.55 | 1.42 | 7.95 | 10.67 | 9.44 | 6.44 | 1.47 | |
16 | 31.56 | 71.84 | 54.13 | 54.7 | 0.99 | 6.15 | 8.27 | 7.47 | 6.88 | 1.09 | Compton et al. Healthy female and male ipioi-dependent-users, age range (18–65); [25] |
24 | 51.93 | 82.74 | 67.56 | 81.1 | 0.83 | 7.95 | 10.67 | 9.44 | 9.1 | 1.04 | |
32 | 68.49 | 102.37 | 84.31 | 103 | 0.82 | 12.41 | 16.29 | 14.21 | 13.93 | 1.02 | |
2 | 5.14 | 9.63 | 7.41 | 6.5 | 1.14 | 0.89 | 1.72 | 1.12 | 0.85 | 1.32 | Greenwald et al. Healthy female and male opioid-dependent-users, age range (34–45); [10] |
16 | 31.56 | 71.84 | 54.13 | 41.9 | 1.29 | 6.15 | 8.27 | 7.47 | 5.15 | 1.45 | Moody et al. Drug Alcohol Depend. (2011) 118(2–3), 479–483; [15] |
16 | 31.56 | 71.84 | 54.13 | 58.4 | 0.93 | 6.15 | 8.27 | 7.47 | 6.97 | 1.07 | |
2 | 5.14 | 9.63 | 7.41 | 10.9 | 0.68 | 0.89 | 1.72 | 1.12 | 1.65 | 0.68 | R. Dong et al. Drugs in R&D (2019) 19, 255–265; [14] |
4 | 8.54 | 22.87 | 15.86 | 18.1 | 0.88 | 1.91 | 3.54 | 2.71 | 2.57 | 1.05 | |
8 | 19.11 | 40.34 | 29.74 | 33.3 | 0.89 | 2.51 | 5.27 | 3.87 | 5 | 0.77 | |
12 | 29.63 | 54.22 | 42.59 | 47.7 | 0.89 | 4.29 | 7.61 | 5.84 | 7.03 | 0.83 | |
16 | 31.56 | 71.84 | 54.13 | 55.6 | 0.97 | 6.15 | 8.27 | 7.47 | 7.84 | 0.95 | |
24 | 51.93 | 82.74 | 67.56 | 73 | 0.93 | 7.95 | 10.67 | 9.44 | 11.7 | 0.81 | |
4 | 8.54 | 22.87 | 15.86 | 23.89 | 0.66 | 1.91 | 3.54 | 2.71 | 3.31 | 0.82 | Kuhlman et al. Journal of Analitical Toxicology Vol 20 Oct 1996, p369; [26] |
2 | 5.14 | 9.63 | 7.41 | 6.789 | 1.09 | 0.89 | 1.72 | 1.12 | 0.78 | 1.44 | Healthy adult male or non-pregnant, non-breastfeeding female volunteers, 18–45 years of age (inclusive), BMI between 18 and 30 kg/m2 (inclusive) and weighed a minimum of 50 kg (110 lbs); [27] |
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Santiago, D.; Mangas-Sanjuan, V.; Melin, K.; Duconge, J.; Zhao, W.; Venkataramanan, R. Pharmacokinetic Characterization and External Evaluation of a Quantitative Framework of Sublingual Buprenorphine in Patients with an Opioid Disorder in Puerto Rico. Pharmaceutics 2020, 12, 1226. https://doi.org/10.3390/pharmaceutics12121226
Santiago D, Mangas-Sanjuan V, Melin K, Duconge J, Zhao W, Venkataramanan R. Pharmacokinetic Characterization and External Evaluation of a Quantitative Framework of Sublingual Buprenorphine in Patients with an Opioid Disorder in Puerto Rico. Pharmaceutics. 2020; 12(12):1226. https://doi.org/10.3390/pharmaceutics12121226
Chicago/Turabian StyleSantiago, Darlene, Victor Mangas-Sanjuan, Kyle Melin, Jorge Duconge, Wenchen Zhao, and Raman Venkataramanan. 2020. "Pharmacokinetic Characterization and External Evaluation of a Quantitative Framework of Sublingual Buprenorphine in Patients with an Opioid Disorder in Puerto Rico" Pharmaceutics 12, no. 12: 1226. https://doi.org/10.3390/pharmaceutics12121226