Physiologically Based Pharmacokinetic Modeling of Metoprolol Enantiomers and α-Hydroxymetoprolol to Describe CYP2D6 Drug-Gene Interactions
Abstract
:1. Introduction
2. Materials and Methods
2.1. Software
2.2. PBPK Model Building
2.3. DGI Modeling
2.4. PBPK Model Evaluation
2.5. DGI Modeling Evaluation
3. Results
3.1. Metoprolol PBPK Model Development and Evaluation
3.2. Metoprolol CYP2D6 DGI Model Development and Evaluation
3.3. Metoprolol Dose Adaptation for CYP2D6 DGIs
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Activity Score | Projected Phenotype | Examples of Relevant CYP2D6 Genotypes |
---|---|---|
0 | PM | *3/*3, *3/*4, *4/*4, *5/*6 |
0.25 | IM | *4/*10, *5/*10 |
0.5 | *4/*41, *5/*17, *10/*10 | |
0.75 | *17/*10, *41/*10 | |
1 | *1/*4, *2/*5, *17/*17, *17/*41 | |
1.25 | NM | *1/*10, *2/*10, *35/*10 |
1.5 | *1/*41, *2/*17, *35/*41 | |
2 | *1/*1, *1/*2, *2/*35 | |
2.25 | *1x2/*17, *35x2/*41 | |
>2.25 | UM | *1/*1x3, *1/*35x2, *2x2/*9 |
Parameter | Unit | (R)-Metoprolol | (S)-Metoprolol | Description | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Value | Source | Literature | Reference | Value | Source | Literature | Reference | |||
MW | g/mol | 267.36 | Lit. | 267.36 | [34] | 267.36 | Lit. | 267.36 | [34] | Molecular weight |
pKa (base) | - | 9.7 | Lit. | 9.70 | [34] | 9.7 | Lit. | 9.70 | [34] | Acid dissociation constant |
Solubility tart. (pH 7.4) | g/mL | 1.00 | Lit. | 1.00 | [35] | 1.00 | Lit. | 1.00 | [35] | Solubility |
Solubility succ. (pH 5.5) | g/mL | 0.16 | Lit. | 0.16 | [36] | 0.16 | Lit. | 0.16 | [36] | Solubility |
logP | - | 1.77 | Lit. | 1.77 | [37] | 1.77 | Lit. | 1.77 | [37] | Lipophilicity |
fu | % | 88 | Lit. | 88 | [38] | 88 | Lit. | 88 | [38] | Fraction unbound |
CYP2D6 Km ⭢ αHM | µmol/L | 10.08 | Lit. | 10.08 ‡ | [39] | 10.75 | Lit. | 10.75 ‡ | [39] | Michaelis-Menten constant |
CYP2D6 kcat ⭢ αHM | 1/min | 6.02 | Optim. † | 7.50 | [39] | 6.55 | Optim. † | 8.27 | [39] | Catalytic rate constant |
CYP2D6 Km ⭢ ODM | µmol/L | 8.82 | Lit. | 8.82 ‡ | [39] | 12.43 | Lit. | 12.43 ‡ | [39] | Michaelis-Menten constant |
CYP2D6 kcat ⭢ ODM | 1/min | 9.87 | Optim. † | 12.30 | [39] | 8.21 | Optim. † | 10.37 | [39] | Catalytic rate constant |
CLhep., unsp. | 1/min | 0.08 | Optim. | - | - | 0.09 | Optim. | - | - | Unspecific hepatic clearance |
GFR fraction | - | 1.00 | Asm. | - | - | 1.00 | Asm. | - | - | Filtered drug in the urine |
EHC continuous fraction | - | 1.00 | Asm. | - | - | 1.00 | Asm. | - | - | Bile fraction cont. released |
Intestinal permeability | cm/min | 4.14 × 10−5 | Optim. | 1.12 × 10−5 | Calc. [40] | 4.14 × 10−5 | Optim. | 1.12 × 10−5 | Calc. [40] | Transcellular intestinal perm. |
Cellular permeability | cm/min | 4.64 × 10−3 | Calc. | PK-Sim | [32] | 4.64 × 10−3 | Calc. | PK-Sim | [32] | Perm. into the cellular space |
Partition coefficients | - | Diverse | Calc. | R&R | [41,42] | Diverse | Calc. | R&R | [41,42] | Cell to plasma partitioning |
NR Weibull time parameter | min | 12.31 | Optim. | - | [43,44] | 12.31 | Optim. | - | [43,44] | Dissolution time (50%) |
NR Weibull shape parameter | - | 0.72 | Optim. | - | [43,44] | 0.72 | Optim. | - | [43,44] | Dissolution profile shape |
CR Weibull time parameter | min | 331.92 | Optim. | - | [45] | 331.92 | Optim. | - | [45] | Dissolution time (50%) |
CR Weibull shape parameter | - | 1.53 | Optim. | - | [45] | 1.53 | Optim. | - | [45] | Dissolution profile shape |
Activity Score | (R)-Metoprolol | (S)-Metoprolol | kcat, rel | ||
---|---|---|---|---|---|
kcat ⭢ αHM | kcat ⭢ ODM | kcat ⭢ αHM | kcat ⭢ ODM | ||
0 | 0.00 1/min | 0.00 1/min | 0.00 1/min | 0.00 1/min | 0% |
0.5 | 1.65 1/min | 2.70 1/min | 1.82 1/min | 2.27 1/min | 19% |
1.25 | 5.73 1/min | 9.40 1/min | 6.30 1/min | 7.89 1/min | 64% |
1.5 | 6.38 1/min | 10.48 1/min | 7.03 1/min | 8.81 1/min | 72% |
2 | 10.17 1/min | 16.69 1/min | 11.19 1/min | 14.02 1/min | 100% |
3 | 19.03 1/min | 31.22 1/min | 20.93 1/min | 26.23 1/min | 213% |
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Rüdesheim, S.; Wojtyniak, J.-G.; Selzer, D.; Hanke, N.; Mahfoud, F.; Schwab, M.; Lehr, T. Physiologically Based Pharmacokinetic Modeling of Metoprolol Enantiomers and α-Hydroxymetoprolol to Describe CYP2D6 Drug-Gene Interactions. Pharmaceutics 2020, 12, 1200. https://doi.org/10.3390/pharmaceutics12121200
Rüdesheim S, Wojtyniak J-G, Selzer D, Hanke N, Mahfoud F, Schwab M, Lehr T. Physiologically Based Pharmacokinetic Modeling of Metoprolol Enantiomers and α-Hydroxymetoprolol to Describe CYP2D6 Drug-Gene Interactions. Pharmaceutics. 2020; 12(12):1200. https://doi.org/10.3390/pharmaceutics12121200
Chicago/Turabian StyleRüdesheim, Simeon, Jan-Georg Wojtyniak, Dominik Selzer, Nina Hanke, Felix Mahfoud, Matthias Schwab, and Thorsten Lehr. 2020. "Physiologically Based Pharmacokinetic Modeling of Metoprolol Enantiomers and α-Hydroxymetoprolol to Describe CYP2D6 Drug-Gene Interactions" Pharmaceutics 12, no. 12: 1200. https://doi.org/10.3390/pharmaceutics12121200