Journal of Shanghai Jiao Tong University (Medical Science) ›› 2024, Vol. 44 ›› Issue (11): 1414-1421.doi: 10.3969/j.issn.1674-8115.2024.11.008
• Clinical research • Previous Articles
MOU Fan1(), HUANG Zhiwei2, CHENG Yu1, ZHAO Xue3, LI Huafang2, YU Shunying1(
)
Received:
2024-05-22
Accepted:
2024-06-24
Online:
2024-11-28
Published:
2024-11-28
Contact:
YU Shunying
E-mail:moufan2021@163.com;yushunying@smhc.org.cn
Supported by:
CLC Number:
MOU Fan, HUANG Zhiwei, CHENG Yu, ZHAO Xue, LI Huafang, YU Shunying. Prediction of drug-drug interactions in clozapine combination therapy based on physiologically based pharmacokinetic model[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(11): 1414-1421.
CYP450 | Sample 1[ | Sample 2[ | Sample 3[ | WM |
---|---|---|---|---|
CYP1A2/(pmol·mg-1) | 42.48 | 42.00 | 42.30 | 42.31 |
CYP2A6/(pmol·mg-1) | 15.63 | - | - | 15.63 |
CYP2B6/(pmol·mg-1) | 4.62 | - | - | 4.62 |
CYP2C9/(pmol·mg-1) | 98.60 | - | 87.20 | 87.19 |
CYP2C19/(pmol·mg-1) | 8.45 | 60.00 | 8.10 | 8.25 |
CYP2D6/(pmol·mg-1) | 20.50 | - | - | 20.50 |
CYP2E1/(pmol·mg-1) | 102.04 | - | - | 102.04 |
CYP3A4/(pmol·mg-1) | 49.34 | 120.00 | 93.00/70.30 | 49.34 |
CYP3A5/(pmol·mg-1) | 42.45 | - | 145.40/82.10 | 42.45 |
Tab 1 Enzyme content of CYP450 subtypes in Chinese population
CYP450 | Sample 1[ | Sample 2[ | Sample 3[ | WM |
---|---|---|---|---|
CYP1A2/(pmol·mg-1) | 42.48 | 42.00 | 42.30 | 42.31 |
CYP2A6/(pmol·mg-1) | 15.63 | - | - | 15.63 |
CYP2B6/(pmol·mg-1) | 4.62 | - | - | 4.62 |
CYP2C9/(pmol·mg-1) | 98.60 | - | 87.20 | 87.19 |
CYP2C19/(pmol·mg-1) | 8.45 | 60.00 | 8.10 | 8.25 |
CYP2D6/(pmol·mg-1) | 20.50 | - | - | 20.50 |
CYP2E1/(pmol·mg-1) | 102.04 | - | - | 102.04 |
CYP3A4/(pmol·mg-1) | 49.34 | 120.00 | 93.00/70.30 | 49.34 |
CYP3A5/(pmol·mg-1) | 42.45 | - | 145.40/82.10 | 42.45 |
Parameter | Clozapine | Source | Fluvoxamine | Source |
---|---|---|---|---|
LogP | 3.23 | DrugBank | 3.68 | Fitted |
fu | 0.02 | FDA, fitted | 0.20 | DrugBank, fitted |
Molecular weight/(g·mol-1) | 326.83 | DrugBank | 318.34 | DrugBank |
pKa | 7.50 | DrugBank | 9.40 | Fitted |
Solubility/(mg·mL-1) | 0.19 | ALOGPS | 0.07 | Fitted |
CLh/(mL·h-1·kg-1) | 2.28 | Fitted | 1.21 | Fitted |
CLr/(mL·h-1·kg-1) | 0.01 | Fitted | 0.02 | FDA, fitted |
Tab 2 Basic physicochemical properties and ADME-related parameters of clozapine and fluvoxamine
Parameter | Clozapine | Source | Fluvoxamine | Source |
---|---|---|---|---|
LogP | 3.23 | DrugBank | 3.68 | Fitted |
fu | 0.02 | FDA, fitted | 0.20 | DrugBank, fitted |
Molecular weight/(g·mol-1) | 326.83 | DrugBank | 318.34 | DrugBank |
pKa | 7.50 | DrugBank | 9.40 | Fitted |
Solubility/(mg·mL-1) | 0.19 | ALOGPS | 0.07 | Fitted |
CLh/(mL·h-1·kg-1) | 2.28 | Fitted | 1.21 | Fitted |
CLr/(mL·h-1·kg-1) | 0.01 | Fitted | 0.02 | FDA, fitted |
Fig 3 Plasma concentration-time curve profiles and residue plot of fluvoxamine after the administration of a single 50 mg dose of fluvoxamine in healthy adults
Drug administration | Pharmacokinetic parameter | Combination therapy/monotherapy | No effect boundary | |
---|---|---|---|---|
mean/% | 90%CI | |||
Administration 1 | Cmax/(ng·mL-1) | 180 | 111%‒223% | 80%‒125% |
AUC/(ng·h·mL-1) | 197 | 105%‒204% | ||
Administration 2 | Cmax/(ng·mL-1) | 175 | 110%‒240% | |
AUC/(ng·h·mL-1) | 189 | 100%‒277% |
Tab 3 Comparison of pharmacokinetic parameters of clozapine-fluvoxamine PBPK model
Drug administration | Pharmacokinetic parameter | Combination therapy/monotherapy | No effect boundary | |
---|---|---|---|---|
mean/% | 90%CI | |||
Administration 1 | Cmax/(ng·mL-1) | 180 | 111%‒223% | 80%‒125% |
AUC/(ng·h·mL-1) | 197 | 105%‒204% | ||
Administration 2 | Cmax/(ng·mL-1) | 175 | 110%‒240% | |
AUC/(ng·h·mL-1) | 189 | 100%‒277% |
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