Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation
Abstract
:1. Introduction
2. Results
2.1. Hydrocodone and Hydromorphone Model Development and Evaluation
2.2. Model-Based DDI Prediction between Ritonavir and Fentanyl Analogs
2.3. Model-Based DDI Prediction between Ritonavir and Hydrocodone
3. Discussion
4. Materials and Methods
4.1. PBPK Modeling Platform and Related Software
4.2. Drug Model Preparation
Parameters | Hydromorphone | Reference/Source | Hydrocodone | Reference/Source |
---|---|---|---|---|
Lipophilicity | 1.8 | [36] | 2.0 | [37] |
Plasma fraction unbound | 0.86 | Drugbank | 0.64 | Drug label |
MW | 285.30 g/mol | Drugbank | 299.40 g/mol | Drugbank |
pKa | 8.5 | PubChem | 8.23 | PubChem |
Solubility | 0.149 mg/mL | PubChem | 0.797 mg/mL | PubChem |
Specific intestinal permeability | 3.27 × 10−6 cm/min | Optimized | 2.00 × 10−4 cm/min | Optimized |
Partition coefficients calculation | Diverse | PK-Sim standard | Diverse | Schmitt |
Cellular permeability | 3.37 × 10−3 cm/min | PK-Sim standard | 4.00 × 10−3 cm/min | Charge-dependent Schmitt normalized to PK-Sim |
UGT2B7 specific clearance | 6.11 1/min | Optimized | NA | |
Formulation | IR dissolved, ER Weibull | Weibull | ||
50% dissolution time | ER 8.48 h | Optimized | Uncoated 0.80 h, ER 6.40 h | Optimized |
Dissolution shape | ER 2.94 | Optimized | Uncoated 0.79 ER 1.79 | Optimized |
GFR fraction | 1.0 | Assumed | 1.0 | Assumed |
Km,CYP3A4 | NA | 2.60 mmol/L | [19] | |
Kcat,CYP3A4 | NA | 361 1/min | Optimized | |
Km,CYP2D6 | NA | 54 μmol/L | [19] | |
Kcat,CYP2D6 (EM) | NA | 7.12 1/min | Optimized | |
Kcat,CYP2D6 (PM) | NA | 1.07 1/min | Optimized | |
UGT2B7-specific clearance | 6.11 1/min | Optimized | NA | |
Hepatic clearance (non-CYP) | NA | 0.36 1/min | Optimized | |
Ritonavir | ||||
Ki,CYP3A4 | 0.25 μM | [38] | ||
Kinact,CYP3A4 | 0.40 1/min | [39] | ||
Kinact_half,CYP3A4 | 0.20 μM | [39] | ||
Ki,CYP2D6 | 0.04 μM | [40] | ||
EC50CYP3A4 | 0.17 μM | [25] | ||
EmaxCYP3A4 | 7.47 | [25] | ||
Ki,P-gp | 0.20 μM | [41] |
4.3. PBPK Modeling-Based Simulation for Ritonavir–Opioid DDIs
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Drugs | CmaxR | AUCR | ||
---|---|---|---|---|
Predicted | Observed | Predicted | Observed | |
Fentanyl | NA | NA | 1.28 | 2.70 |
Hydrocodone | 1.24 | 1.27 | 1.81 | 1.90 |
Drugs | Protocols | AUC0~∞ (ng × h/mL) | T1/2 (h) |
---|---|---|---|
Alfentanil | Alfentanil 20 μg/kg i.v. | 94.9 | 2.29 |
Alfentanil 20 μg/kg i.v. + R 100 mg QD | 2717 (+2766%) | 17.4 (+660%) | |
Alfentanil 20 μg/kg i.v. + R 100 mg BID | 5581 (+5787%) | 63.7 (+2681%) | |
Sufentanil | Sufentanil 5 μg/kg i.v. | 4.58 | 5.42 |
Sufentanil 5 μg/kg i.v. + R 100 mg QD | 59.1 (+1192%) | 11.4 (+110%) | |
Sufentanil 5 μg/kg i.v. 84 h after R 100 mg QD withdrawal | 5.54 | 5.38 | |
Sufentanil 5 μg/kg i.v. + R 100 mg BID | 117 (+2448%) | 39.8 (+634%) | |
Sufentanil 5 μg/kg i.v. 96 h after R 100 mg BID withdrawal | 5.57 | 6.46 |
Protocols | Cmax/Cmax-ss (ng/mL) | AUC/AUCss (ng×h/mL) | T1/2 (h) | |||
---|---|---|---|---|---|---|
HYD | HYM | HYD | HYM | HYD | HYM | |
HYD ER 10 mg SD | 7.11 | 0.09 | 135 | 2.35 | 13.1 | 19.7 |
HYD ER 10 mg SD + R 100 mg QD | 10.4 (46.3%) | 0.13 (44.4%) | 241 (78.5%) | 4.22 (79.6%) | 12.3 (−6.1%) | 18.9 (−4.1%) |
HYD ER 10 mg SD + R 100 mg BID | 10.5 (46.3%) | 0.13 (44.4%) | 248 (83.7%) | 3.87 (64.7%) | 15.7 (19.8%) | 20.8 (5.6%) |
HYD ER 10 mg BID | 12.24 | 0.20 | 135 | 2.24 | 10.2 | 13.9 |
HYD ER 10 mg BID + R 100 mg QD | 21.2 (73.2%) | 0.39 (95.0%) | 235 (74.1%) | 3.78 (68.8%) | 13.6 (33.3%) | 24.1 (73.4%) |
HYD ER 10 mg BID + R 100 mg BID | 22.1 (80.6%) | 0.31 (55.0%) | 245 (81.5%) | 3.40 (51.8%) | 13.6 (33.3%) | 24.1 (73.4%) |
HYD uncoated 5 mg q6h | 17.1 | 0.23 | 65.1 | 1.07 | 5.73 | 5.22 |
HYD uncoated 5 mg q6h + R 100 mg QD | 26.4 (54.4%) | 0.42 (82.6%) | 116 (78.2%) | 2.01 (87.9%) | 7.11 (24.1%) | 8.89 (70.3%) |
HYD uncoated 5 mg q6h + R 100 mg BID | 27.3 (59.6%) | 0.32 (39.1%) | 122 (87.4%) | 1.60 (49.5%) | 7.11 (24.1%) | 8.89 (70.3%) |
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Ni, L.; Cao, Z.; Jiang, J.; Zhang, W.; Hu, W.; Zhang, Q.; Shen, C.; Chen, X.; Zheng, L. Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation. Pharmaceuticals 2024, 17, 640. https://doi.org/10.3390/ph17050640
Ni L, Cao Z, Jiang J, Zhang W, Hu W, Zhang Q, Shen C, Chen X, Zheng L. Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation. Pharmaceuticals. 2024; 17(5):640. https://doi.org/10.3390/ph17050640
Chicago/Turabian StyleNi, Liang, Zhihai Cao, Jiakang Jiang, Wei Zhang, Wei Hu, Qian Zhang, Chaozhuang Shen, Xijing Chen, and Liang Zheng. 2024. "Evaluating Drug Interactions between Ritonavir and Opioid Analgesics: Implications from Physiologically Based Pharmacokinetic Simulation" Pharmaceuticals 17, no. 5: 640. https://doi.org/10.3390/ph17050640