Development and Evaluation of Physiologically Based Pharmacokinetic Drug–Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Modeling Software and Strategy
2.2. Model Structure
2.2.1. Physicochemical Properties
2.2.2. Absorption
2.2.3. Distribution
2.2.4. Elimination
2.3. Population Specific (System) Data
2.3.1. Disease-Specific Pathophysiological Changes
Tuberculosis
Liver Cirrhosis
2.4. Ethics
2.5. Pharmacokinetic Data
2.6. Model Evaluation
2.7. Simulations in Different Clinical Scenarios
3. Results
3.1. Healthy Population
3.2. Tuberculosis Patients
3.3. Liver Cirrhosis Patients
4. Discussion
5. Conclusions
6. Limitations
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Parameters | Reported Values | Model Input Values | Reference |
---|---|---|---|
Physicochemical Properties | |||
Molecular weight (g/mol) | 822.9 | 822.9 | [34] |
LogPo:w | 2.7 | 2.7 | [34] |
pKa1 | 1.7 | 1.7 | [24] |
pKa2 | 7.9 | 7.9 | [24] |
Compound type | Ampholyte | ||
Absorption | |||
Model | ADAM | ||
Peff,man (cm/s) | 2.15 × 10−4 | 2.4 × 10−4 a | [23] |
Distribution | |||
Model | Full PBPK | ||
Prediction Method 2 | Rodger and Rowland method | ||
B/P ratio | 0.52–0.90 | 0.67 a | [24,25] |
fu | 0.15 | 0.34 a | [24] |
Vss (L/kg) | 0.33–0.53 | 0.33 | [23,24,25] |
Elimination | |||
CLiv (L/h) | 7 | 7 | [24] |
CLR (L/h) | 1.5 | 1.5 | [25] |
No | Population | No. of Subjects | Dose | Route | Age (Years) | Weight (kg) | Female Proportion | Reference Study * |
---|---|---|---|---|---|---|---|---|
1 | Healthy | 2 | 450 mg | Intravenous infusion | 25–60 | 0 | [40] | |
2 | Healthy | 6 | 600 mg | Intravenous infusion | 25–60 | 0 | [40] | |
3 | Healthy | 12 | 300 mg | Oral | 25–53 | 48–88 | 0 | [41] |
4 | Healthy | 24 | 600 mg | Oral | 19–45 | 60–101.4 | 0 | [42] |
5 | Healthy | 18 | 600 mg | Oral | 18–55 | >50 | 0 | [43] |
6 | Healthy | 22 | 600 mg | Oral | 18–55 | >50 | 0 | [44] |
7 | Healthy | 16 | 600 mg | Oral | 28–59 | 51–80 | 0.68 | [28] |
8 | Healthy | 18 | 600 mg | Oral | 18–40 | Mean: 68.73 | 0.5 | [26] |
9 | Healthy | 66 | 450 mg | Oral | 18–55 | >50 | 0.5 | [45] |
10 | Healthy | 61 | 600 mg | Oral | 18–55 | >50 | [45] | |
11 | Healthy | 19 | 600 mg | Oral | 19–29 | 49–95 | 0.73 | [27] |
12 | Healthy | 8 | 600 mg | Oral | 18–50 | Mean: 79.3 | 0.5 | [46] |
13 | Healthy | 6 | 10 mg/kg | Oral | 60–95 | 44–81 | 0.33 | [47] |
14 | Healthy | 13 | 450 mg | Oral | 18–45 | 0 | [48] | |
15 | Healthy | 13 | 450 mg | Oral | 15–59 | 0 | [37] | |
16 | Healthy | 30 | 300 mg | Oral | 0.5 | [49] | ||
17 | Healthy | 24 | 10 mg/kg | Oral | 18–65 | 0.6 | [15] |
No. | Population | No. of Subjects | Dose | Route | Age (Years) | Weight (kg) | Female Proportion | Reference Study |
---|---|---|---|---|---|---|---|---|
1 | Tuberculosis | 24 | 10 mg/kg | Oral | 18–65 | 0.6 | [15] | |
2 | Tuberculosis | 23 | 600 mg | Oral | 18–55 | Mean: 47 | 0.47 | [50] |
3 | Tuberculosis | 24 | 450 mg | Oral | 18–55 | Mean: 47 | 0.47 | [50] |
4 | Tuberculosis | 18 | 450 mg | Oral | 18–60 | 47.3 | 0.61 | [51] |
5 | Tuberculosis | 13 | 450 mg | Oral | 15–59 | 0 | [37] | |
6 | Tuberculosis | 20 | 450 mg | Oral | Mean: 40.5 | Mean: 42.9 | 0.4 | [52] |
7 | Liver cirrhosis | 7 | 4 mg/kg | Oral | 18–60 | [53] | ||
8 | Liver cirrhosis | 7 | 6 mg/kg | Oral | 18–60 | [53] | ||
9 | Liver cirrhosis | 7 | 8 mg/kg | Oral | 18–60 | [53] | ||
10 | Liver cirrhosis | 7 | 10 mg/kg | oral | 18–60 | [53] |
PK Parameters | Dose | Healthy | Tuberculosis | Liver Cirrhosis | |||
---|---|---|---|---|---|---|---|
Observed | Predicted | Observed | Predicted | Observed | Predicted | ||
Intravenous Administration | |||||||
AUC0–∞ (µg/mL·h) | 450 mg | 52.49 | 58.16 | ||||
600 mg | 73.50 | 96.38 | |||||
CL (L/h) | 450 mg | 7.86 | 6.23 | ||||
600 mg | 8.15 | 6.22 | |||||
Cmax (µg/mL) | 450 mg | 12.53 | 9.80 | ||||
600 mg | 13.61 | 13.07 | |||||
Oral Administration | |||||||
AUC0–∞ (µg/mL·h) | 300 mg | 29.93 | 40.19 | ||||
450 mg | 42.04 | 60.20 | 65.52 | 64.67 | |||
600 mg | 76.95 | 81.06 | 93.40 | 86.70 | |||
4 mg/kg | 29.6 | 33.8 | |||||
6 mg/kg | 70.4 | 50.7 | |||||
8 mg/kg | 65.2 | 67.6 | |||||
10 mg/kg | 68.85 | 86.20 | 66.7 | 95.3 | 95.1 | 84.5 | |
CL (L/h) | 300 mg | 9.98 | 7.38 | ||||
450 mg | 10.77 | 7.44 | 7.15 | 6.92 | |||
600 mg | 8.25 | 7.44 | 6.4 | 0.9 | |||
4 mg/kg | 0.135 | 0.113 | |||||
6 mg/kg | 0.085 | 0.113 | |||||
8 mg/kg | 0.122 | 0.113 | |||||
10 mg/kg | 0.145 | 0.115 | 0.14 | 0.10 | 0.105 | 0.113 | |
Cmax (µg/mL) | 300 mg | 5.37 | 5.47 | ||||
450 mg | 5.88 | 9.08 | 8.30 | 11.45 | |||
600 mg | 9.85 | 10.30 | 13.3 | 15.6 | |||
4 mg/kg | 5.50 | 5.52 | |||||
6 mg/kg | 12.10 | 8.28 | |||||
8 mg/kg | 11.70 | 11.04 | |||||
10 mg/kg | 10.8 | 10.55 | 8.50 | 18.4 | 17.40 | 13.80 |
Parameters | Mean Ratioobs/pred (Range) | AFE | RMSE |
---|---|---|---|
Intravenous Application in Healthy Population | |||
AUC0–∞ (µg/mL·h) | 0.82 (0.76–0.89) | 0.78 | 19.39 |
CL (L/h) | 1.28 (1.26–1.31) | 1.27 | 1.78 |
Cmax (µg/mL) | 1.16 (1.04–1.27) | 1.14 | 1.96 |
Oral Application in Healthy Population | |||
AUC0–∞ (µg/mL·h) | 0.84 (0.51–1.47) | 0.80 | 51.80 |
CL (L/h) | 1.22 (0.65–1.86) | 1.14 | 2.83 |
Cmax (µg/mL) | 0.88 (0.36–1.67) | 0.79 | 5.95 |
Oral Application in Tuberculosis Population | |||
AUC0–∞ (µg/mL·h) | 0.96 (0.69–1.31) | 0.93 | 16.10 |
CL (L/h) | 1.08 (0.76–1.42) | 1.02 | 1.04 |
Cmax (µg/mL) | 0.69 (0.46–0.85) | 0.66 | 13.82 |
Oral Application in Liver Cirrhosis Population | |||
AUC0–∞ (µg/mL·h) | 1.09 (0.87–1.38) | 1.30 | 11.27 |
CL (L/h) | 0.94 (0.72–1.14) | 0.98 | 0.009 |
Cmax (µg/mL) | 1.19 (0.99–1.46) | 1.10 | 2.67 |
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Rasool, M.F.; Khalid, S.; Majeed, A.; Saeed, H.; Imran, I.; Mohany, M.; Al-Rejaie, S.S.; Alqahtani, F. Development and Evaluation of Physiologically Based Pharmacokinetic Drug–Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations. Pharmaceutics 2019, 11, 578. https://doi.org/10.3390/pharmaceutics11110578
Rasool MF, Khalid S, Majeed A, Saeed H, Imran I, Mohany M, Al-Rejaie SS, Alqahtani F. Development and Evaluation of Physiologically Based Pharmacokinetic Drug–Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations. Pharmaceutics. 2019; 11(11):578. https://doi.org/10.3390/pharmaceutics11110578
Chicago/Turabian StyleRasool, Muhammad F., Sundus Khalid, Abdul Majeed, Hamid Saeed, Imran Imran, Mohamed Mohany, Salim S. Al-Rejaie, and Faleh Alqahtani. 2019. "Development and Evaluation of Physiologically Based Pharmacokinetic Drug–Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations" Pharmaceutics 11, no. 11: 578. https://doi.org/10.3390/pharmaceutics11110578