Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. HPLC Analytical Method Development
2.3. Dose Banding and Selection of Strengths
2.4. Dissolution
2.5. Kinetic Modelling
2.6. Extended-Release Mini Tablet Production
2.7. Hardness
2.8. Friability
2.9. Development of a Nifedipine PBPK Model for Use in Virtual Clinical Trials
2.9.1. Validation in Adults
2.9.2. Formulation Performance in Virtual Adults
2.9.3. Formulation Performance in Virtual Paediatrics
2.9.4. Developing a Dosing Approach in Children
2.9.5. Predictive Performance
2.10. Statistical Analysis
3. Results and Discussion
3.1. Acceptability of Mini-Tablets
3.2. Paediatric Formulation Development Approach for Extended Release Mini-Tablets and Formulation Composition Optimisation
3.3. Virtual Clinical Trials Analysis of Nifedipine Model in Adults and Children
3.4. Formulation Performance in Virtual Adults
3.5. Formulation Performance in Virtual Paediatrics
3.6. Developing a Dosing Approach in Children
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Model | Equation |
---|---|
Zero order | Q1 = Q0 + K0t |
First order | Log Ct = Log C0 − k t/2.303 |
Higuchi | Q = KH t1/2 |
Korsmeyer–Peppas | Qt/Q∞ = Ktn |
Composition | F1 (% w/w) | F2 (% w/w) | F3 (% w/w) | F4 (% w/w) |
---|---|---|---|---|
Nifedipine | 10 | 10 | 10 | 10 |
Lactose | 89.25 | 59.25 | 39.25 | 19.25 |
HPMC (K4M) | - | 30 | 50 | 70 |
Mg stearate | 0.5 | 0.5 | 0.5 | 0.5 |
AEROSIL® | 0.25 | 0.25 | 0.25 | 0.25 |
Formulation | Zero Order | First Order | Higuchi | Korsmeyer–Peppas | (n) |
---|---|---|---|---|---|
F1 (immediate) | 0.645 | 0.987 | 0.348 | 0.331 | 0.05 |
F2 (30% HPMC) | 0.387 | 0.717 | 0.638 | 0.895 | 0.15 |
F3 (50% HPMC) | 0.936 | 0.985 | 0.993 | 0.984 | 0.58 |
F4 (70% HPMC) | 0.932 | 0.971 | 0.994 | 0.990 | 0.53 |
Study | Dose | Cmax (ng/mL) | tmax (h) | AUC (ng/mL·h) | Mean Cmax Ratio | Mean tmax Ratio | Mean AUC Ratio | |
---|---|---|---|---|---|---|---|---|
Ohashi et al. (1993) [37] | Single (20 mg) | Predicted | 245 ± 152 | 0.6 ± 0.2 | 501 ± 124 | - | - | - |
Observed G1 | nr | nr | 680 ± 135 | - | - | 0.74 | ||
Observed G1 | nr | nr | 809 ± 318 | - | - | 0.62 | ||
Observed G1 | nr | nr | 579 ± 191 | - | - | 0.87 | ||
Tateishi et al. (1989) [38] | Single (20 mg) | Predicted | 245 ± 152 | 0.6 ± 0.2 | 501 ± 124 | - | - | - |
Observed | 236 ± 70 | 1 ± 0.9 | 623 ± 139 | 1.04 | 0.6 | 0.8 | ||
Ohashi et al. (1990) [39] | Single (20 mg) | Predicted | 238 ± 142 | 1.1 ± 0.8 | 357.1 ± 124.9 | - | - | - |
Observed | 421 ± 177 | nr | 453.6 ± 176.2 | 0.57 | - | 0.79 | ||
Smith et al. (1987) [40] | Single (20 mg) | Predicted | 101 (62–225) | 1 ± 0.5 | 279 (307–435) | - | - | - |
Observed | 131 (97–179) | 0.5 | 266 (322–415) | 0.77 | 2 | 1.04 | ||
Multiple (10 mg) | Predicted | 82 (62–225) | 1 ± 0.5 | 201 (142–235) | - | - | - | |
Observed | 56 (42–74) | 0.5 | 134 (113–158) | 1.46 | 2 | 1.5 | ||
Wonnerman et al. (2008) [42] | Single OROS (30 mg) | Predicted | 21.8 (15.9–42) | 5 (3–17) | 319 (214–517) | - | - | - |
Observed | 17.6 (11.6–30.8) | 6 (5–24) | 358 (160–906) | 1.23 | 0.83 | 0.89 |
Formulation | Dose | Cmax (ng/mL) | tmax (h) | AUC (ng/mL·h) |
---|---|---|---|---|
F1 | 30 mg BD | 229 ± 94.2 | 1.2 ± 0.15 | 703 ± 425.6 |
60 mg OD | 466 ± 187 | 1.2 ± 0.24 | 1459 ± 876.8 | |
F2 | 30 mg BD | 167.1 ± 70.16 | 1.23 ± 0.18 | 617.9 ± 366.8 |
60 mg OD | 331 ± 133 | 1.25 ± 0.26 | 1270.7 ± 751 | |
F3 | 30 mg BD | 76.68 ± 39.5 | 2.25 ± 1.99 | 711.6 ± 407 |
60 mg OD | 126.8 ± 62 | 5.5 ± 1.34 | 1432.8 ± 817 |
Formulation | Dosing | Age Range (Years) | Cmax (ng/mL) | tmax (h) | AUC (ng/mL·h) |
---|---|---|---|---|---|
F1 | OD | 5–7 | 113 | 1.2 | 398.2 |
7–11 | 101.6 | 1.2 | 300 | ||
BD | 5–7 | 113 | 1.6 | 397.7 | |
7–11 | 105.8 | 1.36 | 300 | ||
TDS | 5–7 | 113 | 1.43 | 398.1 | |
7–11 | 107.1 | 1.38 | 301 | ||
F2 | OD | 5–7 | 113 | 2.2 | 364 |
7–11 | 101 | 2.16 | 274 | ||
BD | 5–7 | 111 | 2.2 | 363 | |
7–11 | 102 | 2.16 | 275 | ||
TDS | 5–7 | 123 | 2.15 | 362 | |
7–11 | 106 | 2.13 | 274 | ||
F3 | OD | 5–7 | 39 | 5.3 | 418 |
7–11 | 31 | 4.7 | 314 | ||
BD | 5–7 | 46 | 3 | 417 | |
7–11 | 37 | 2.45 | 314 | ||
TDS | 5–7 | 63 | 2.4 | 418 | |
7–11 | 49 | 2.16 | 313 |
Dose | Age Range (Years) | Cmax (ng/mL) | Cmin (ng/mL) | tmax (h) | AUC (ng/mL·h) | <0 ng/mL a (%) | Dose (mg) |
---|---|---|---|---|---|---|---|
350 µg/kg | 3–5 | 62.48 ± 35 | 31.76 ± 25.9 | 3.35 ± 2 | 563.3 ± 376 | 36 | 5.75 ± 0.87 |
5–7 | 53.97 ± 25.3 | 25.6 ± 15.6 | 2.59 ± 2 | 458.9 ± 248.3 | 46 | 7.03 ± 1.37 | |
450 µg/kg | 3–5 | 80.45 ± 45.8 | 40.85 ± 33 | 3.35 ± 2 | 726 ± 485.2 | 23 | 7.4 ± 1.1 |
5–7 | 69.5 ± 32.6 | 32.8 ± 20.1 | 2.59 ± 2 | 590.8 ± 319 | 20 | 9.04 ± 1.7 |
Dosing Strategy | Average Weight (kg) | Dose (mg) | 5 mg Tablets Required |
---|---|---|---|
250 μg/kg | 3 years: 14 kg 5 years: 18 kg 7 years: 23 kg | 3.5 ≈ 5 4.5 ≈ 5 5.8 ≈ 5 | 1 1 1 |
350 μg/kg | 3 years: 14 kg 5 years: 18 kg 7 years: 23 kg | 4.9 ≈ 5 6.3 ≈ 5 8.1 ≈ 10 | 1 1 2 |
450 μg/kg | 3 years: 14 kg 5 years: 18 kg 7 years: 23 kg | 6.3 ≈ 5 8.1 ≈ 10 10.4 ≈ 10 | 1 2 2 |
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Khan, D.; Badhan, R.; Kirby, D.J.; Bryson, S.; Shah, M.; Mohammed, A.R. Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use. Pharmaceutics 2023, 15, 556. https://doi.org/10.3390/pharmaceutics15020556
Khan D, Badhan R, Kirby DJ, Bryson S, Shah M, Mohammed AR. Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use. Pharmaceutics. 2023; 15(2):556. https://doi.org/10.3390/pharmaceutics15020556
Chicago/Turabian StyleKhan, Dilawar, Raj Badhan, Daniel J. Kirby, Simon Bryson, Maryam Shah, and Afzal Rahman Mohammed. 2023. "Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use" Pharmaceutics 15, no. 2: 556. https://doi.org/10.3390/pharmaceutics15020556