External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia
Abstract
:1. Introduction
2. Methods
2.1. Literature Search for the PopPK Models of MTX in ALL Children
2.2. Dataset for External Evaluation
2.3. Evaluation of Predictive Performance
3. Results
3.1. Literature Search and Summary of Published PopPK Models
3.2. Characteristics of the Evaluation Dataset
3.3. Model Evaluation
4. Discussion
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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Characteristics | Aumente et al. [21] | Gao et al. [19] | Hui et al. [20] | Medellin-Garibay et al. [11] | Zhang et al. [26] | Jonsson et al. [36] | Evaluation Dataset |
---|---|---|---|---|---|---|---|
Tumor Type | ALL | ALL | ALL | ALL | ALL | ALL | ALL |
N | 37 | 311 | 36 | 41 | 96 | 304 | 51 |
M/F | 17/20 | 197/114 | 23/13 | NA | 66/30 | NA | 40/11 |
Age (years) | 5.0 (0.5–17.0) | 5.0 (0.75–15.2) | 5.3 (1.3–15.8) | 5.0 (1.0–15.0) | 7.4 ± 3.1 | 5.0 (0.4–17.8) | 5.5 (1.0–13.0) |
Weight (kg) | 24.2 (7.5–80.0) | 19.0 (4.5–113.0) | 18.4 (10.4–57.8) | 21.2 (8.0–57.3) | 26.1 ± 10.4 | 19.0 (5.8–93.3) | 19.0 (9.5–62.0) |
Height (cm) | 115 (69–174) | 112 (67–175) | 107 (77–176) | 115 ± 24 | 120 ± 21 | 110 (63–192) | 113 (73–168) |
BSA (m2) | 1.07 (0.30–1.90) | NA | 0.74 (0.47–1.64) | 0.79 (0.41–1.6) | 0.97 ± 0.29 | 0.76 (0.31–2.19) | 0.77 (0.41–1.60) |
MTX dose (g/m2) | 1.23–5.23 | 1–5 | 2–5 | 2.89 ± 0.9 | 2–3.5 | 5–8 | 1–5 |
ALT (IU/L) | NA | 16.0 (2.0–390.0) | 16.5 (5.0–247.0) | 19.1 (7.2–98.2) | 32.7 ± 44.5 | 31.2 (6.0–228.6) | 32.5 (4.0–250.0) |
AST (IU/L) | NA | 26.0 (8.0–135.0) | NA | 25.8 (13.9–112.7) | 45.3 ± 34.5 | NA | 36.0 (17.0–131.0) |
Scr (mg/dL) | 0.5 (0.3–0.8) | 0.3 (0.1–1.5) | 0.362 (0.11–1.07) | 0.37 ± 0.11 | 0.36 ± 0.10 | NA | 0.31 (0.16–0.71) |
Studies | Structural Model | Fixed Parameters and Covariate Models | IIV (%) (IOV (%)) | RUV |
---|---|---|---|---|
Aumente et al. [21] | 2 CMT | K12 (1/h) = 0.0155 K21 (1/h) = 0.0724 CL (L/h, age > 10 years) = 0.149 × Weight CL (L/h, age < 10 years) = 0.287 × Weight0.876 V1 (L, age > 10 years) = 0.437 × Weight V1 (L, age < 10 years) = 0.465 × Weight | K12 = 20.8 K21 = 35.2 CL = 41.7 V1 = 41.6 | Prop = 16.2% Add = 0.0035 μmol/L |
Gao et al. [19] | 3 CMT | CL (L/h) = 6.9 × (Weight/19 kg)0.75 × (1 + (Scr-26) × (−0.0097)) × eηCL V1 (L) = 20.7 × (Weight/19 kg) V2 (L) = 41.0 × (Weight/19 kg) × eηV2 Q1 (L/h) = 0.255 × (Weight/19 kg)0.75 V3 (L) = 3.17 × (Weight/19 kg) Q2 (L/h) = 0.217 × (Weight/19 kg)0.75 | CL = 17.9 V1 = 26.2 | Prop * = 35.4% |
Hui et al. [20] | 2 CMT | CL (L/h) = 7.73 × (BSA/0.735)0.721 × (eGFR × 1.73/192 × BSA)0.256 × eηCL+IOV V1 (L) = 19.0 × (BSA/0.735)0.985 Q (L/h) = 0.283 × (Age/5.29)0.278 V2 (L) = 6.63 × eηV2 | CL = 14.3 (14.9) V2 = 34.6 | Prop = 30.2% |
Medellin-Garibay et al. [11] | 2 CMT | CL (L/h) = 6.5 × BSA0.62 × eηCL V1 (L) = 0.36 × Weight × eηV1 Q (L/h) = 0.41 V2 (L) = 3.2 × eηV2 | CL = 8.2 V1 = 25.9 V2 = 26.7 | Prop = 20.1% |
Zhang et al. [26] | 2 CMT | CL (L/h) = (5.04 × (1 − 0.278 × Gender) × BSA0.777 + (OH/100)0.514) × eηCL V1 (L) = 16.1 × eηV1 Q (L/h) = 0.203 × (Age/10)1.56 × eηQ V2 (L) = 7.05 × (Age/10)1.76 × eηV2 | CL = 49.6 V1 = 29.4 Q = 137.6 V2 = 107.7 | Prop = 19.0% Add = 0.0872 μmol/L |
Jonsson et al. [36] | 2 CMT | CL (L/h) = Weight × 0.185 × eηCL V1 (L) = Weight × 1.27 × eηV1 Q (L/h) = Weight × 0.017 × eηQ V2 = Weight × 1.02 × eηV2 | CL = 109.0 V1 = 26.0 Q = 22.0 V2 = 44.0 | NR |
Model | IPRED | PRED | ||||
---|---|---|---|---|---|---|
Median PE (%) | MPE (%) | RMSE (%) | Median PE (%) | MPE (%) | RMSE (%) | |
Aumente et al. [21] | 6.52 | 12.06 | 76.09 | −31.70 | −25.51 | 81.15 |
Gao et al. [19] | −25.20 | 1.33 | 63.96 | −26.76 | 3.22 | 72.39 |
Hui et al. [20] | −10.43 | 8.78 | 82.96 | −33.23 | −8.24 | 62.88 |
Medellin-Garibay et al. [11] | −0.75 | 22.71 | 75.55 | −7.56 | 6.39 | 68.33 |
Zhang et al. [26] | 1.16 | 16.00 | 63.39 | −29.92 | 15.62 | 145.92 |
Jonsson et al. [36] | 5.25 | 64.44 | 152.25 | 442.04 | 780.87 | 1182.24 |
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Wang, S.; Yin, Q.; Yang, M.; Cheng, Z.; Xie, F. External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia. Pharmaceutics 2023, 15, 569. https://doi.org/10.3390/pharmaceutics15020569
Wang S, Yin Q, Yang M, Cheng Z, Xie F. External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia. Pharmaceutics. 2023; 15(2):569. https://doi.org/10.3390/pharmaceutics15020569
Chicago/Turabian StyleWang, Shengfeng, Qiufen Yin, Minghua Yang, Zeneng Cheng, and Feifan Xie. 2023. "External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia" Pharmaceutics 15, no. 2: 569. https://doi.org/10.3390/pharmaceutics15020569
APA StyleWang, S., Yin, Q., Yang, M., Cheng, Z., & Xie, F. (2023). External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia. Pharmaceutics, 15(2), 569. https://doi.org/10.3390/pharmaceutics15020569