Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Design and Patient Eligibility
2.2. Data Analysis
2.3. Population Pharmacokinetic Analysis
- A1(0) = 0; A2(0) = 0; A3(0) = 1;
- Rtot(0) = R0 = ksyn/kdeg
- kin = kout × A3(0)
2.4. Simulations
3. Results
3.1. Patients and Data Collection
3.2. Population Pharmacokinetic Analysis
3.3. Simulations
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Characteristic | Median | Mean | Standard Deviation | |
---|---|---|---|---|
Age (years) | 42 | 39 | 11 | |
Body weight (Kg) | 65.7 | 66.98 | 14.69 | |
Height (cm) | 163.5 | 163.60 | 8.99 | |
Body surface area (m2) | 1.7 | 1.72 | 0.21 | |
TKV (mL) | Men | 678.85 | 822.18 | 486.22 |
Female | 846.55 | 924.14 | 404.27 | |
TCV (mL) | 310.3 | 339.93 | 201.19 | |
Serum creatinine (mg/dL) | 0.72 | 0.77 | 0.14 | |
CrCL (mL/min/1.73 m2) | 105.7 | 103.43 | 22.63 | |
n | % | |||
Race | Caucasian | 15 | 75 | |
Afro-American | 1 | 5 | ||
Other | 4 | 20 | ||
Gender | Female | 14 | 70 | |
Male | 6 | 30 |
Final PK Model | Bootstrap Analysis (n = 500) | ||||||
---|---|---|---|---|---|---|---|
Parameter | Units | Value | Median | RSE [%] | 2.5th | 97.5th | |
Fixed-effects | CL | [L/h] | 9.64 × 10−3 | 1.00 × 10−2 | 18 | 6.24 × 10−3 | 1.26 × 10−2 |
V1 | [L] | 2.63 | 2.65 | 6 | 2.47 | 2.84 | |
V1 change (D = 50 mg) | [%] | 53 | 56 | 14 | 43 | 69 | |
Q | [L/h] | 2.88 × 10−2 | 2.09 × 10−2 | 34 | 8.38 × 10−3 | 3.42 × 10−2 | |
V2 | [L] | 9.92 × 10−3 | 9.52 × 10−3 | 47 | 4.61 × 10−3 | 2.60 × 10−2 | |
Kss | [mg/L] | 15.5 | 16.42 | 50 | 7.85 | 44.68 | |
kint | [h-1] | 4.94 × 10−3 | 4.94 × 10−3 | 39 | 1.46 × 10−3 | 9.45 × 10−3 | |
Rtot | [mg/L] | 1.05 × 10−2 | 1.15 × 10−2 | 58 | 5.29 × 10−3 | 3.32 × 10−2 | |
Rtotp | [mg/L] | 956 | 891 | 82 | 142 | 3481 | |
Kout | [h-1] | 1.33 × 10−2 | 1.36 × 10−2 | 48 | 5.66 × 10−3 | 3.18 × 10−2 | |
S50 | [mg/L] | 8.57 | 7.74 | 23 | 4.70 | 11.07 | |
Smax | 3.18 | 2.90 | 29 | 1.99 | 5.46 | ||
Inter-individual variability | Rtotp | [%] | 135 (14) | 158 | 107 | 65 | 287 |
Kout | [%] | 197 (21) | 226 | 71 | 131 | 413 | |
Residual error | Additive | [%] | 48 (4) | 46 | 8 | 41 | 54 |
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de Castro-Suárez, N.; Trame, M.N.; Ramos-Suzarte, M.; Dávalos, J.M.; Bacallao-Mendez, R.A.; Maceo-Sinabele, A.R.; Mangas-Sanjuán, V.; Reynaldo-Fernández, G.; Rodríguez-Vera, L. Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease. Pharmaceutics 2020, 12, 1147. https://doi.org/10.3390/pharmaceutics12121147
de Castro-Suárez N, Trame MN, Ramos-Suzarte M, Dávalos JM, Bacallao-Mendez RA, Maceo-Sinabele AR, Mangas-Sanjuán V, Reynaldo-Fernández G, Rodríguez-Vera L. Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease. Pharmaceutics. 2020; 12(12):1147. https://doi.org/10.3390/pharmaceutics12121147
Chicago/Turabian Stylede Castro-Suárez, Niurys, Mirjam N. Trame, Mayra Ramos-Suzarte, José M. Dávalos, Raymed A. Bacallao-Mendez, Anaelys R. Maceo-Sinabele, Víctor Mangas-Sanjuán, Gledys Reynaldo-Fernández, and Leyanis Rodríguez-Vera. 2020. "Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease" Pharmaceutics 12, no. 12: 1147. https://doi.org/10.3390/pharmaceutics12121147