Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Study Design
Determination of Plasma Concentrations of Levodopa, 3-OMD, and Ropinirole
2.3. Mathematical Modelling and Parameter Estimation of Levodopa and 3-OMD
2.3.1. Pharmacokinetic Model for the Drug-Metabolite System
2.3.2. Population PK Modelling
2.4. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Plasma Concentration of Levodopa and 3-OMD
3.3. Pharmacokinetic Population Modelling
3.4. Pharmacokinetic Parameters of Levodopa and 3-OMD
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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Demographic and Clinical Data (Mean, SD, Range) | Patients Administrating Both Levodopa and Ropinirole (n = 13) | Patients Administrating Levodopa But Not Ropinirole (n = 14) | p-Value |
---|---|---|---|
Sex (M/F) | 10 M/3 F | 10 M/4 F | Ns |
Age (yr) | 68.4 ± 7.3 57–83 | 70.9 ± 10.8 45–86 | Ns |
Weight (kg) | 79.3 ± 16.4 60–113 | 79.8 ± 21.6 50–110 | Ns |
UPDRS score | 25.3 ± 9.9 10–44 | 21.8 ± 10.6 6–36 | Ns |
Disease duration (yr) | 8.5 ± 5.9 1–21 | 5.3 ± 3.2 1–11 | Ns |
Levodopa treatment duration (yr) | 7.2 ± 4.9 0.5–20 | 3.9 ± 3.5 0.5–11 | Ns |
Current levodopa dosage (mg/d) | 692.9 ± 245.6 400–1100 | 592.9 ± 200.8 300–950 | Ns |
Ropinirole treatment duration (yr) | 3.3 ± 2.5 1–8 | - | - |
Current ropinirole dosage (mg/d) | 7.3 ± 2.2 4–10 | - | - |
Motor complications (fluctuations and/or dyskinesias) | 8 Yes/5 No | 4 Yes/10 No | Ns |
Demographic and Clinical Data (Mean, SD, Range) | Patients with Motor Complications (Fluctuations or Dyskinesias) (n = 12) | Patients without Motor Complications (Fluctuations and/or Dyskinesias) (n = 15) | p-Value |
---|---|---|---|
Sex (M/F) | 8 M/5 F | 13 M/2 F | Ns |
Age (yr) | 72.6 ± 9.0 57–86 | 67.1 ± 8.8 45–79 | Ns |
Weight (kg) | 68.2 ± 12.3 50–85 | 88.7 ± 18.6 51–113 | <0.002 |
UPDRS score | 28.1 ± 9.2 15–44 | 20.2 ± 9.8 6–35 | Ns |
Disease duration (yr) | 10.5 ± 4.7 6–21 | 3.8 ± 2.4 1–8 | <0.001 |
Levodopa treatment duration (yr) | 9.1 ± 4.0 4–20 | 2.4 ± 1.9 0.5–6 | <0.001 |
Current levodopa dosage (mg/d) | 811.5 ± 167.3 600–1100 | 496.7 ± 158.6 300–900 | <0.001 |
Ropinirole treatment duration (yr) | 3.6 ± 2.6 1–8 (n = 8) | 2.0 ± 1.4 1–3 (n = 5) | Ns |
Current ropinirole dosage (mg/d) | 8.0 ± 2.2 4–10 (n = 8) | 6.0 ± 1.4 4–8 (n = 5) | Ns |
PK Parameter | Covariate | Significance (p) |
---|---|---|
Weight | 0.013 | |
Movement disorder | <0.001 | |
Age | 0.007 | |
Ropinirole therapy | 0.019 | |
Sex | <0.001 | |
Ropinirole concentration at 2 h | <0.001 |
Parameter | Patients Administrating Both Levodopa and Ropinirole (n = 13) | Patients Administrating Levodopa but Not Ropinirole (n = 14) | p-Value |
---|---|---|---|
levodopa | levodopa | ||
lag time (min) | 9.97 ± 11.3 | 16.6 ± 10,6 | Ns |
V/F (L) | 32.4 ± 10.3 | 36.1 ± 11.8 | Ns |
CL/F (L/min) | 0.816 ± 0.323 | 0.835 ± 0.336 | Ns |
AUC0–∞ () | 150 ± 83 | 147 ± 83 | Ns |
tmax (min) | 35.5 ± 34.6 | 46.4 ± 26.8 | Ns |
Cmax (mg/L) | 2.27 ± 1.56 | 1.79 ± 0.95 | Ns |
MRT (min) | 41.6 ± 6.6 | 45.1 ± 6.9 | Ns |
ka (min−1) | 0.18 ± 0.16 | 0.31 ± 0.42 | Ns |
k10 (min−1) | 0.0213 ± 0.0038 | 0.0195 ± 0.0034 | Ns |
k12 (min−1) | 0.00333 ± 0.0056 | 0.00318 ± 0.00040 | Ns |
k20 (min−1) | 0.000262 ± 0.000043 | 0.000204 ± 0.000029 | 0.002 |
3-OMD | 3-OMD | ||
tmax 3-OMD (min) | 305 ± 207 | 304 ± 152 | Ns |
MET3-OMD (min) | 3997 ± 666 | 5040 ± 612 | 0.001 |
Cmax 3-OMD (mg/L) | 0.476 ± 0.316 | 0.423 ± 0.188 | Ns |
AUC3-OMD [0–∞] () | 1993 ± 1277 | 2232 ± 1032 | Ns |
Parameter | Patients with Motor Complications (Fluctuations and/or Dyskinesias) (n = 12) | Patients without Motor Complications (Fluctuations and/or Dyskinesias) (n = 15) | p-Value |
---|---|---|---|
levodopa | levodopa | ||
lag time (min) | 1.51 ± 0.19 | 22.9 ± 4.1 | <0.0001 |
V/F (L) | 28.2 ± 10.9 | 39.2 ± 8.7 | 0.01 |
CL/F (L/min) | 0.674 ± 0.330 | 0.948 ± 0.271 | 0.01 |
AUC0–∞ () | 191 ± 103 | 114 ± 34 | 0.01 |
tmax (min) | 30.5 ± 31.2 | 49.6 ± 28.5 | 0.02 |
Cmax (mg/L) | 2.47 ± 1.56 | 1.66 ± 0.90 | Ns |
MRT (min) | 44.8 ± 8.1 | 42.2 ± 5.7 | Ns |
ka (min−1) | 0.19 ± 0.18 | 0.29 ± 0.40 | Ns |
k10 (min−1) | 0.0197 ± 0.0042 | 0.0208 ± 0.0032 | Ns |
k12 (min−1) | 0.00327 ± 0.00047 | 0.00324 ± 0.00050 | Ns |
k20 (min−1) | 0.000247 ± 0.000046 | 0.000220 ± 0.000044 | Ns |
3-OMD | 3-OMD | ||
tmax 3-OMD (min) | 290 ± 174 | 315 ± 261 | Ns |
MET3-OMD (min) | 4260 ± 812 | 4759 ± 784 | Ns |
Cmax 3-OMD (mg/L) | 0.580 ± 0.324 | 0.343 ± 0.101 | 0.01 |
AUC3-OMD [0–∞] () | 2588 ± 1425 | 1740 ± 688 | 0.04 |
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Adamiak-Giera, U.; Jawień, W.; Pierzchlińska, A.; Białecka, M.; Kobierski, J.D.; Janus, T.; Gawrońska-Szklarz, B. Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications. Pharmaceutics 2021, 13, 1395. https://doi.org/10.3390/pharmaceutics13091395
Adamiak-Giera U, Jawień W, Pierzchlińska A, Białecka M, Kobierski JD, Janus T, Gawrońska-Szklarz B. Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications. Pharmaceutics. 2021; 13(9):1395. https://doi.org/10.3390/pharmaceutics13091395
Chicago/Turabian StyleAdamiak-Giera, Urszula, Wojciech Jawień, Anna Pierzchlińska, Monika Białecka, Jan Dariusz Kobierski, Tomasz Janus, and Barbara Gawrońska-Szklarz. 2021. "Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications" Pharmaceutics 13, no. 9: 1395. https://doi.org/10.3390/pharmaceutics13091395
APA StyleAdamiak-Giera, U., Jawień, W., Pierzchlińska, A., Białecka, M., Kobierski, J. D., Janus, T., & Gawrońska-Szklarz, B. (2021). Pharmacokinetics of Levodopa and 3-O-Methyldopa in Parkinsonian Patients Treated with Levodopa and Ropinirole and in Patients with Motor Complications. Pharmaceutics, 13(9), 1395. https://doi.org/10.3390/pharmaceutics13091395