Table 2.
Parameter estimates for the final LD/CD population pharmacokinetic model and results from the SIR evaluation
| Parameter | Levodopa (%RSE) § [%Shrinkage] | Carbidopa (%RSE) § [%Shrinkage] | Levodopa SIR (%RSE) § [95% CI¶] | Carbidopa SIR (%RSE) § [95% CI¶] | Levodopa× (%RSE) § [%Shrinkage] | Carbidopa× (%RSE) § [%Shrinkage] |
|---|---|---|---|---|---|---|
| CL/F (L/min)*(WT/70)0.75 | 1.31† (10.7) | 1.05 (8.46) | 1.31† (10.6) [1.08–1.63] | 1.05 (8.57) [0.881–1.23] | 1.21† (10.1) | 1.05 (8.34) |
| VC/F (L)*(WT/70) | 45.4 (9.85) | 168 (8.50) | 46.0 (9.17) [38.6–55.2] | 167 (8.13) [142–195] | 45.5 (9.91) | 168 (8.58) |
| Q/F (L/min)*(WT/70)0.75 | 0.667 (15.7) | – | 0.667 (11.2) [0.548–0.837] | – | 0.661 (15.3) | – |
| VP/F (L)*(WT/70) | 44.9 (5.90) | – | 44.8 (6.01) [40.0–50.3] | – | 45.1 (5.88) | – |
| MTT1 (min) | 16.1 (6.15) | 34.6 (6.20) | 16.1 (6.05) [14.3–18.2] | 34.7 (5.73) [30.9–38.7] | 16.1 (6.11) | 34.6 (6.05) |
| MTT2 (min) | 86.2 (6.39) | 121 (6.01) | 85.9 (4.69) [78.1–94.4] | 121 (5.27) [109–134] | 86.5 (6.27) | 120 (5.40) |
| FREL | 1 FIX | 1 FIX | 1 FIX | 1 FIX | 1 FIX | 1 FIX |
| fa1‡ | 0.749 (5.35) | 0.570 (7.10) | 0.749 (4.67) [0.678–0.816] | 0.570 (6.61) [0.50–0.65] | 0.747 (5.36) | 0.570 (6.73) |
| Pre-dose concentration (μg/mL) | 0.120 (42.3) | 0.0256 (38.8) | 0.129 (45.9) [0.0542–0.268] | 0.0256 (32.5) [0.01–0.04] | 0.120 (42.3) | 0.0255 (39.5) |
| INTERCL/F-CDAMT (mg) | 86.7 (36.3) | – | 94.6 (32.8) [52.0–161.5] | – | 119.1 (37.3) | – |
| CL/F-AGE | – | − 0.0119 FIX | – | − 0.0119 FIX | – | − 0.0114 (19.8) |
| CL/F-HY | − 0.0616 FIX | 0.0141 FIX | − 0.0616 FIX | 0.0141 FIX | − 0.0967 (27.0) | – |
| FREL-AGE | 0.00172 FIX | – | 0.00172 FIX | – | – | – |
| MTT2-SEX | – | 0.178 FIX | – | 0.178 FIX | – | – |
| IIVCL/F | 15.0 (31.8) [25.8] | 20.9 (16.0) [18.4] | 16.4 (27.6) [8.45–23.7] | 21.8 (19.8) [14.5–29.6] | 14.6 (32.0) [26.8] | 21.0 (16.1) [18.4] |
| IIVVC/F | 39.5 (22.8) [17.3] | – | 41.2 (17.4) [28.2–53.9] | – | 38.9 (22.1) [17.0] | – |
| IIVMTT1 | 34.5 (13.8) [6.49] | 31.9 (10.6) [6.55] | 35.3 (14.3) [26.6–45.9] | 32.9 (12.7) [25.6–40.9] | 34.4 (13.7) [6.34] | 32.1 (10.3) [6.39] |
| IIVMTT2 | 15.2 (34.7) [18.0] | 27.2 (19.5) [3.98] | 16.5 (28.5) [8.67–24.5] | 27.6 (15.2) [20.6–36.2] | 15.3 (33.5) [17.7] | 29.2 (12.4) [3.47] |
| IIVfa1‡ | 99.6 (15.8) [10.0] | 81.2 (19.2) [9.53] | 104 (17.0) [77.6–139] | 84.7 (16.4) [62.9–112] | 99.1 (15.6) [10.5] | 80.5 (17.0) [9.54] |
| IIVFrel | 28.3 (20.6) [4.89] | 48.1 (9.69) [1.60] | 28.7 (14.3) [21.2–36.4] | 49.5 (12.7) [38.5–61.8] | 28.8 (19.7) [4.55] | 48.4 (9.63) [1.56] |
| IIVPre-dose concentration | 180 (11.3) [28.3] | 89.6 (24.9) [59.3] | 187 (15.1) [138–239] | 102 (36.3) [55.6–156] | 1.80 (11.3) [28.3] | 90.1 (24.9) [59.2] |
| Proportional error (%) | ||||||
| Healthy subjects | 15.0 (11.3) | 7.70 (14.1) | 15.0 (6.14) [13.5–17.1] | 7.70 (11.4) [6.08–9.49] | 15.0 (11.3) | 7.66 (13.8) |
| Patients | 7.02 (14.6) | 3.86 (35.3) | 7.07 (6.51) [6.22–8.04] | 3.86 (20.2) [2.21–5.27] | 7.03 (14.5) | 3.89 (33.8) |
| Additive error (μg/mL) | ||||||
| Healthy subjects | 0.00406 (16.6) | 0.00415 (14.2) | 0.00406 (9.15) [0.00343–0.00491] | 0.00418 (5.85) [0.00372–0.00468] | 0.00407 (16.5) | 0.00415 (14.3) |
| Patients | – | 0.00684 (28.3) | – | 0.00693 (13.5) [0.00526–0.00880] | – | 0.00677 (27.5) |
†Per milligram carbidopa for typical individual with 0 mg carbidopa and mean HY 1.53; ‡Logit transformed; §NONMEM point estimate and the associated % relative standard error (% RSE, reported on the approximate standard deviation scale (SE/variance estimate)/2). ¶The median and 95% confidence interval (2.5th and 97.5th percentiles). ×With unfixed parameter-covariate coefficients (relationships with little influence were removed). CI, confidence interval; CDAMT, carbidopa dose; HY, Hoehn and Yahr; IIV, inter-individual variability (CV%); SIR, sampling importance resampling