TABLE 2.
Population PK parameter estimates from the final model using pooled data from the two phase 2a trials and one phase 2b triald
| Parametera | Population estimate (% RSE)b | 95% CIc for population estimate | % CV for BSV (% RSE)b | 95% CIc for % CV for BSV |
|---|---|---|---|---|
| F (%) | 100 (fixed) | 37.6 (8.20) | 32.1 to 45.8 | |
| MTT (h) | 3.18 (5.21) | 3.05 to 3.73 | 54.1 (5.86) | 49.9 to 66.2 |
| No. of transit compartments | 5.27 (13.4) | 5.16 to 8.01 | 300 (6.01) | 204 to 397 |
| Metabolite dADT | ||||
| CL/FdADT (liters/h) | 15.8 (4.42) | 15.1 to 17.9 | 19.7 (7.07) | 16.6 to 22.5 |
| V/FdADT (liters) | 88.8 (4.93) | 84.4 to 103 | 25.9 (7.41) | 20.1 to 28.5 |
| Whole blood-to-plasma matrix conversion factor (%) | −14.5 (3.55) | −19.4 to −7.41 | ||
| DBS-to-plasma matrix conversion factor (%) | −13.7 (3.96) | −19.0 to −4.55 | ||
| RUVplasma (% CV) | 48.6 (6.30) | 44.1 to 59.4 | ||
| RUVwhole blood (% CV) | 61.2 (6.36) | 52.7 to 72.8 | ||
| RUVDBS (% CV) | 68.8 (7.93) | 54.0 to 81.7 | ||
| Metabolite adADT | ||||
| CL/FadADT (liters/h) | 65.8 (10.1) | 59.6 to 87.0 | 116 (8.66) | 105 to 172 |
| V/FadADT (liters) | 15.7 (9.89) | 11.5 to 18.1 | 30.3 (46.8) | 25.9 to 54.3 |
| Whole blood-to-plasma matrix conversion factor (%) | 5.00 (1.70) | 2.16 to 9.51 | ||
| DBS-to-plasma matrix conversion factor (%) | 7.00 (4.15) | −1.45 to 17.7 | ||
| RUVplasma (CV%) | 39.4 (7.58) | 31.4 to 44.3 | ||
| RUVwhole blood (% CV) | 46.9 (6.34) | 38.5 to 53.6 | ||
| RUVDBS (% CV) | 46.7 (10.8) | 37.1 to 63.7 | ||
| Covariate effects | ||||
| Age on CL/FdADT (%) | −1.19 (9.14) | −1.35 to −0.88 | ||
| Formulation on MTT (%) | 42.9 (29.2) | 16.0 to 61.4 | ||
| Split 50-mg tablets on MTT (%) | −79.4 (12.1) | −100 to −60.2 |
Population parameter estimates are presented for a typical patient at 45 years of age weighing 52 kg and receiving the 200-mg formulation as whole tablets and with drug concentrations measured in plasma.
Computed population mean values are from NONMEM. Between-subject variability (BSV) is calculated as . Relative standard errors (RSEs) are calculated as 100(standard deviation/mean value).
Based on nonparametric bootstrap diagnostics of the final PK model (n = 1,000). The 95% confidence intervals (CI) are displayed as the 2.5th to the 97.5th percentile of bootstrap estimates.
The two phase 2a trials included 68 patients and have been described previously (16), and the phase 2b trial included 125 patients. dADT, deacetylated amidantel; adADT, acetylated dADT; F, relative bioavailability; MTT, mean absorption transit time; CL/F, apparent elimination clearance; V/F, apparent volume of distribution; CV, coefficient of variation; DBS, dried blood spots; RUVplasma, residual unexplained variability for plasma; RUVwhole blood, residual unexplained variability for whole blood; RUVDBS, residual unexplained variability for DBS; Age on CL/FdADT, linear covariate relationship between age and CL/FdADT centered on the median age of 45 years; Formulation on MTT, the formulation effect on MTT (200 mg or 50 mg); Split 50-mg tablets on MTT, the effect of breaking the administered tablets (i.e., a 50-mg tablet broken in half) on MTT.