TABLE 2.
Final parameter estimates of the population pharmacokinetic model of delamanid/DM-6705c
| Parameter | Estimate | %RSE |
|---|---|---|
| Structural model parameters of delamanid | ||
| CL/F (L/h) | 17.2 | 3.36 |
| Vc/F (L) | 346 | 8.15 |
| Q/F (L/h) | 62.4 | 17.6 |
| Vp/F (L) | 296 | 13.8 |
| MAT (h) | 2.73 | 7.41 |
| Structural model parameters of DM-6705 | ||
| CLM/F (L/h) | 54.2 | 6.61 |
| VcM/F (L) | 77.0 | 46.0 |
| QM/F (L/h) | 425 | 5.34 |
| VpM/F (L) | 13,150 | 4.27 |
| Covariate effect | ||
| Allometric exponent for wt on CL/F, Q/F, CLM/F, and QM/F | 0.75 | Fixed |
| Allometric exponent for wt on Vc/F, Vp/F, VcM/F, and VpM/F | 1.00 | Fixed |
| Formulation (dispersible tablet) on MAT | 0.495 | Fixeda |
| Formulation (dispersible tablet) on F1 | −0.158 | Fixeda |
| Age on F1: linear slope below 2 yrs (1/yrs) | 0.201 | 35.5 |
| Age on FM: linear slope below 6 yrs (1/yrs) | 0.0654 | 17.9 |
| Dose on F1: increase dose = 50 mg and lower | 0.580 | Fixedb |
| IIV/IOV (CV%) | ||
| IIV on CL/F | 16.3 | 32.9 |
| Correlation IIV term between CL/F and CLM/F | 71.0 | 29.7 |
| IIV on CLM/F | 33.9 | 25.5 |
| IIV on Vp/F | 58.5 | 34.6 |
| IIV on FM | 13.5 | 39.8 |
| IOV on F1 | 26.8 | 16.2 |
| IOV on MAT | 60.7 | 23.8 |
| RV (CV%) | ||
| Proportional error, delamanid | 30.8 | 7.25 |
| Correlation RV term between delamanid and DM-6705 | 39.4 | 14.5 |
| Proportional error, DM-6705 | 18.1 | 7.23 |
The formulation effect (dispersible tablet versus film-coated tablet) on F1 and MAT was fixed to the estimates from the population PK model including adult bioequivalence study (trial 245) data.
Fixed based on the estimates from the adult population PK model using data with a dose range of ∼50 to 400 mg (29).
CL/F, clearance; Vc/F, central volume of distribution; Q/F, intercompartmental clearance; Vp/F, peripheral volume of distribution; MAT, mean absorption time; CLM/F, clearance of DM-6705; VcM/F, central volume of distribution of DM-6705; QM/F, intercompartmental clearance of DM-6705; VpM/F, peripheral volume of distribution of DM-6705; IIV, interindividual variability; IOV, interoccasional variability; CV%, percent coefficient of variation; F1, bioavailability; FM, fraction metabolized; RV, residual variability; %RSE, percent relative standard error. Standard errors of estimates are obtained by the sampling importance resampling (SIR) approach. Covariate effects for delamanid are modeled as follows: CL/F (L/h) = 17.2 × [BW (kg)/33.5]0.75, Vc/F (L) = 346 × [BW (kg)/33.5]1.0, Q/F (L/h) = 62.4 × [BW (kg)/33.5]0.75, Vp/F (L) = 296 × [BW (kg)/33.5]1.0, MAT = 2.73 × (1 + 0.495) (if the formulation is a dispersible tablet), and F1 = 1.0{1 − 0.201 × [2 − age (years)]} (if age is >2.0 years) × (1 − 0.158) (if the formulation is a dispersible tablet) × (1 + 0.580) (if the dose is ≤50 mg). Covariate effects for DM-6705 are modeled as follows: CLM/F (L/h) = 54.2 × [BW (kg)/33.5]0.75, VcM/F (L) = 77.0 × [BW (kg)/33.5]1.0, QM/F (L/h) = 425 × [BW (kg)/33.5]0.75, VpM/F (L) = 13,150 × [BW (kg)/33.5]1.0, and FM = 1.0 × {1 − 0.0654 × [6 − age (years)]} (if age is <6 years).