Table 3.
Population estimates for the base pharmacokinetic model
| Studies 1 and 3 (with smokers) | Studies 2 and 4 (with nonsmokers) | |||
|---|---|---|---|---|
| Parameter | Mean estimate | IIVa | Mean estimate | IIVa |
| Riociguat | ||||
| Absorption rate, 1/h | 3 fixb | 68.7 | 3 fixb | 66.7 |
| Presystemic metabolism, 1/h | 0.0122 | NA | 0.00787 | NA |
| Clearance by renal secretion, L/h | 0.106 | 78.5 | 0.06985 | 90.9 |
| Clearance by metabolism to M1, L/h | 2.32 | 98.0 | 1.24 | 74.4 |
| Clearance by nonrenal mechanisms,c L/h | 0.630 | 82.3 | 0.424 | 61.1 |
| Central volume of distribution, L/kg | 0.271 | 30.3 | 0.238 | 22.1 |
| Intercompartmental clearance, L/h | 2.23 | NA | 2.54 | NA |
| Peripheral volume of distribution, L/kg | 0.114 | 37.1 | 0.132 | 41.7 |
| Metabolite M1 | ||||
| Clearance by renal secretion, L/h | 0.345 | 81.4 | 0.266 | 79.9 |
| Nonrenal clearance, L/h | 1.74 | 37.1 | 1.71 | 38.5 |
| Central volume of distribution, L/kg | 0.130 | 29.6 | 0.108 | 31.6 |
| Intercompartmental clearance, L/h | 10.3 | NA | 12.9 | NA |
| Peripheral volume of distribution, L/kg | 0.376 | 26.3 | 0.449 | 16.6 |
| Absorption lag time, hours | 0.243 | 35.1 | 0.221 | 36.3 |
| Proportional residual error (plasma), % | 19.4 | … | 17.7 | … |
| Proportional residual error (urine), % | 34.9 | … | 41.2 | … |
Note
IIV: interindividual variability; M1: main metabolite of riociguat; NA: not available.
a
Calculated as the square root of the variance (which is approximately equivalent to the coefficient of variation [%]).
b
Absorption rate constant (KA) was fixed to achieve a stable model that would allow precise estimates of IIV. The KA value of 3 was chosen because this was the estimated KA value during early steps in model development.
c
Other than conversion to M1.