Table 3.
Estimated parameters for the developed model describing the PK after inhalation in healthy volunteers, patients with asthma, and patients with COPD
| Parameter | Abbreviation | Unit | Population estimate (%RSE) | BSV, %CV (%RSE) |
|---|---|---|---|---|
| Systemic disposition model 6 | ||||
| Central volume of distribution (CMT 1)* | VC | [l] | 23.5 (4.35) | 26.2 (10.4) |
| Peripheral volume of distribution (CMT 2)* | V2 | [l] | 2590 (35.7) | — |
| Peripheral volume of distribution (CMT 3)* | V3 | [l] | 473 (10.7) | — |
| Peripheral volume of distribution (CMT 4)* | V4 | [l] | 16.1 (19.7) | — |
| Inter‐compartmental clearance (to CMT 2)* | Q2 | [l h−1] | 31.7 (12.3) | 25.7 (13.5) |
| Inter‐compartmental clearance (to CMT 3)* | Q3 | [l h−1] | 65.7 (5.28) | 16.8 (13.5) |
| Inter‐compartmental clearance (to CMT 4)* | Q4 | [l h−1] | 22.5 (8.06) | — |
| Renal clearance * | CLR | [l h−1] | 10.5 (4.55) | — |
| Non‐renal clearance * | CLNR | [l h−1] | 63.7 (8.49) | 26.8 (13.5) |
| Pulmonary absorption model (reference healthy volunteer, non‐smoker, Caucasian, BSA: 1.89 m 2 ) | ||||
| Slow absorption rate constant | k a(slow) | [h−1] | 0.0375 (6.91) | 88.5 (4.85) |
| Intermediate absorption rate constant | k a(int) | [h−1] | 0.447 (3.65) | — |
| Fast absorption rate constant | k a(fast) | [h−1] | 2.41 (12.1) | 62.6 (6.09) |
| Pulmonary bioavailable Fraction | PBIO | [% ND] | 48.7 (2.71) | BSV:
25.2 (7.88) BOV: 37.0 (2.60) |
| First proportionality factor | PF1 | — | 0.746 (3.79) | 20.1 (4.76) |
| Second proportionality factor | PF2 | — | 0.850 (0.691) | — |
| Fraction slowly absorbed † | — | [% PBIO] | 74.6 ‡ | — |
| Fraction intermediately absorbed † | — | [% PBIO] | 21.6 § | — |
| Fraction fast absorbed † | — | [% PBIO] | 3.81 ¶ | — |
| Covariate model * | ||||
| COPD on the PBIO | — | — | 0.198 (36.3) | — |
| COPD on PF1 | — | — | 0.312 (51.9) | — |
| COPD on k a(slow) | — | — | −0.509 (11.2) | — |
| COPD on k a(fast) | — | — | 0.808 (27.4) | — |
| Asthma on PF1 | — | — | 0.834 (19.8) | — |
| Asthma on k a(fast) | — | — | 0.928 (28.2) | — |
| Smoking on k a(slow) | — | — | −0.235 (38.9) | — |
| Smoking on k a(fast) | — | — | 0.562 (26.7) | — |
| BSA on the PBIO | — | [m−2] | −0.815 (19.0) | — |
| Black on the PBIO | — | — | 0.358 (36.8) | — |
| Asian on the PBIO | — | — | 0.989 (38.0) | — |
| Residual variability model | ||||
| Proportional residual variability (plasma) | — | [% CV] | 23.3 (0.562) | — |
| Proportional residual variability (urine) | — | [% CV] | 48.8 (0.909) | — |
*
Covariates are represented in the form of the parameter estimates, which are implemented as described in the methods section. Transformed pulmonary absorption characteristics for every covariate can be found in Table 4.
†
Transformed parameters derived from the model estimates.
‡
Value equal to PF1.
§
Calculated by (1 − PF1) * PF2.
¶
Calculated by (1 − PF1) * (1 − PF2), also see methods section.
BSV: between‐subject variability; BOV: between‐occasion variability; CV: coefficient of variation; ND: nominal dose (ex‐mouthpiece); PBIO: pulmonary bioavailable fraction; RSE: relative standard error.