Table 1.
Summary of PK and NE activity model parameter estimates
| Parameter | Description | Estimate | 90% CI |
|---|---|---|---|
| AZD7986 pharmacokinetics | |||
| Vc (L/kg) | Apparent volume per kg bodyweight of central plasma compartment | 0.368 | (0.257, 0.529) |
| Vp,fast (L/kg) | Apparent volume per kg bodyweight of rapidly equilibrating tissue compartment | 2.45 | (2.15, 2.79) |
| Vp,slow (L/kg) | Apparent volume per kg bodyweight of slowly equilibrating tissue compartment (single dose) | 1.97 | (1.70, 2.28) |
| Vp,slow,steadystate_change (%) | Percent change in volume of slowly equilibrating tissue compartment between first dose and steady state | 34.0 | (23.6, 45.2) |
| CL (L/h) | Apparent clearance from central compartment | 12.0 | (10.7, 13.4) |
| Qfast (L/h) | Apparent intercompartmental clearance between plasma and rapidly equilibrating tissues | 122 | (96.4, 154) |
| Qslow (L/h) | Apparent intercompartmental clearance between plasma and slowly equilibrating tissues | 14.7 | (11.2, 19.4) |
| Frel,5 mg | Relative bioavailability at 5 mg (single dose) | 1 (fixed) | — |
| Fslope | Slope parameter for bioavailability vs. dose power model | 0.228 | (0.180, 0.288) |
| Fsteadystate_change (%) | Percent change in bioavailability between first dose and steady state | 24.3 | (22.5, 26.2) |
| ka (h−1) | Absorption rate constant | 0.809 | (0.640, 1.02) |
| Alag (h) | Absorption lag time | 0.159 | (0.144, 0.176) |
| IIV Vc (%) | Interindividual variability in Vcentral | 53.6 | (23.8, 75.5) |
| IIV CL (%) | Interindividual variability in CL | 22.2 | (15.4, 27.5) |
| IIV Frel (%) | Interindividual variability in Frel | 18.2 | (13.4, 22.0) |
| IIV ka (%) | Interindividual variability in ka | 28.8 | (20.4, 35.5) |
| IIV Alag (%) | Interindividual variability in Alag | 21.3 | (0, 30.3) |
| εPK (%) | Additive error on log scale | 10.5 | (10.3, 10.7) |
| Neutrophil elastase activitya | |||
| N | Number of transit compartments in neutrophil maturation model | 27b | — |
| MTT (h) | Mean transit time from NE activation to neutrophil release into systemic circulation | 348 | (318, 381) |
| t1/2, NE blood (h) | Blood neutrophil half‐life | 7 (fixed)c | — |
| IC50 (nM) | Half‐maximum inhibitory concentration of AZD7986 | 394 | (319, 486) |
| Imax | Maximum achievable inhibition of NE activity | 1 (fixed)d | — |
| nH | Hill coefficient | 0.697 | (0.594, 0.819) |
| IIV MTT (%) | Interindividual variability in MTT | 10.6 | (0, 15.8) |
| IIV IC50 (%) | Interindividual variability in IC50 | 33.3 | (0, 53.5) |
| εNE (%) | Additive error on log scale | 14.9 | (14.2, 15.6) |
a
A complete list of NE activity parameter estimates can be found at the end of the Supplementary Methods.
b
See Figure S2 for objective function values using different numbers of compartments.
c
Fixed according to reported vascular neutrophil half‐life in healthy subjects.22
d
Fixed based on in vitro and preclinical data supporting complete NE inhibition at high AZD7986 concentrations.