Table 2.
PopPK parameters before (pharmacostatistical model) and after inclusion of covariates (final model with covariates)
| Parameter | Pharmacostatistical model | Final model with covariates | |||
|---|---|---|---|---|---|
| Estimate | % RSE | Estimate | % RSE | [95% CI] (shrinkage %) | |
| Typical value of CLL (θ1, L/h)a | 0.0114 | 9.07 | 0.0124 | 2.99 | [0.0116; 0.0131] |
| Effect of WT on CLL (θ12)a | NA | NA | 2.92·10−4 | 3.24 | [2.73·10−4; 3.11·10−4] |
| Effect of STATIN on CLL (θ13)a | NA | NA | 6.44·10−3 | 6.08 | [5.66·10−3; 7.22·10−3] |
| Typical value of V2 (θ2, L) | 2.66 | 6.54 | 3.19 | 3.63 | [2.95; 3.42] |
| Typical value of Ka (θ3, 1/h) | 0.0129 | 5.44 | 7.68·10−3 | 2.45 | [7.31·10−3; 8.06·10−3] |
| Typical value of V3 (θ4, L)b | 1.81 | 5.21 | 2.79 | 2.95 | [2.62; 2.95] |
| Effect of age on V3 (θ15)b | NA | NA | 0.310 | 12.3 | [0.233; 0.386] |
| Typical value of Q (θ5, L/h) | 0.0156 | 7.29 | 0.0185 | 4.95 | [0.0166; 0.0203] |
| Typical value of Vm (θ6, mg.h/L) | 0.172 | 11.1 | 0.183 | 4.96 | [0.165; 0.202] |
| Typical value of Km (θ7, mg/L)c | 9.49 | 11.3 | 7.73 | 6.39 | [6.74; 8.72] |
| Effect of FPCSK9 on Km (θ14)c | NA | NA | − 0.541 | 8.97 | [− 0.638; − 0.444] |
| Typical value of F (θ10) | 0.590 | 5.44 | 0.862 | 0.13 | [0.860; 0.865] |
| Typical value of LAG (θ11, h) | 0.643 | 2.76 | 0.641 | 2.58 | [0.608; 0.674] |
| Interindividual variability (CV %) | |||||
| ω2 CLL | 0.402 (63.4%) | 7.09 | 0.232 (48.2%) | 4.37 | [0.212; 0.252] (18.5) |
| ω2 V2 | 0.485 (69.7%) | 4.34 | 0.589 (76.7%) | 4.42 | [0.537; 0.641] (42.5) |
| ω2 V3 | 0.151 (38.9%) | 11.1 | 0.0735 (27.1%) | 17.1 | [0.0483; 0.0986] (60.4) |
| ω2 km | 0.337 (58.1%) | 12.0 | 0.298 (54.6%) | 8.92 | [0.245; 0.351] (55.4) |
| Block ηV3/F − ηKMd | − 0.994 | 10.4 | − 0.793 | 14.4 | NA |
| ω 2 F | 0.206 (45.3%e) | 18.1 | 1.060 (103%e) | 6.59 | [0.920; 1.20] (49.5) |
| Residual variability | |||||
| Proportional term (θ8) | 0.261 (26.1%) | 0.45 | 0.259 (25.9%) | 0.45 | [0.257; 0.262] |
| Additive term (θ9, mg/L) | 0.0488 | 7.59 | 0.0465 | 6.46 | [0.0405; 0.0526] |
θ and ω are the PopPK parameters (θ) and the variance of their associated interindividual variability (ω)
CI confidence interval, CLL linear clearance, CV coefficient of variation, F bioavailability factor, FPCSK9 free proprotein convertase subtilisin/kexin type 9, Ka absorption constant, Km Michaelis–Menten parameter, LAG lag time, NA not applicable, PopPK population pharmacokinetic, Q intercompartmental clearance, % RSE percentage of relative standard error (100% × [standard error/estimate]), V2 distribution volume from the depot to the central compartment, V3 distribution volume from the central to peripheral compartments, Vm Michaelis–Menten parameter, WT weight
aThe expression of linear elimination clearance including covariates effects is CLL = TVCLL + COV1 × (WT − 82.9) + COV2 × STATIN, where WT is weight, with a median value of 82.9 in the available data. STATIN was coded as 0 if no coadministration, and 1 if coadministration, of rosuvastatin (dose < 20 mg/day) or atorvastatin (dose < 40 mg/day) or simvastatin (whatever dose)
bThe expression of the distribution volume of the peripheral compartment is V3 = TVV3 × (AGE/60)COV4, where 60 is the median value of age in the available data
cThe expression of the Michaelis–Menten parameter Km is Km = TVKM + COV3 × (FPCSK9/72.9), where FPCSK9 is the time-varying free PCSK9 concentration, with a median value of 72.9 in the available data
dThe value presented here is the correlation coefficient (r)
eEstimated in logit space