Table 2.
CPI population PBPK model parameter estimates
| Parameter | kSYN in blood (FLsyn = 0) | kSYN in liver (FLsyn = 1) | ||||
|---|---|---|---|---|---|---|
| Fixeda | BSVb | BOVc | Fixeda | BSVb | BOVc | |
| System parameter | ||||||
| ksyn, nMol/h | 18.4 (11) | 10 (30) | ‐ | 33.1 (12) | 7.3 (87) | ‐ |
| CLB, L/h | 6.24 (24) | 38.2 (23) | 34.4 (21) | 5.28 (8) | 16 (28) | 14.2 (16) |
| CLR, L/h | 2.7 (6) | 12.7 (30) | ‐ | 2.7 (6) | 13.5 (28) | ‐ |
| VC, L | 11.9 (21) | 25.8 (29) | ‐ | 13 (16) | 24.9 (29) | ‐ |
| CLactive,0, L/h | 1397 (32) | ‐ | ‐ | 930 (15) | ‐ | ‐ |
| Ki, μM | 0.93 (7) | ‐ | ‐ | 1.44 (10) | ‐ | ‐ |
| Covariates | ||||||
| FRAX | 0.269 (13) | ‐ | ‐ | 0.486 (13) | ‐ | ‐ |
| COVGEN d | 0.788 | ‐ | ‐ | 0.673 | ‐ | ‐ |
| COVRACE | 0.417 (18) | ‐ | ‐ | 0.323 (16) | ‐ | ‐ |
| COVSEX | 0.232 (24) | ‐ | ‐ | 0.26 (21) | ‐ | ‐ |
| Residual unexplained variabilities | ||||||
| σprop (%) – plasma | 13.2 (5) | ‐ | ‐ | 13.3 (5) | ‐ | ‐ |
| σadd, nM – plasma | 0.001 FIXED | ‐ | ‐ | 0.001 FIXED | ‐ | ‐ |
| σprop (%) – urine | 34.8 (8) | ‐ | ‐ | 34.9 (8) | ‐ | ‐ |
| σadd, nMol – urine | 2.3 (50) | ‐ | ‐ | 2.18 (59) | ‐ | ‐ |
σprop, proportional residual error; σadd, additive residual error; BOV, between occasion variability; BSV, between subject variability; CLB, biliary clearance; CLR, renal clearance; CLuptake,0, hepatic active uptake clearance (CLactive,u) in white men with SLCO1B1 521TT genotype; COVGEN, fractional change in CLactive,u in SLCO1B1 521CC genotype; COVRACE, fractional change in CLactive,u in Asian‐Indian subjectss; COVsex, fractional change in ksyn in women relative to men; CPI, coproporphyrin I; FLsyn, fraction CPI synthesis in the liver; FRAX, surrogate variable of genetic effect; Ki, total rifampicin OATP1B1 inhibition constant (equivalent to 0.10 µM as unbound K i calculated with rifampicin fu,p of 0.11); ksyn, rate of coproporphyrin I synthesis; PBPK, physiologically‐based pharmacokinetic; Vc, volume of blood (central) compartment.
aThe population (fixed effect) parameters. Values within parentheses represent relative standard errors (RSE, %). bEstimated BSV (%) and its RSE (%). cEstimated BOV (%) and its RSE (%). dCalculated based on the population (fixed effect) parameter estimate of FRAX.