Table 1.
Population pharmacokinetic and pharmacodynamic parameters of BCT197 and bootstrap validation
| Population mean | Between‐subject variability | |||||
|---|---|---|---|---|---|---|
| Parameter | Final estimate | RSEc (%) | Bootstrap median and 90% CId | Final estimate (%CV)e | RSEc (%) | Bootstrap median and 90% CId |
| Population PKa | ||||||
| CL/F (L/h) | 1.76 | 10 | 1.77 [1.47;2.05] | 25.5 | 36 | 26.1 [20.9;37.7] |
| V1/F (L) | 71.9 | 16 | 71.5 [58.1;98.7] | 42.4 | 43 | 43.6 [34.3;67.9] |
| V2/F (L)f | 25.5 | 14 | [25.3] [19.3;31.1] | — | — | — |
| Bmax (µg) | 500 | 30 | 507 [308;806] | — | — | — |
| Kd (µg) | 367 | 35 | 371 [228;660] | — | — | — |
| CLd/F (L/h) | 7.47 | 15 | 7.46 [5.70;9.42] | — | — | — |
| Kt=Kint1 (1/h) | 1.12 | 14 | 1.13 [0.934;1.42] | 59.6 | 35 | 58.7 [43.8;81.0] |
| Ks (1/h) | 5 (fixed) | — | — | 172 | 29 | 167 [110;263] |
| Tlag (h) | 0.232 (fixed) | — | — | 44.0 | 14 | 44.1 [38.8;49.7] |
| fc (−)g | 0.344 | 9.1 | 0.342 [0.291;0.392] | — | — | — |
| Rate (µg/h) | 2300 | 5.3 | 2310 [2170;2530] | — | — | — |
| K1b (1/h) | 0.0106 | 15 | 0.0105 [0.00791;0.0132] | — | — | — |
| Db (h) | 0.1 (fixed) | — | — | — | — | — |
| Tpump (h) | 18 (fixed) | — | — | — | — | — |
| Residual error (%) | 13.4 | 3.7 | 13.3 [12.5;14.2] | — | — | — |
| Population PDb | ||||||
| Imax (−) | 0.663 | 6.4 | 0.668 [0.6121;0.752] | — | — | — |
| IC50 (µg/L)h | 44.3 | 24 | 44.3 [30.6;65.5] | — | ||
| Kin (ng/mL) | 1830 | 32 | 1850 [977;3020] | — | — | — |
| Ktol (1/h) | 0.00276 | 44 | 0.00281 [0.00173;0.00529] | — | — | — |
| Kout (1/h) | 0.348 | 35 | 0.353 [0.170;0.592] | 32.5 | 18 | 31.9 [27.1;37.4] |
| t0 (h) | 13.3 | 16 | 13.3 [11.9;14.3] | — | — | — |
| A (ng/mL) | 0.207 | 21 | 0.208 [0.161;0.317] | — | ||
| Residual error (%) | 21.2 | 3.9 | 21.1 [19.8;22.5] | — | — | — |
Bmax, total binding capacity; CL/F, oral drug clearance; CLd/F, intercompartmental distribution clearance; Db, duration of zero‐order drug release from the shunt compartment (Ashunt) into the intestinal compartment (Aint); fc, fraction of oral dose (tablet) that is absorbed in a zero‐order fashion; K1b, first order transfer rate from central compartment into the shunt compartment (Ashunt); Kd, equilibrium dissociation constant; Kint1, first order absorption rate constant of shunted drug into central compartment; Kt/Ks, first‐order oral absorption rate constant of tablet/solution; Rate, zero order oral absorption rate (tablet); Tpump, shunt compartment (Ashunt) emptying lag time; V1/F, volume of central compartment; V2/F, volume of peripheral compartment.
A, amplitude of the oscillatory baseline; IC50, concentration at half maximum inhibition; Imax, maximum inhibition; Kin, zero order production rate of drug response; Kout, first order degradation rate of drug response; Ktol, first order production rate of negative feedback; t0, shifted peak of oscillating baseline.
RSE, relative standard error calculated as 100 x (standard error/mean value) from 500 iterations of a nonparametric bootstrap.
The 90% CI is displayed as the 5th−95th percentiles of 500 iterations of a nonparametric bootstrap.
The CV% between‐subject variability is presented as 100x(EXP(mean estimate)−1)0.5.
Vss/F ranged 97.4 L (V1/F+V2/F) when dose approaches infinity to 132 L (V1/F + V2/F•(1+Bmax/Kd)) when dose approaches zero.
Fraction of dose modeled in logit domain and back transformed.
IC50 was modeled as fraction of predose baseline value (α•E(0)), where α is the fraction of baseline and E(0) the predose baseline response. Population median α and 90% CI was 10.5 [7.22;15.5].