Table 4.
Population PK parameter estimates from the final model
| Parameter | Final model | RSE, %a |
|---|---|---|
| Cladribine | ||
| CLR coefficientb (typical patient with CLCR = 6.31), L/hc | 3.52 (22.2) | 9.26 |
| CLNR, L/h | 23.4 | 9.58 |
| Central volume, L | 44.0 | 22.77 |
| Intercompartmental Q3, L/h | 14.3 | 7.73 |
| Intercompartmental Q4, L/h | 53.7 | 19.06 |
| Peripheral volume V3, L | 347 | 6.07 |
| Peripheral volume V4, L | 89.5 | 7.97 |
| Absorption rate constant, h−1 | 1.08 | 21.14 |
| Absorption rate constant (unknown/fed state), h−1 | 1.03 | 11.62 |
| Bioavailability | 0.456 | 7.03 |
| Bioavailability (unknown/fed state) | 0.4 | 5.28 |
| Lag time for phase III, h | 0.319 | 12.41 |
| Mean transit time (fed state), h | 0.910 | 11.03 |
| Number of transit compartments | 2.24 | 27.15 |
| Fold increase in CLNR in the presence of IFNβ-1a | 1.21 | 8.46 |
| BSVCLNR | 0.00574 | 64.41 |
| BSVV | 0.209 | 72.51 |
| BSVQ3,Q4,V3,V4 | 0.0365 | 28.47 |
| BSVKa | 0.102 | 62.53 |
| BSVF d | 0.223 | 19.13 |
| BSVResidual variability | 0.159 | 16.66 |
| RUV plasma (intravenous), % | 20.0 | 11.21 |
| RUV plasma (oral), % | 34.7 | 16.19 |
| RUV plasma (oral; studies 26127, 26486), % | 22.8 | 5.84 |
| RUV plasma (oral; study 25643), % | 35.3 | 6.74 |
| RUV urine, % | 87.1 | 10.89 |
| 2-Chloroadenine | ||
| CLR e (Vmax), μg/h | 0.00280 | 25.53 |
| CLR e (Km), ng/L | 0.0114 | 58.14 |
| Apparent hepatic CL, L/hf | 653 | 10.64 |
| Apparent central volume V, Lf | 365 | 13.27 |
| RUV plasma, % | 34.3 | 19.64 |
| RUV plasma (study 25643), % | 31.8 | 76.38 |
| RUV urine, % | 104 | 14.32 |
BSV between subject variability for the random-effects distribution of the parameter, CL clearance, CL CR creatinine clearance, CL NR non-renal clearance, CL R renal clearance, F bioavailability, IFN interferon, Ka absorption rate constant, Km metabolite concentration at which the half maximal renal clearance rate is achieved, PK pharmacokinetic, Q 3 intercompartment clearance between the central and first peripheral compartment, Q 4 intercompartment clearance between the central and second peripheral compartment, RSE relative standard error, RUV residual unexplained variability (proportional component), V volume of distribution, V 3 peripheral one-compartment volume of distribution, V 4 peripheral two-compartment volume of distribution, V max maximal CLR rate for metabolite
aRSEs from bootstrap (n = 100) in NONMEM
bScaled parameter to be dimensionless. Original parameter estimated in NONMEM run had units of L/h
cCLR, L/h = coefficient × CLCR, L/h
dVariance on a logit scale
eCLR = V max × CM/(KM + CM); saturable elimination, where CM = metabolite concentration
fCorrected for the fraction metabolized to 2-chloroadenine