Table 3.
PK and PD parameter estimates for the final model
| Parameter (unit) | Estimate | RSE % | Inter-individual variability | |
|---|---|---|---|---|
| SD | RSE (%) [Shrinkage %] | |||
| ka (day−1) | 0.157 | 5.80 | 0.652 | 3.95 [52] |
| β(ka,lwt70) | − 0.457 | 27.1 | – | |
| F (–) | 0.685 | 3.10 | 0.531 | 9.00 [72] |
| Vc (L) | 2.62 | 2.11 | 0.116 | 19.3 [NA] |
| β(Vc,lwt70) | 1.2 | 8.66 | – | – |
| ke(P) (days−1) | 1.31 | 8.93 | 1.14 | 5.10 [65] |
| β(ke(P),AI) | 0.713 | 22.2 | – | – |
| ksyn0 (nmol/L/day) | 0.985 | 5.91 | 0.0559 | 64.1 [99] |
| β(ksyn0,lwt70) | − 1.52 | 12.1 | – | – |
| R0 (nmol/L) | 32.5 | 5.86 | 0.91 | 4.66 [61] |
| β(R0,AI) | − 0.544 | 21.5 | – | – |
| β(R0,IV) | 0.987 | 24.9 | – | – |
| CL (L/day) | 0.34 | 2.99 | 0.486 | 4.66 [53] |
| β(CL,lwt70) | 1.52 | 4.87 | – | – |
| β(CL,IV) | − 1.07 | 10.9 | – | – |
| Q (L/day) | 0.358 | 10.9 | 0.705 | 27.3 [81] |
| β(Q,IV) | − 2.31 | NA | – | – |
| Vp (L) | 2.8 | – | – | – |
| KD (nmol/L) | 0.167 | – | – | – |
| koff (day−1) | 5.53 | – | – | – |
| kdes (year−1) | 2.58 | 5.69 | 0.654 | 7.01 [58] |
| ksyn∞ (nmol/L/day) | 0.0554 | 36.3 | 2.16 | 10.3 [64] |
| β(ksyn∞,IV) | 2.49 | 25.3 | – | – |
| B0 (cells/µL) | 194 | 1.25 | 0.394 | 2.63 [26] |
| β(B0,lage38) | − 0.282 | 17.1 | – | – |
| β(B0,lwt70) | 0.271 | 18.9 | – | – |
| Emax (–) | 159 | 3.18 | 0.587 | 4.17 [57] |
| β(Emax,lBc200) | 0.275 | 11.6 | – | – |
| β(Emax,APLIOS) | 0.503 | 9.35 | – | – |
| EC50 (mg/L) | 0.0057 | 8.52 | 0.927 | 9.68 [81] |
| Gamma (–) | 2.81 | 11.6 | 1.46 | 4.79 [80] |
| kout (day−1) | 0.0124 | 5.15 | 0.922 | 4.64 [64] |
| β(kout,lwt70) | − 0.624 | 19.8 | – | – |
| β(kout,MIRROR) | − 0.554 | 14.1 | – | – |
| QB (L/day) | 0.78 | – | – | – |
| Vb (L) | 3.7 | 6.26 | 1.37 | 5.16 [51] |
| Corr_Vb_Emax | 0.28 | 22.6 | ||
| Corr_kout_Vb | − 0.336 | 17.9 | ||
| Corr_kout_Vb | 0.423 | 12.3 | ||
| Corr_ka_CL | − 0.294 | 21.0 | ||
| Corr_kdes_CL | 0.642 | 10.4 | ||
| Corr_kdes_ka | 0.433 | 23.2 | ||
| Corr_ke(P)_R0 | − 0.551 | 8.69 | ||
| Corr_ksyn∞_R0 | 0.47 | 13.6 | ||
| Corr_ksyn∞_ke(P) | − 0.464 | 13.6 | ||
| Ofatumumab conc. additive (mg/L) | 0.0316 | 3.28 | ||
| Ofatumumab conc. proportional | 0.278 | 1.72 | ||
| B cell count additive (cells/µL) | 0.153 | – | ||
| B cell count proportional | 0.381 | – | ||
B0 baseline B cell count, CL clearance, conc. concentration, EC50 concentration producing 50% of maximum drug effect, Emax maximum drug effect, F bioavailability, Gamma sigmoidicity parameter for drug effect in indirect model, IV intravenous, ka absorption rate constant, KD dissociation constant, kdes time rate constant on ksyn, ke(P) elimination rate constant for complex, koff dissociation rate constant, kout B cell elimination rate constant, ksyn synthesis rate constant, ksyn0 synthesis rate constant at time 0, ksyn∞ synthesis rate constant at time infinity, L liter, lwt70 log-transformed body weight normalized to 70 kg, NA not available, P drug–receptor complex, PD pharmacodynamic, PK pharmacokinetic, Q intercompartmental flow, QB flow between B cell compartments, R0 receptor amount at baseline, RSE relative standard error, SD standard deviation, Vb peripheral volume of distribution of B cells, Vc central volume of distribution, Vp peripheral volume of distribution of ofatumumab, β covariate effect