Table 3.
Parameters of the ’classical’ four-compartment pharmacokinetic-pharmacodynamic (PK-PD) model for the urine and serum PK of ibandronate and uCTX response to i.v. administration of ibandronate
| Estimate | BSV (CV %) | RSE (CV %) | |
|---|---|---|---|
| PK parameters | |||
| V1 (l) | 4.30 | 17 | 4 |
| CL (l day−1) | 57.00 | 20 | 5 |
| V2 (l) | 2.80 | – | 4 |
| Q2 (l day−1) | 69.43 | – | 13 |
| V3 (l) | 8.70 | – | 5 |
| Q3 (l day−1) | 18.57 | Small | 5 |
| V4 (l) | 609.00 | – | 9 |
| Q4 (l day−1) | 51.71 | 3 | 4 |
| PD parameters | |||
| KS (µg mmolCR−1 day−1) | 231.43 | 84 | 10 |
| IC50 (µg l−1) | 0.37 | 40 | 8 |
| uCTXss (ug mmolCR−1) | 339 | 34 | 5 |
| Rtar (µg mmolCR−1 day−1) | 194.29 | – | 15 |
| kqq (1 day−1) | 0.0024 | 475 | 39 |
| Hill coefficient | 1.92 | — | 9 |
| Derived parameters | |||
| KS at 26 weeks (µg mmolCR−1 day−1) | 218.00 | ||
| uCTX at 26 weeks (µg mmolCR−1) | 319 | ||
| kqq half-life (weeks) | 40 | ||
| KD (1 day−1) | 0.68 | ||
| kqq (1 day−1) | 0.0024 | ||
| Residual error | |||
| Plasma ibandronate concentration (% CV) | 16 | ||
| Urine ibandronate amount (% CV) | 44 | ||
| uCTX concentration (% CV) | 27 | ||
| NONMEM objective function | −2221 |
BSV, Between-subject variability; CV, coefficient of variation; RSE, relative standard error; V1-V4, volumes of PK distributional compartments 1-4, respectively; Q2-Q4, intercompartmental clearance between compartment 1 and the PK distributional compartments 2-4, respectively; KS, synthesis rate (uCTX); uCTXss, steady-state uCTX concentration; KD, degradation rate constant (uCTX); IC50, ibandronate concentration in ’bone’ compartment producing half maximum inhibition of uCTX formation; CL, renal clearance of ibandronate; HILL, shape factor; uCTX, urinary CTX; Rtar, limit value for uCTX formation rate (T→); kqq, rate constant by which Rtar is attained.