TABLE 3.
Summary of PAR drug-dependent parameters
| Parameter | Value | Methods/Reference |
|---|---|---|
| Molecular weight | 329.3 | Jornil et al., 2010 |
| Log Po:w | 3.55 | Martin et al., 2008 |
| pKa | 9.66 | Martin et al., 2008 |
| B/P ratio | 1.25 | Jornil et al., 2010 |
| fu,p | 0.05 | Kaye et al., 1989 |
| Fa | 0.94 | Predicteda |
| ka (h−1) | 1.14 | Predicteda |
| Fg | 0.92 | Predicted by Qgut model |
| Vss (l/kg) | 12.95 | Optimized b |
| CL2D6 EM (l/h) | 80.7 | Predictedc |
| CLr (l/h) | 0.5 | Sindrup et al., 1992a |
| Vmax (µl/min/pmol) | Jornil et al., 2010 | |
| Vmax,2D6 | 9,7 | |
| Vmax,3A4 | 5.3 | |
| Vmax,3A5 | 1.6 | |
| Vmax,1A2 | 0.63 | |
| Vmax,2C19 | 2.4 | |
| Km,unbound (µM) | Jornil et al., 2010 | |
| Km,2D6 | 0.03 | |
| Km,3A4 | 13.3 | |
| Km,3A5 | 108 | |
| Km,1A2 | 8.8 | |
| Km,2C9 | 26 | |
| CLint,other (µl/min/mg protein) | 55.2 | Optimizedd |
| Kinact (2D6) (min−1) | 0.17 | Bertelsen et al., 2003 |
| KI, unbound (2D6) (µM) | 0.315 | Bertelsen et al., 2003; Venkatakrishnan and Obach, 2005 |
| Kinact (3A4) (min−1) | 0.011 | Obach et al., 2007 |
| KI, unbound (3A4) (µM) | 4.03 | Obach et al., 2007 |
| fm at steady state (2D6 EM) (%) | Predicted via IVIVE e | |
| fm,2D6 | 79.9 | |
| fm,3A | 9.6 | |
| fm,other | 9.7 |
Qgut, hybrid parameter of blood flow and drug permeability; Vss, volume of distribution at steady state.
Predicted from Caco-2 permeability of 17*10−6 cm/s (Jornil et al., 2010) in Simcyp (version 11.1).
Vss was not reported in the literature. The predicted Vss according to Rodgers and Rowland (2007) is 7.5 l/kg. This value was further optimized to 12.95 l/kg by applying a global Kp scalar of 1.7, to improve prediction of Cmax. Reported Vd following i.v. infusion is 17.2 ± 9.9 l/kg (range 8.0–28.0) (Kaye et al., 1989).
Simcyp-predicted CL in CYP2D6 EM individuals via IVIVE is 80.7 ± 13.8 l/h (n = 100). Reported CL is 74.9 ± 14 l/h (range 63–91.7, n = 4) following 23–28 mg i.v. over 30 minutes (Kaye et al., 1989). The genotype of these subjects was not determined.
In CYP2D6 PM subjects, both single-dose and steady-state median CLoral were significantly underpredicted by a factor of 2.9 and 3.5, respectively, using the IVIVE approach (Jornil et al., 2010). To match single-dose and steady-state CLoral in P450 2D6 PMs, an un-identified pathway (CLint,other) was incorporated into the IVIVE model.
fm is dose- and time-dependent. Following 20 mg single-dose (n = 100 subjects), the predicted time-averaged mean fm is 94.3% (2D6), 2.8% (3A4), 0.1% (1A2), 0.1% (2C19), and 2.7% (unidentified CL), respectively, in EMs. Following 20 mg daily (n = 100 subjects), the predicted time-averaged mean fm at steady-state is 80% (2D6), 9.6% (3A4), 0.5% (1A2), 0.2% (2C19), and 9.7% (unidentified CL), respectively, in EMs. In CYP2D6 PMs, the predicted time-averaged mean fm is similar following 20 mg single-dose versus 20 mg daily: 48.5% (3A4), 2.6% (1A2), 1.1% (2C19), and 47.5% (unidentified CL) versus 46.9% (3A4), 2.7% (1A2), 1.1% (2C19), and 49.0% (unidentified CL).