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Abstract
This study was to clarify population pharmacokinetics (PK) of sildenafil and its metabolite, N-desmethyl sildenafil (NDS) in Korean healthy male population using a pooled data from multiple clinical trials in consideration of inter-institution and inter-laboratory difference. A population PK analysis was performed with data of 243 healthy volunteers from five single-center (4 centers) comparative PK trials. The dataset included 7,376 sildenafil and NDS concentration (3,688 for each analyte) observed during 24 hours after the single dose of original sildenafil (either 50 mg or 100 mg of Viagra®). The plasma concentration was assayed in two laboratories. Various model structure was tested and the final model was evaluated using visual predictive checks. Demographic and clinical variables were assessed as potential covariates for PK parameters. A one-compartment first-order elimination model with proportional error was selected for the dispositional characteristics of sildenafil, and two-compartment model was chosen for NDS. Three transit compartments with Erlang-type absorption for fast absorption pathway and one compartment for slow absorption pathway constructed overall absorption model. The first-pass effect was rejected since it does not improve the model. The difference of NDS level by the bioanalysis laboratory was selected as the only covariate. Even though a direct comparison was difficult, the general trend in PK of sildenafil and NDS for Korean healthy male was considered similar to that of the other populations reported previously. It is recommended that the laboratory effect should be explored and evaluated when dataset is built using results from several laboratories.
References
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Figure 2.
Visual predictive check. Solid line: prediction median, Colored band: 90% prediction interval.
Table 1.
The five clinical trial protocols and their properties
Table 2.
Final sildenafil and NDS parameter estimates
| Parameters | Description | Estimates | % RSEa |
|---|---|---|---|
| Fixed effects | |||
| Ka,1 (h−1) | Rate constant of rapid absorption | 9.38 | 1.663 |
| Ka,2 (h−1) | Rate constant of slow absorption | 0.119 | 1.118 |
| CL/F (L/h) | Apparent clearance of sildenafil | 37.1 | 2.106 |
| V5/F (L) | Apparent volume of sildenafil central compartment | 174 | 1.644 |
| V6/F (L) | Apparent volume of NDS central compartment | 14.2 | 5.282 |
| K60 (h−1) | Elimination rate constant of NDS | 11.3 | 3.531 |
| V7/F (L) | Apparent volume of NDS peripheral compartment | 444 | 7.658 |
| QM/F (L/h) | Inter-compartmental clearance of NDS | 40.9 | 5.515 |
| LVF | Inter-laboratory variability factor on NDS concentration | –0.347 | –2.634 |
| Random effects | |||
| ωKa,1 | Between-subject variability of Ka,1 | 0.301 | 9.701 |
| ωKa,2 | Between-subject variability of Ka,2 | NE | – |
| ωCL/F | Between-subject variability of CL/F | 0.137 | 12.993 |
| ωV5/F | Between-subject variability of V5/F | 0.137 | 13.645 |
| ωV6/F | Between-subject variability of V6/F | 0.194 | 7.01 |
| ωk60 | Between-subject variability of K60 | NE | – |
| ωV7/F | Between-subject variability of V7/F | 0.0369 | 98.92 |
| ωQM/F | Between-subject variability of QM/F | 0.184 | 21.63 |
| Residual errorb | |||
| σadditive,1 | Additive error for sildenafil | NE | – |
| σprop,1 | Proportional error for sildenafil | 0.441 | – |
| σadditive,2 | Additive error for NDS | NE | – |
| σprop,2 | Proportional error for NDS | 0.515 | 1.464 |
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