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Abstract
The Cmax and AUC of rosuvastatin increase when it is coadministered with telmisartan. The aim of this study was to explore which of the pharmacokinetic (PK) parameters of rosuvastatin are changed by telmisartan to cause such an interaction. We used data from drug–drug interaction (DDI) studies of 74 healthy volunteers performed in three different institutions. Rosuvastatin population PK models with or without telmisartan were developed using NONMEM (version 7.3). The plasma concentration–time profile of rosuvastatin was best described by a two-compartment, first-order elimination model with simultaneous Erlang and zero-order absorption when given rosuvastatin alone. When telmisartan was coadministered, the zero-order absorption fraction of rosuvastatin had to be omitted from the model because the absorption was dramatically accelerated. Notwithstanding the accelerated absorption, the relative bioavailability (BA) parameter estimate in the model demonstrated that the telmisartan-induced increase in BA was only about 20% and the clearance was not influenced by telmisartan at all in the final PK model. Thus, our model implies that telmisartan may influence the absorption process of rosuvastatin rather than its metabolic elimination. This may be used as a clue for further physiologically based PK (PBPK) approaches to investigate the mechanism of rosuvastatin–telmisartan DDI.
References
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Figure 2.
Mean plasma concentration-time profiles of rosuvastatin following oral administration of rosuvastatin 20 mg alone (R) or rosuvastatin 20 mg with telmisartan 80 mg (R+T) per institution (A, B, C). Linear and semilogarithmic scales shown on left and right panels, respectively.
Figure 3.
Rosuvastatin PK models. INST, institutional difference (fixed as 1 for institutiona A); Frel, relative bioavailability of rosuvastatin with telmisartan (fixed as 1 for without telmisartan group); Fr1, fraction of the dose absorbed through the Erlang absorption (fixed as 1 for with telmisartan group); D2, duration of zero-order absorption (fixed as 0 for with telmisartan); Ka1, absorption rate constant without telmisartan; Ka2, absorption rate constant with telmisartan; CL/F, apparent clearance; Vc/F, apparent volume of central compartment; Q/F, apparent intercompartmental clearance; Vp/F, apparent volume of peripheral compartment.
Figure 4.
Basic goodness-of-fit plots of the final model. The grey solid y = x or y = 0 lines are included for reference. The bold blue lines are the loess (local regression smoother) trend lines.
Figure 5.
Visual predictive check for the final model by each institution (Institution A, B and C) and treatment group (R; rosuvastatin alone, R+T; rosuvastatin with telmisartan). The circles show the observed rosuvastatin concentrations. The solid and dashed lines show median and 90% prediction intervals of simulation, respectively.
Table 3.
Summary of final population PK parameter estimates
| Parameter | Description | Estimate | % RSEa | Bootstrap median (95% CI)b |
|---|---|---|---|---|
| Structural model | ||||
| CL/F (L/h) | Apparent clearance | 106 | 11.5 | 103 (88.2–111) |
| Vc/F (L) | Apparent volume of central compartment | 426 | 14.8 | 404 (339–449) |
| Q/F (L/h) | Apparent intercompartmental clearance | 48.2 | 13.0 | 47.8 (38.8–54.8) |
| Vp/F (L) | Apparent volume of peripheral compartment | 829 | 16.6 | 778 (634–969) |
| Without Telmisartan | ||||
| Ka1 (h−1) | Absorption rate constant of Erlang absorption without telmisartan | 0.910 | 11.8 | 0.912 (0.815–0.974) |
| Fr1 | Fraction absorbed by Erlang absorption | 0.197 | 20.7 | 0.200 (0.160–0.238) |
| D2 (h) | Duration of dosing for zero-order absorption | 3.56 | 4.8 | 3.56 (3.41–3.75) |
| With Telmisartan | ||||
| Ka2 (h−1) | Absorption rate constant of Erlang absorption with telmisartan | 9.77 | 8.0 | 9.82 (8.61–11.2) |
| Frel | Relative bioavailability of rosuvastatin with telmisartan when that without telmisartan assumed to be 1 | 1.30 | 4.3 | 1.29 (1.23–1.37) |
| Inter-study difference (INST) | ||||
| Inst_A | Fixed study difference of Inst_A | 1.0 (Fixed) | – | – |
| Inst_B | Fixed study difference of Inst_B compared to Inst_A | 1.58 | 9.1 | 1.54 (1.19–1.96) |
| Inst_C | Fixed study difference of Inst_C compared to Inst_A | 1.48 | 9.6 | 1.44 (1.15–1.87) |
| Inter-individual variability | ||||
| ωCL/F (%) | Interindividual variability of CL/F | 43.3 | 13.1 | 40.9 (34.6–46.7) |
| ωVc/F (%) | Interindividual variability of Vc/F | 64.8 | 11.7 | 58.7 (49.3–66.3) |
| ωVp/F (%) | Interindividual variability of Vp/F | 67.1 | 16.0 | 61.1 (49.0–73.3) |
| ωQ/F (%) | Interindividual variability of Q/F | 60.6 | 11.9 | 54.0 (41.7–68.3) |
| ωka1 (%) | Interindividual variability of Ka1 | 19.7 | 38.6 | 19.8 (0.40–40.6) |
| ωka2 (%) | Interindividual variability of Ka2 | 49.0 | 14.5 | 45.8 (37.7–53.9) |
| ωFrel (%) | Interindividual variability of Frel | 22.0 | 13.1 | 21.7 (16.7–25.0) |
| ρCL/F∼Vc/F | Correlation coefficient between CL/F and Vc/F | 0.920 | 12.9 | 0.919 (0.874–0.952) |
| ρCL/F∼Vp/F | Correlation coefficient between CL/F and Vp/F | 0.941 | 14.2 | 0.945 (0.880–0.999) |
| ρVc/F∼Vp/F | Correlation coefficient between Vc/F and Vp/F | 0.971 | 12.7 | 0.973 (0.900–1.000) |
| Residual error | ||||
| σadd (ng/mL) | Additive error | 0.292 | 19.6 | 0.289 (0.103–0.406) |
| σprop | Proportional error | 0.202 | 1.8 | 0.201 (0.190–0.217) |
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