Article Figures & Data
Figures
- Fig. 1.
Diagram of DDI in the liver (A) and the structures of PBPK models (B–D). (A) CER is transported into the liver by OATP1B1 and then metabolized by CYP2C8 and CYP3A4. Coadministration of CER and CsA, an inhibitor of OATP1B1 and CYP3A4 or GEM, inhibitors of OATP1B1 and CYP2C8 as GEM and its glucuronide (GEM-glu)) increases the AUC and Cmax of CER. (B–D) Structures of the PBPK models for CER (B), CsA (C), and GEM/GEM-glu (D). These models were based on previously reported models with some modifications (Yoshikado et al., 2016).
- Fig. 2.
Blood concentration-time profile of CER after single i.v. (0.1 mg) or p.o. (0.2 mg) administration. Fitting analysis was performed by CNM. Solid lines represent the fitted time course results using the 30 most optimized drug-dependent parameter sets selected to minimize the WSS from the observed intravenous and oral data after optimization of model parameters to explain the PK data under intravenous conditions. The closed circles represent the observed values (Mück et al., 1997). Optimized parameters are described in Table 1. Fixed pharmacokinetic parameters are described in Supplemental Table 1.
- Fig. 3.
Blood concentration-time profile of GEM/GEM-glu after single oral administration of GEM (600 mg). Fitting analysis was performed by the CNM. Solid lines represent the fitted time course results using the first to fifth most optimized drug-dependent parameter sets, which were selected to minimize the WSS from the observed PK data of GEM/GEM-glu. Closed circles represent the observed values (Honkalammi et al., 2011). Optimized parameters are described in Table 2. Fixed PK parameters are described in Supplemental Table 3.
- Fig. 4.
Simulated blood concentration-time profile of CER under control and DDI conditions using the best described in vitro parameter sets (Table 3) after the sensitivity analyses (Supplemental Figs. 4 and 5) of model parameters to explain PK data under DDI conditions. (A) Control and DDI with CsA after single oral administration of 0.2 mg CER (111 mg of CsA was orally administered twice daily for 6 days). The solid blue and red lines represent the simulated time course under control and DDI conditions, respectively. The open circles represent the observed values (Mück et al., 1999). (B) Control and DDI with GEM after single oral administration of 0.3 mg CER (600 mg of GEM was orally administered twice daily for 3 days). The solid blue and red lines represent the simulated time course under control and DDI conditions, respectively. The open circles represent the observed values (Backman et al., 2002).
Tables
- TABLE 1
Average, S.D., and coefficient of variant (CV%) of the 30 most optimized drug-dependent parameter sets of CER selected to minimize the WSS from the observed i.v. and p.o. data after the optimization of model parameters by CNM to explain the pharmacokinetic data under i.v. conditions
Parameters Units Initial Range Average S.D. CV% Vcentral L/kg 0.075–0.75 0.092 0.039 42.5 ka /h 0.06–6 3.249 1.274 39.2 ktransit /h 0.06–6 0.769 0.535 69.6 1/β 1.1–10 2.358 1.643 69.7 fb*CLint,all L/h/kg 0.0372–3.72 0.638 0.033 5.2 kbile /h 0.06–6 4.029 1.082 26.9 1/fbile 1.1–10 1.411 0.087 6.2 - TABLE 2
Optimized top five drug-dependent parameter sets of GEM/GEM-glu selected to minimize the weighted sum of squares (WSS) from the observed clinical data by Cluster Newton Method (CNM)
Parameters Units Initial Range 1st 2nd 3rd 4th 5th GEM Vcentral L/kg 0.075–0.75 0.077 0.075 0.077 0.089 0.076 ka /h 0.06–6 1.463 2.574 1.611 1.275 4.733 ktransit /h 0.06–6 3.645 2.872 2.378 6.585 1.488 fb*CLint,all L/hr/kg 0.0105–1.05 0.157 0.173 0.165 0.154 0.199 1/fglu 1.1–10 1.210 1.118 1.263 1.105 1.273 GEM-glu Vcentral L/kg 0.075–0.75 0.076 0.076 0.087 0.150 0.088 ka /h 0.06–6 0.258 0.109 0.106 0.155 0.142 Rdif 0.0275–0.11 0.051 0.103 0.064 0.079 0.096 1/β 1.1–10 5.727 2.119 6.318 14.039 2.779 fb*CLint,all L/hr/kg 0.0156–1.56 0.245 0.159 0.293 0.314 0.184 kbile /h 0.06–6 0.205 0.209 2.235 0.095 3.807 kdeconj /h 0.06–6 0.856 1.179 0.073 0.189 0.824 kf /h 0.06–6 0.938 1.414 0.906 0.067 2.466 WSS 1.202 1.319 1.514 1.521 1.586 Parameters Units Values Sources DDI conditions with CsA Ki_OATP1B1 of CsA µM 0.014 Supplemental Fig. 4A Ki_CYP3A4 of CsA µM 3.71 Supplemental Fig. 4B FaFg of CER 0.791 (control)/1 (DDI) Supplemental Fig. 4C ka of CER /h 0.789 (control)/2.5 (DDI) Supplemental Fig. 4D fm_CYP2C8 of CER 0.85 Supplemental Fig. 5D DDI conditions with GEM Ki_OATP1B1 of GEM µM 4.00 Supplemental Fig. 5A Ki_OATP1B1(glu)/Ki_OATP1B1(GEM) 0.371 Ratio of geometric mean of in vitro Ki (Supplemental Table 5) Ki_OATP1B1 of GEM-glu µM 1.48 Ki,app_CYP2C8 of GEM-glu µM 26.7 Supplemental Fig. 5B kinact_CYP2C8 of GEM-glu /h 4.05 Supplemental Fig. 5C fm_CYP2C8 of CER 0.85 Supplemental Fig. 5D CsA, cyclosporine A; DDI, drug-drug interactions; GEM, gemfibrozil.
Data Supplement
- Supplemental Data -
Supplemental Figure 1 - Fitted blood concentration-time profile of cyclosporine A (CsA)
Supplemental Figure 2 - Fitted blood concentration-time profile of cerivastatin (CER) under control conditions in the study of DDI with CsA (A) (0.2 mg CER was administered on day 6) or with gemfibrozil (GEM) (B) (0.3 mg CER was administered on day 3)
Supplemental Figure 3 - Simulated blood concentration-time profiles of CER under control and DDI conditions using the geometric mean of in vitro inhibition constants after the optimization of model parameters to explain PK
data under control conditions (Supplemental Table 5) (Kim et al., 2017)Supplemental Figure 4 - Sensitivity analyses of the in vitro parameters of CER and CsA under DDI conditions with CsA (multiple oral administration, 111 mg (fitted value, same as Supplemental Fig. 3(A)) twice a day for 6 days) after single oral administration of 0.2 mg CER on day 6
Supplemental Figure 5 - Sensitivity analyses of the in vitro parameters of CER and GEM/GEM-glu under DDI conditions with GEM (multiple oral administration, 600 mg twice a day for 3 days) after single oral administration of 0.3 mg CER on day 3
Supplemental Figure 6 - Simulated blood concentration-time profile of CER under control and DDI conditions with GEM (600 mg of GEM was orally administered twice a day for 3 days) using the best-fit in vitro parameter sets (Table
3) after the sensitivity analyses (Figs. 5 and 6) of model parameters to explain PK data under DDI conditionsSupplemental Figure 7 - Simulated blood concentration-time profiles of cerivastatin under control and DDI conditions with cyclosporine A in each liver model using the geometric mean of in vitro inhibition constants after the
optimization of model parameters to explain PK data under control conditions (Supplemental Table 5; Ki_OATP1B1 and Ki_CYP3A4 were 0.024 μM and 3.71 μM, respectively.)Supplemental Figure 8 - The results of PBPK analyses of CER in the model without EHC
Supplemental Table 1 - Pharmacokinetic parameters for cerivastatin (CER)
Supplemental Table 2 - Optimized parameter values of cyclosporine A (CsA) after the fitting analysis by Napp
Supplemental Table 3 - Pharmacokinetic parameters for gemfibrozil (GEM)/gemfibrozil 1-O-β-glucuronide (GEM-glu)
Supplemental Table 4 - A) Optimized parameters of CER in the DDI study with CsA under control conditions after the fitting analysis by Napp
Supplemental Table 5 - Summary of in vitro inhibition constants reported by Kim et al. (Kim et al., 2017)
Supplemental Table 6 - Average, SD and CV% of the 30 most-optimized drug-dependent parameter sets of CER
in 1- and 3-liver models selected to minimize the WSS from the observed i.v. and p.o. data after the optimization of model parameters by CNM to explain the PK data under i.v. conditionsSupplemental Table 7 - Optimized parameters of CER in the DDI study with CsA under control conditions after the fitting analysis by Napp
Supplemental Table 8 - Optimized parameters of CsA after the fitting analysis by Napp in 1- and 3-liver models
Supplemental Table 9 - Average, SD and CV% of the 30 most-optimized drug-dependent parameter sets of CER
in the model without EHC selected to minimize the WSS from the observed i.v. and p.o. data after the optimization of model parameters by CNM to explain the PK data under i.v. conditionsSupplemental Table 10 - Optimized parameters of CER in the DDI study with CsA under control conditions after the fitting analysis by Napp in the model without EHC
References
Model equations for cerivastatin (CER)
- Supplemental Data -
In this issue
PBPK Modeling Analysis of Complex DDIs of Cerivastatin
