Korean J Physiol Pharmacol.  2018 May;22(3):321-329. 10.4196/kjpp.2018.22.3.321.

Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans

• Bae SH
• Park WS
• Han S
• Park GJ
• Lee J
• Hong T
• Jeon S
• Yim DS

• KMID: 2410096
• DOI: http://doi.org/10.4196/kjpp.2018.22.3.321

Abstract

It was recently reported that the C(max) and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan-rosuvastatin case, simulated rosuvastatin C(maxI)/C(max) and AUC(I)/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the T(max) changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (C(maxI)/C(max): 2.01, AUCI/AUC:1.18, T(max): 5 h → 0.75 h). In the next case of cyclosporine-rosuvastatin, the simulated rosuvastatin C(maxI)/C(max) and AUC(I)/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CL(int,BCRP,intestine) of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin-telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin-cyclosporine interaction).

Keyword

Cyclosporine; Intestinal BCRP transporter; Physiologically-based pharmacokinetics; Rosuvastatin; Telmisartan

MeSH Terms

Area Under Curve
Cyclosporine
Drug Interactions*
Rosuvastatin Calcium*
Cyclosporine
Rosuvastatin Calcium

Figure

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  Fig. 1 Simulated and observed plasma telmisartan concentration–time profiles after a single and multiple (for 6 days) oral administration of 80 mg telmisartan.Solid line and dashed lines represent mean and 95th and 5th percentiles of simulated telmisartan concentrations and dots are observed data from references [83637] for a single and [33839] for multiple dosing, respectively.

• 

  Fig. 2 Simulated and observed plasma concentration–time profile of rosuvastatin after a single oral administration of 20 mg rosuvastatin.Simulated concentration profiles of 10 trials are represented by solid lines (mean) and dashed lines (95th and 5th percentiles). (A) Simcyp library model (based on Caucasian data), (B) our model modified using clinical (Korean) data listed in Table 3. Observed data are from references [332].

• 

  Fig. 3 Simulated and observed plasma concentration–time profiles of rosuvastatin in rosuvastatin–telmisartan study.Plasma concentrations of rosuvastatin (time after the last dose, 0–24 h) were simulated after 20 mg of rosuvastatin was orally coadministered with (black solid line) or without (blue solid line) 80 mg telmisartan for 6 days. The dashed lines represent the upper (95%) and lower (5%) percentile concentrations of rosuvastatin, respectively. Observed data are from references [332].

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  Fig. 4 Predicted enterocyte concentration of rosuvastatin in the jejunum I, a representative GI segment.

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  Fig. 5 Predicted hepatic unbound extracellular water concentration (CuEW, lower black lines) and hepatic unbound intracellular water concentration (CuIW, upper blue lines) of rosuvastatin (A) and sinusoidal uptake clearance of rosuvastatin (B).

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  Fig. 6 Simulated plasma concentration–time profiles of rosuvastatin in rosuvastatin–cyclosporine study (A) and simulated vs. observed whole blood exposures of cyclosporine (B).The dashed lines represent the upper (95%) and lower (5%) percentile concentrations of rosuvastatin (A) and cyclosporine (B). Dots are observed data from references [3435].

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