Physiologically Based Pharmacokinetic Modeling of Rosuvastatin to Predict Transporter-Mediated Drug-Drug Interactions.

PURPOSE: To build a physiologically based pharmacokinetic (PBPK) model of the clinical OATP1B1/OATP1B3/BCRP victim drug rosuvastatin for the investigation and prediction of its transporter-mediated drug-drug interactions (DDIs). METHODS: The Rosuvastatin model was developed using the open-source PBPK software PK-Sim®, following a middle-out approach. 42 clinical studies (dosing range 0.002-80.0 mg), providing rosuvastatin plasma, urine and feces data, positron emission tomography (PET) measurements of tissue concentrations and 7 different rosuvastatin DDI studies with rifampicin, gemfibrozil and probenecid as the perpetrator drugs, were included to build and qualify the model. RESULTS: The carefully developed and thoroughly evaluated model adequately describes the analyzed clinical data, including blood, liver, feces and urine measurements. The processes implemented to describe the rosuvastatin pharmacokinetics and DDIs are active uptake by OATP2B1, OATP1B1/OATP1B3 and OAT3, active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUClast ratios (AUClast during DDI/AUClast without co-administration) and DDI Cmax ratios (Cmax during DDI/Cmax without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values. CONCLUSIONS: A whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3).

Effects of ABCG2 and SLCO1B1 gene variants on inflammation markers in patients with hypercholesterolemia and diabetes mellitus treated with rosuvastatin.

PURPOSE: Dysregulation of angiogenesis and inflammation play important roles in the development of atherosclerosis. Rosuvastatin (RST) was widely used in atherosclerosis therapy. Genetic variations of transporters may affect the rosuvastatin concentration in plasma and reflect different clinical treatment. The aim of this study was to explore the drug transport related single-nucleotide polymorphisms (SNPs) on RST pharmacokinetic and the further on pro-angiogenic and pro-inflammatory factors. METHODS: A total of 269 Chinese patients with hypercholesterolemia and diabetes mellitus were enrolled. They were treated with RST to lower cholesterol. The plasma concentration of RST was determined using a validated UPLC-MS/MS method. Seven single-nucleotide polymorphisms (SNPs) in six genes were genotyped using the Sanger dideoxy DNA sequencing method. The serum concentrations of inflammation markers were determined using ELISA kits. RESULTS: ABCG2 421C > A (rs2231142) and SLCO1B1 521 T > C (rs4149056) variations were highly associated with plasma concentrations of RST (P < 0.01, FDR < 0.05). The serum MCP-1, sVCAM-1, and TNF-α levels were significantly different between the ABCG2 421C > A and SLCO1B1 521 T > C genetic variation groups (P < 0.01). RST concentration was negatively correlated with sVCAM-1 concentration (r = 0.150, P = 0.008). CONCLUSION: ABCG2 421C > A (rs2231142) and SLCO1B1 521 T > C (rs4149056) genetic variants affect RST concentration significantly and potentially affect serum levels of pro-inflammatory and pro-angiogenic markers. The effects on anti-inflammation might not be related to high plasma exposure of RST.

Comprehensive Evaluation of the Utility of 20 Endogenous Molecules as Biomarkers of OATP1B Inhibition Compared with Rosuvastatin and Coproporphyrin I.

Endogenous biomarkers can be clinically relevant tools for the assessment of transporter function in vivo and corresponding drug-drug interactions (DDIs). The aim of this study was to perform systematic evaluation of plasma data obtained for 20 endogenous molecules in the same healthy subjects (n = 8-12) in the absence and presence of organic anion transporting polypeptide (OATP) inhibitor rifampicin (600 mg, single dose). The extent of rifampicin DDI magnitude [the ratio of the plasma concentration-time area under the curve (AUCR)], estimated fraction transported (fT), and baseline variability was compared across the biomarkers and relative to rosuvastatin and coproporphyrin I (CPI). Out of the 20 biomarkers investigated tetradecanedioate (TDA), hexadecanedioate (HDA), glycocholic acid, glycodeoxycholic acid (GDCA), taurodeoxycholic acid (TDCA), and coproporphyrin III (CPIII) showed the high AUCR (2.1-8.5) and fT (0.5-0.76) values, indicative of substantial OATP1B-mediated transport. A significant positive correlation was observed between the individual GDCA and TDCA AUCRs and the magnitude of rosuvastatin-rifampicin interaction. The CPI and CPIII AUCRs were significantly correlated, but no clear trend was established with the rosuvastatin AUCR. Moderate interindividual variability (15%-62%) in baseline exposure and AUCR was observed for TDA, HDA, and CPIII. In contrast, bile acids demonstrated high interindividual variability (69%-113%) and significant decreases in baseline plasma concentrations during the first 4 hours. This comprehensive analysis in the same individuals confirms that none of the biomarkers supersede CPI in the evaluation of OATP1B-mediated DDI risk. Monitoring of CPI and GDCA/TDCA may be beneficial for dual OATP1B/sodium-taurocholate cotransporting polypeptide inhibitors with consideration of challenges associated with large inter- and intraindividual variability observed for bile acids. Benefit of monitoring combined biomarkers (CPI, one bile acid and one fatty acid) needs to be confirmed with larger data sets and against multiple OATP1B clinical probes and perpetrators.

An African-specific profile of pharmacogene variants for rosuvastatin plasma variability: limited role for SLCO1B1 c.521T>C and ABCG2 c.421A>C.

Studies in Caucasian and Asian populations consistently associated interindividual and interethnic variability in rosuvastatin pharmacokinetics to the polymorphisms SLCO1B1 c.521T>C (rs4149056 p. Val174Ala) and ABCG2 c.421C>A (rs2231142, p. Gln141Lys). To investigate the pharmacogenetics of rosuvastatin in African populations, we first screened 785 individuals from nine ethnic African populations for the SLCO1B1 c.521C and ABCG2 c.421CA variants. This was followed by sequencing whole exomes from individuals of African Bantu descent, who participated in a 20 mg rosuvastatin pharmacokinetic trial in Harare Zimbabwe. Frequencies of SLCO1B1 c.521C ranged from 0.0% (San) to 7.0% (Maasai), while ABCG2 c.421A ranged from 0.0% (Shona) to 5.0% (Kikuyu). Variants showing significant association with rosuvastatin exposure were identified in SLCO1B1, ABCC2, SLC10A2, ABCB11, AHR, HNF4A, RXRA and FOXA3, and appear to be African specific. Interindividual differences in the pharmacokinetics of rosuvastatin in this African cohort cannot be explained by the polymorphisms SLCO1B1 c.521T>C and ABCG2 c.421C>A, but appear driven by a different set of variants.

Association between individual cholesterol and proteinuria response and exposure to atorvastatin or rosuvastatin.

AIM: The PLANET trials showed that atorvastatin 80 mg but not rosuvastatin at either 10 or 40 mg reduced urinary protein to creatinine ratio (UPCR) at similar effects on LDL-cholesterol. However, individual changes in both UPCR and LDL-cholesterol during treatment with these statins varied widely between patients. This inter-individual variability could not be explained by patients' physical or biochemical characteristics. We assessed whether the plasma concentrations of both statins were associated with LDL-cholesterol and UPCR response. MATERIALS AND METHODS: The PLANET trials randomized patients with a UPCR of 500-5000 mg/g and fasting LDL-cholesterol >2.33 mmol/L to a 52-week treatment with atorvastatin 80 mg, rosuvastatin 10 mg or 40 mg. For the current analysis, patients with available samples at week 52 and treatment compliance >80% by pill count were included (N = 295). The main outcome measurements were percentage change in UPCR and absolute change in LDL-cholesterol (delta LDL) from baseline to week 52. RESULTS: Median (interquartile range) plasma concentration at week 52 for atorvastatin 80 mg was 3.9 ng/mL (IQR: 2.1 to 8.7), for rosuvastatin 10 mg 1.0 ng/mL (IQR: 0.7 to 2.0) and for rosuvastatin 40 mg 3.5 ng/mL (IQR: 2.0 to 6.8). Higher plasma concentration of statin was associated with larger LDL-cholesterol reductions at week 52 [rosuvastatin r = -0.40 (P < .001); atorvastatin r = -0.28 (P = .006)]. The plasma concentration of both statins did not correlate with UPCR change [rosuvastatin r = 0.07 (P = .30); atorvastatin r = 0.16 (P = .13)]. CONCLUSIONS: Individual variation in plasma concentrations of rosuvastatin and atorvastatin was associated with LDL-cholesterol changes in patients. The individual variation in UPCR change was not associated with the plasma concentration of both statins.

Effects of SLCO1B1 and GATM gene variants on rosuvastatin-induced myopathy are unrelated to high plasma exposure of rosuvastatin and its metabolites.

Myotoxicity is a significant factor contributing to the poor adherence and reduced effectiveness in the treatment of statins. Genetic variations and high drug plasma exposure are considered as critique causes for statin-induced myopathy (SIM). This study aims to explore the sequential influences of rosuvastatin (RST) pharmacokinetic and myopathy-related single-nucleotide polymorphisms (SNPs) on the plasma exposure to RST and its metabolites: rosuvastatin lactone (RSTL) and N-desmethyl rosuvastatin (DM-RST), and further on RST-induced myopathy. A total of 758 Chinese patients with coronary artery disease were enrolled and followed up SIM incidents for 2 years. The plasma concentrations of RST and its metabolites were determined through a validated ultra-performance liquid chromatography mass spectrometry method. Nine SNPs in six genes were genotyped by using the Sequenom MassArray iPlex platform. Results revealed that ABCG2 rs2231142 variations were highly associated with the plasma concentrations of RST, RSTL, and DM-RST (Padj < 0.01, FDR < 0.05). CYP2C9 rs1057910 significantly affected the DM-RST concentration (Padj < 0.01, FDR < 0.05). SLCO1B1 rs4149056 variant allele was significantly associated with high SIM risk (OR: 1.741, 95% CI: 1.180-2.568, P = 0.0052, FDR = 0.0468). Glycine amidinotransferase (GATM) rs9806699 was marginally associated with SIM incidents (OR: 0.617, 95% CI: 0.406-0.939, P = 0.0240, FDR = 0.0960). The plasma concentrations of RST and its metabolites were not significantly different between the SIM (n = 51) and control groups (n = 707) (all P > 0.05). In conclusion, SLCO1B1 and GATM genetic variants are potential biomarkers for predicting RST-induced myopathy, and their effects on SIM are unrelated to the high plasma exposure of RST and its metabolites.

A simple, rapid and fully validated HPLC method for simultaneous quantitative bio-analysis of rosuvastatin and candesartan in rat plasma: Application to pharmacokinetic interaction study.

A simple, precise and accurate HPLC method was developed, optimized and validated for simultaneous determination of rosuvastatin and candesartan in rat plasma using atorvastatin as an internal standard. Solid-phase extraction was used for sample cleanup and its subsequent optimization was carried out to achieve higher extraction efficiency and to eliminate matrix effect. A quality by design approach was used, wherein three-level factorial design was applied for optimization of mobile phase composition and for assessing the effect of pH of the mobile phase using Design Expert Software. Adequate separation for both analytes was achieved with a Waters C18 column (250 × 4.6 mm, 5 µm) using acetonitrile-5 mm sodium acetate buffer (70:30, v/v; pH adjusted to 3.5 with acetic acid) as a mobile phase at a flow rate of 1.0 mL/min and wavelength of 254 nm. The calibration curves were linear over the concentration ranges 5-150 and 10-300 ng/mL for rosuvastatin (ROS) and candesartan (CAN), respectively. The validated method was successfully applied to a pharmacokinetic study in Wistar rats and the data did not reveal any evidence for a potential drug-drug interaction between ROS and CAN. This information provides evidence for clinical rational use of ROS and CAN.

Rosuvastatin pharmacokinetics in Pakistani healthy volunteers in comparison with other population.

In current study, the pharmacokinetics (PK) of rosuvastatin were evaluated in Pakistani healthy volunteers and compared with those reported in other population. This was a randomized and open labeled clinical trial in which a single oral dose of 40 mg rosuvastatin was administered to the overnight fasted healthy volunteers. Plasma concentrations of rosuvastatin were quantified by a validated liquid chromatography-tandem mass spectrometry method. The PK parameters of rosuvastatin and its metabolite N-desmethyl-rosuvastatin were determined by PK specific software i.e., PK-Summit® (PK-Solutions). A total of 20 healthy volunteers having BMI in the normal ranges were included in this study. All PK parameters were represented as mean ± SD and 95% confidence intervals of the means have been calculated. The Cmax (29.07 ± 6.88 ng/mL), [AUC]xo (206.65 ± 55.27 ng/hr/mL) and CL/F (3275.26 ± 1072.87 mL/hr) were slightly higher in our study, whereas the values of Vd (19377.23 ± 9114.29 mL) and tmax (3.0 ± 0.46 hr) were comparatively smaller. Overall, the PK parameters of rosuvastatin determined in our study were in compliance with other reported. Therefore, no adjustments in the dosing schedule or dose are warranted.

Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters.

PURPOSE: Cefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters. METHODS: DDI potentials of cefiderocol as inhibitors were assessed in a clinical study consisting of 3 cohorts. Twelve or 13 healthy adult subjects per cohort orally received a single dose of furosemide 20 mg (for OAT1/3), metformin 1000 mg (for OCT1/2 and MATE2-K), or rosuvastatin 10 mg (for OATP1B3) with or without co-administration with cefiderocol 2 g every 8 h with 3-h infusion (a total of 3, 6, and 9 doses of cefiderocol with furosemide, metformin, and rosuvastatin, respectively). DDI potentials were assessed based on the pharmacokinetics of the substrates. RESULTS: Ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve were 1.00 (0.71-1.42) and 0.92 (0.73-1.16) for furosemide, 1.09 (0.92-1.28) and 1.03 (0.93-1.15) for metformin, and 1.28 (1.12-1.46) and 1.21 (1.08-1.35) for rosuvastatin, respectively. Exposures to furosemide or metformin did not change when co-administered with cefiderocol. Slight increase in rosuvastatin exposure was observed with co-administered with cefiderocol, which was not considered to be clinically significant. Each treatment was well tolerated. CONCLUSIONS: Cefiderocol has no clinically significant DDI potential via drug transporters.

Simultaneous quantitation of rosuvastatin and ezetimibe in human plasma by LC-MS/MS: Pharmacokinetic study of fixed-dose formulation and separate tablets.

A simple, high-throughput and highly sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method has been developed for the simultaneous estimation of rosuvastatin and free ezetimibe. Liquid-liquid extraction was carried out using methyl-tert butyl ether after prior acidification from 300 µL human plasma. The recovery for both the analytes and their deuterated internal standards (ISs) ranged from 95.7 to 99.8%. Rosuvastatin and ezetimibe were separated on Symmetry C18 column using acetonitrile and ammonium formate buffer, pH 3.5 (30:70, v/v) as the mobile phase. The analytes were well resolved with a resolution factor of 3.8. Detection and quantitation were performed under multiple reaction monitoring using ESI(+) for rosuvastatin (m/z 482.0 → 258.1) and ESI(-) for ezetimibe (m/z 407.9 → 271.1). A linear response function was established in the concentration ranges of 0.05-50.0 ng/mL and 0.01-10.0 ng/mL for rosuvastatin and ezetimibe, respectively, with correlation coefficient, r2 ≥ 0.9991. The IS-normalized matrix factors for the analytes ranged from 0.963 to 1.023. The developed method was successfully used to compare the pharmacokinetics of a fixed-dose combination tablet of rosuvastatin-ezetimibe and co-administered rosuvastatin and ezetimibe as separate tablets to 24 healthy subjects. The reliability of the assay was also assessed by reanalysis of 115 subject samples.

Magnetic nanoparticles modified with organic dendrimers containing methyl methacrylate and ethylene diamine for the microextraction of rosuvastatin.

Magnetic nanoparticles (MNPs) modified with organic dendrimers are shown to be a viable sorbent of the microextraction of the drug rosuvastatin (RST; also known as Crestor). The MNPs were prepared from iron(II) chloride and iron(III) chloride and then coated with silicon dioxide. The coated MNPs produced by this method have diameters ranging from 10 to 60 nm according to scanning electron microscopy. The MNPs were further modified with organic dendrimers containing methyl methacrylate and ethylene diamine. The resulting MNPs were characterized by SEM, Fourier transform infra-red and thermal gravimetry analysis. Then, the efficacy of the modified MNPs with respect to the extraction of RST was studied. The adsorption of RST by MNPs can be best described by a Langmuir isotherm. Following elution with buffer, RST was quantified by HPLC. The method was applied to the determination of RST in (spiked) human blood plasma, urine, and in tablets. RST extraction efficiencies are 54.5% in plasma, 86.6% from the drug matrix, and 94.3% in urine. The highest adsorption capacity of the RST by the MNPs adsorbent was 61 mg⋅g-1. Graphical abstract Co-precipitation was used to synthesize magnetic nanoparticles (MNPs). They were coated with a layer of SiO2 and then branched by organic dendrimers containing methyl methacrylate (MMA) and ethylene diamine (EDA). Rosuvastatin (RST) drug was trapped between dendrimer branches, therefore adsorption capacity of the drug was strongly increased.

Hydrophilic Interaction Liquid Chromatography-Electrospray Ionization Mass Spectrometry for Therapeutic Drug Monitoring of Metformin and Rosuvastatin in Human Plasma.

In this work a hydrophilic interaction liquid chromatography/positive ion electrospray mass spectrometric assay (HILIC/ESI-MS) has been developed and fully validated for the quantitation of metformin and rosuvastatin in human plasma. Sample preparation involved the use of 100 µL of human plasma, following protein precipitation and filtration. Metformin, rosuvastatin and 4-[2-(propylamino) ethyl] indoline 2 one hydrochloride (internal standard) were separated by using an X-Bridge-HILIC BEH analytical column (150.0 × 2.1 mm i.d., particle size 3.5 µm) with isocratic elution. A mobile phase consisting of 12% (v/v) 15 mM ammonium formate water solution in acetonitrile was used for the separation and pumped at a flow rate of 0.25 mL min−1. The linear range of the assay was 100 to 5000 ng mL−1 and 2 to 100 ng mL−1 for metformin and rosuvastatin, respectively. The current HILIC-ESI/MS method allows for the accurate and precise quantitation of metformin and rosuvastatin in human plasma with a simple sample preparation and a short a chromatographic run time (less than 15 min). Plasma samples from eight patients were further analysed proving the capability of the proposed method to support a wide range of clinical studies.

Inhibition of Intestinal OATP2B1 by the Calcium Receptor Antagonist Ronacaleret Results in a Significant Drug-Drug Interaction by Causing a 2-Fold Decrease in Exposure of Rosuvastatin.

Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC50 = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC50 = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.

Impact of curcumin on the pharmacokinetics of rosuvastatin in rats and dogs based on the conjugated metabolites.

1. Plasma concentrations of curcumin-O-glucuronide (COG) and curcumin-O-sulfate (COS) significantly increased after Sprague-Dawley rats dealt with the Oatp inhibitor rifampicin, with the Cmax ascending 2.9 and 6.7 times, and the AUC0-∞ ascending 4.4 and 10.8 times, respectively. When pretreated with the Oat inhibitor probenecid, the Cmax increased 4.4 and 20 times, and the AUC0-∞ increased 3.2 and 13.9 times, respectively. The results suggested that COG and COS may be the substrates of Oatp and Oat. 2. The accumulation of curcumin significantly increased in organic anion transporting polypeptide (OATP)- and organic anion transporter (OAT)-transfected human embryonic kidney (HEK) 293 systems, which suggested that curcumin was a substrate of OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT3; and COG was a substrate of OATP1B1, OATP1B3, and OAT3. 3. Inhibition study using rosuvastatin as the substrate in OATP1B1- and OATP1B3-transfected cells indicated that curcumin was an OATP1B1 and 1B3 inhibitor, with IC50 at 5.19 ± 0.05 and 3.68 ± 0.05 µM, respectively; the data for COG were 1.04 ± 0.01 and 1.08 ± 0.02 µM, respectively. COS was speculated to be an inhibitor of hepatic OATP1B1 as calculated using the ADMET Predictor. 4. COG and COS are substrates and inhibitors of OATP/Oatp. Co-administration of curcumin significantly increased rosuvastatin concentration in rat and dog plasma.

Pharmacokinetic and bioequivalence study comparing a candesartan cilexetil/rosuvastatin calcium fixed-dose combination with the concomitant administration of candesartan cilexetil and rosuvastatin calcium in healthy Korean subjects
.

CONTEXT: A fixed-dose combination (FDC) of candesartan and rosuvastatin was recently developed for the treatment of cardiovascular disease and expected to enhance patient compliance. OBJECTIVE: This study was performed to compare the single-dose pharmacokinetic properties and tolerability of DP-R208 (candesartan and rosuvastatin FDC) to those of each component administered alone in healthy Korean male volunteers. MATERIALS AND METHODS: A total of 40 healthy Korean volunteers were enrolled in this randomized, open-label, single-dose, two-treatment, two-way crossover study. During each treatment period, subjects received the test formulation (FDC tablet containing candesartan and rosuvastatin) or reference formulation (co-administration of candesartan and rosuvastatin). Plasma samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, and 48 hours post-dose. Safety and tolerability were assessed by the evaluation of adverse events (AEs), physical examinations, laboratory assessments, 12-lead electrocardiograms (ECGs), and vital sign measurements. RESULTS: The 90% confidence intervals (CIs) of the geometric least-square mean ratios of Cmax, AUClast, and AUCinf were 0.86 - 1.00, 0.92 - 1.04, and 0.92 - 1.03 for candesartan, and 0.88 - 1.06, 0.91 - 1.08, and 0.91 - 1.03 for rosuvastatin, respectively. All of the AEs were mild, and there was no significant difference in the incidence of AEs between the formulations. Furthermore, the pharmacokinetic properties of the test and reference formulations met the regulatory criteria for bioequivalence. Discussion and conclusion: Both formulations were safe and well tolerated, and no significant difference was observed in the safety assessments of the treatments.
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Population pharmacokinetics of rosuvastatin in pediatric patients with heterozygous familial hypercholesterolemia.

PURPOSE: Data from two clinical studies (hyperCholesterolaemia in cHildren and Adolescents taking Rosuvastatin OpeN label [CHARON; NCT01078675] and Study 4522IL/0086) were used to describe rosuvastatin pharmacokinetics in patients with heterozygous familial hypercholesterolemia aged ≥6 to <18 years. METHODS: Rosuvastatin concentration-time data were analyzed via non-linear mixed-effects modeling (NONMEM), with clearance (CL/F) as the pre-defined key pharmacokinetic parameter of interest. In addition, descriptive comparisons between pediatric patients and adults (healthy and dyslipidemic) were performed. The dataset included 214 pediatric patients, with 2,029 rosuvastatin concentrations. RESULTS: A linear two-compartment model with first-order absorption and elimination processes adequately described the combined dataset. Weight and gender were significant covariates for CL/F, with moderate between-patient variability remaining (coefficient of variation (CV) 40 %): CL/F in female children was approximately 30 % lower than in male children, and there was a twofold mean difference in CL/F across the observed weight range. Age was not a significant covariate after accounting for weight and gender differences. However, weight and gender only reduced between-patient variability from 45 (without covariates) to 40 % and are considered unlikely to be clinically relevant. CONCLUSIONS: Rosuvastatin pharmacokinetics appeared generally predictable with respect to dose, and time (study duration) and the exposure (dose-normalized area under the plasma concentration-time curve at steady state (AUCss)) in children and adolescents appeared to be similar or lower than adult patients with dyslipidemia.

No effects of pantoprazole on the pharmacokinetics of rosuvastatin in healthy subjects.

PURPOSE: Rosuvastatin disposition is modulated by the expression and activity of several membrane transporters including BCRP (ABCG2). The objective of our study was to investigate the effects of pantoprazole, a previously proposed BCRP inhibitor, on the disposition of rosuvastatin. METHODS: The impact of pantoprazole (40 mg ID for 2 days) on rosuvastatin pharmacokinetics was evaluated in healthy volunteers (n = 16) who received a single oral dose of rosuvastatin (10 mg) either alone or with pantoprazole. Rosuvastatin, N-desmethylrosuvastatin, and rosuvastatin lactone levels were quantified in plasma while rosuvastatin and N-desmethylrosuvastatin excretion were measured in urine. RESULTS: Ratios and 90 % standard confidence interval of geometric means for C max (1.03 [0.91-1.16]), AUC0-∞ (1.03 [0.89-1.19]) and renal clearance (0.96 [0.85-1.09]) were all within the pre-specified range of 0.8-1.25, indicating a lack of drug-drug interaction between pantoprazole and rosuvastatin. CONCLUSIONS: Concomitant administration of pantoprazole with rosuvastatin did not affect rosuvastatin plasma concentrations. The use of pantoprazole as a BCRP inhibitor should be revisited when characterizing BCRP-mediated transport in humans.

Telmisartan increases systemic exposure to rosuvastatin after single and multiple doses, and in vitro studies show telmisartan inhibits ABCG2-mediated transport of rosuvastatin.

PURPOSE: The ATP-binding cassette transporter G2 (ABCG2) plays an important role in the disposition of rosuvastatin. Telmisartan, a selective angiotension-II type 1 (AT1) receptor blocker, inhibits the transport capacity of ABCG2, which may result in drug interactions. This study investigated the pharmacokinetic interaction between rosuvastatin and telmisartan and the potential mechanism. METHODS: In this two-phase fixed-order design study, healthy subjects received single doses of 10 mg rosuvastatin at baseline and after telmisartan 40 mg daily for 14 days. Patients with hyperlipidaemia who had been taking rosuvastatin 10 mg daily for at least 4 weeks were given telmisartan 40 mg daily for 14 days together with rosuvastatin. Plasma concentrations of rosuvastatin were measured over 24 h before and after telmisartan administration. In vitro experiments using a bidirectional transport assay were performed to investigate the involvement of ABCG2 in the interaction. RESULTS: Co-administration of telmisartan significantly increased the maximum plasma concentration (C max) and the area under the plasma concentration-time curve (AUC) of rosuvastatin by 71 and 26 %, respectively. The T max values were reduced after administration of telmisartan. There was no significant difference in the interaction of rosuvastatin with telmisartan between healthy volunteers and patients receiving long-term rosuvastatin therapy or among subjects with the different ABCG2 421 C>A genotypes. The in vitro experiment demonstrated that telmisartan inhibited ABCG2-mediated efflux of rosuvastatin. CONCLUSION: This study demonstrated that telmisartan significantly increased the systemic exposure to rosuvastatin after single and multiple doses.

Evaluation of the usefulness of breast cancer resistance protein (BCRP) knockout mice and BCRP inhibitor-treated monkeys to estimate the clinical impact of BCRP modulation on the pharmacokinetics of BCRP substrates.

PURPOSE: To evaluate whether the impact of functional modulation of the breast cancer resistance protein (BCRP, ABCG2 421C>A) on human pharmacokinetics after oral administration is predictable using Bcrp knockout mice and cynomolgus monkeys pretreated with a BCRP inhibitor, elacridar. METHODS: The correlation of the changes of the area under the plasma concentration-time curve (AUC) caused by ABCG2 421C>A with those caused by the Bcrp knockout in mice, or BCRP inhibition in monkeys, was investigated using well-known BCRP substrates (rosuvastatin, pitavastatin, fluvastatin, and sulfasalazine). RESULTS: In mice, the bioavailability changes, which corrected the effect of systemic clearance by Bcrp knockout, correlated well with the AUC changes in humans, whereas the correlation was weak when AUC changes were directly compared. In monkeys, the AUC changes pretreated with elacridar resulted in a good estimation of those in humans within approximately 2-fold ranges. CONCLUSIONS: This study suggests that pharmacokinetics studies that use the correction of the bioavailability changes in Bcrp knockout mice are effective for estimating clinical AUC changes in ABCG2 421C>A variants for BCRP substrate drugs and those studies in monkeys that use a BCRP inhibitor serve for the assessment of BCRP impact on the gastrointestinal absorption in a non-rodent model.

Rosuvastatin pharmacokinetics and pharmacogenetics in Caucasian and Asian subjects residing in the United States.

PURPOSE: Systemic exposure to rosuvastatin in Asian subjects living in Japan or Singapore is approximately twice that observed in Caucasian subjects in Western countries or in Singapore. This study was conducted to determine whether pharmacokinetic differences exist among the most populous Asian subgroups and Caucasian subjects in the USA. METHOD: Rosuvastatin pharmacokinetics was studied in Chinese, Filipino, Asian-Indian, Korean, Vietnamese, Japanese and Caucasian subjects residing in California. Plasma concentrations of rosuvastatin and metabolites after a single 20-mg dose were determined by mass spectrometric detection. The influence of polymorphisms in SLCO1B1 (T521>C [Val174Ala] and A388>G [Asn130Asp]) and in ABCG2 (C421>A [Gln141Lys]) on exposure to rosuvastatin was also assessed. RESULTS: The average rosuvastatin area under the curve from time zero to time of last quantifiable concentration was between 64 and 84 % higher, and maximum drug concentration was between 70 and 98 % higher in East Asian subgroups compared with Caucasians. Data for Asian-Indians was intermediate to these two ethnic groups at 26 and 29 %, respectively. Similar increases in exposure to N-desmethyl rosuvastatin and rosuvastatin lactone were observed. Rosuvastatin exposure was higher in subjects carrying the SLCO1B1 521C allele compared with that in non-carriers of this allele. Similarly, exposure was higher in subjects carrying the ABCG2 421A allele compared with that in non-carriers. CONCLUSION: Plasma exposure to rosuvastatin and its metabolites was significantly higher in Asian populations residing in the USA compared with Caucasian subjects living in the same environment. This study suggests that polymorphisms in the SLCO1B1 and ABCG2 genes contribute to the variability in rosuvastatin exposure.