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).

Proteomics-Informed Prediction of Rosuvastatin Plasma Profiles in Patients With a Wide Range of Body Weight.

Rosuvastatin is a frequently used probe to study transporter-mediated hepatic uptake. Pharmacokinetic models have therefore been developed to predict transporter impact on rosuvastatin disposition in vivo. However, the interindividual differences in transporter concentrations were not considered in these models, and the predicted transporter impact was compared with historical in vivo data. In this study, we investigated the influence of interindividual transporter concentrations on the hepatic uptake clearance of rosuvastatin in 54 patients covering a wide range of body weight. The 54 patients were given an oral dose of rosuvastatin the day before undergoing gastric bypass or cholecystectomy, and pharmacokinetic (PK) parameters were established from each patient's individual time-concentration profiles. Liver biopsies were sampled from each patient and their individual hepatic transporter concentrations were quantified. We combined the transporter concentrations with in vitro uptake kinetics determined in HEK293-transfected cells, and developed a semimechanistic model with a bottom-up approach to predict the plasma concentration profiles of the single dose of rosuvastatin in each patient. The predicted PK parameters were evaluated against the measured in vivo plasma PKs from the same 54 patients. The developed model predicted the rosuvastatin PKs within two-fold error for rosuvastatin area under the plasma concentration versus time curve (AUC; 78% of the patients; average fold error (AFE): 0.96), peak plasma concentration (Cmax ; 76%; AFE: 1.05), and terminal half-life (t1/2 ; 98%; AFE: 0.89), and captured differences in the rosuvastatin PKs in patients with the OATP1B1 521T

Cholesterol (Blood lipid) lowering potential of Rosuvastatin chitosan nanoparticles for atherosclerosis: Preclinical study in rabbit model.

Atherosclerosis is the condition of narrowing of arteries due to plaque buildup on the artery walls. Aortic valve calcification (AVC) is one of the reasons of atherosclerosis which leads to narrowing at the opening of the aortic valve which is commonly referred as Aortic valve stenosis (AS). The Rosuvastatin-chitosan (ROS-chitosan) nanoparticles were prepared using ionotropic gelation method. Nanoparticulate formulation was optimized by 3 factor, 2 level full factorial design to find the effect of independent variables on particle size and percentage encapsulation efficiency. Particle size, encapsulation efficiency, scanning electron microscopy, in vitro drug release of nanoparticles was determined. The adult male rabbit of 4-5 months old were chosen for the study. Hypercholesterolemia was induced in experimental animals by administering diet with Cholesterol and Cholic acid (1.25 % and 0.5% respectively.) Blood lipid profile, interleukin 6 levels and histopathological study was performed. Rosuvastatin was found to be significantly effective in lowering the blood lipid levels. It helps to attenuate atherosclerosis as well as calcification of various valve tissues in experimental animals.

Effects of Multiple-Dose Administration of Aprocitentan on the Pharmacokinetics of Rosuvastatin.

Aprocitentan is an investigational, orally active, dual, endothelin receptor antagonist that targets a novel pathway in the treatment of difficult-to-control (resistant) hypertension. The drug-drug interaction potential of aprocitentan on the breast cancer resistance protein (BCRP) transporter substrate rosuvastatin was investigated in this single-center, open-label, single-sequence study. Twenty healthy male subjects received a single dose of 10-mg rosuvastatin on days 1 and 13 followed by pharmacokinetic and tolerability assessments for up to 120 hours. From day 5 to day 17, subjects received 25 mg of aprocitentan once daily. Seventeen of 20 enrolled subjects completed the treatment. At steady state, aprocitentan did not affect the pharmacokinetics of rosuvastatin in a clinically relevant way. The maximum plasma concentration was increased by 40% with a 90% confidence interval of 1.19 to 1.65. However, the ratio of the geometric means for both area under the plasma concentration-time curve from time 0 to time t and area under the plasma concentration-time curve from time 0 to infinity was close to 1 with the 90% confidence interval within a reference interval of 0.80 to 1.25. Adverse events leading to study discontinuation were reported in 2 subjects. Overall, the combination of rosuvastatin and aprocitentan was well tolerated. Based on these data, aprocitentan does not affect BCRP and can be administered concomitantly with drugs dependent on BCRP transport.

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.

Scutellarin inhibition of the rosuvastatin uptake in rat hepatocytes and the competition for organic anion transporting polypeptide 1B1 in HEK293T cells.

In this report, we investigated the hepatocytic uptake of rosuvastatin when administered with scutellarin (a Chinese herbal medicine) in rats and the role of organic anion transporting polypeptide 1B1 (OATP1B1) plays in the uptake. Forty-eight rats were randomly divided into two groups according to the medicine administered: rosuvastatin alone and rosuvastatin in combination with a series concentration of scutellarin. Rosuvastatin concentrations in blood and liver were measured using the liquid chromatography-tandem mass spectrometry (LC-MS) method. The uptake was also measured in rat primary hepatocytes and OATP1B1 transfected human embryonic kidney 293 T (HEK293T) cells. The uptake was investigated under the optimal intake conditions. The rosuvastatin Cmax and AUC0-∞ in rat plasma increased 55% and 61%, respectively in the combination treatment group; and the liver scutellarin concentrations decreased 32%, 34%, and 33% at 1 h, 2 h, and 6 h, respectively. All scutellarin dosages (20, 50, and 100 µM) inhibited the uptake of rosuvastatin in rat primary hepatocytes (4.71%, 22.73%, and 45.89%). Scutellarin of 10 µM significantly inhibited the in vitro uptake of rosuvastatin in OATP1B1-HEK293T cells (P < 0.05), with an IC50 of 60.53 ± 5.74 µM. Scutellarin increases the plasma concentration of rosuvastatin and inhibits the uptake in rat primary hepatocytes and OATP1B1-HEK293T cells, suggesting a drug interaction between scutellarin and rosuvastatin and OATP1B1 as a potential mechanism.

Statin reload before off-pump coronary artery bypass graft: Effect on biomarker release kinetics.

Objectives: Statins confer protection from ischemia/reperfusion through various pathways including pleiotropic mechanisms. Following chronic administration, activation of intrinsic cellular mechanisms causes attenuation of these pleiotropic effects. Methods: Since coronary artery bypass surgery (CABG) represents a reversible ischemia-reperfusion sequence, we assessed if statin reload is effective in patients undergoing off-pump CABG (n = 100) in limiting myocardial injury. Patients received loading dose of rosuvastatin (40 mg initiated 7 days before surgery) while nonloaded patients continued whatever statin dose they were receiving and served as controls. Cardiac biomarkers (Troponin-I, creatine kinase muscle/brain [CK-MB], and B-type natriuretic peptide [BNP]) were measured at 8, 24, and 48 h postoperatively. The primary end-point was the extent of perioperative myocardial injury (area under the curve [AUC]: AUC of each biomarker). Results: Despite similar baseline levels, all biomarkers at 8, 24, and 48 h were significantly lower in the loaded group. The AUC for each biomarker was also significantly lower in the loaded group (cTnI 37.96 vs. 70.12 ng. hr/ml, CK-MB 229.64 vs. 347.04 ng. hr/ml, and BNP 5257.56 vs. 15606.68 pg. hr/ml, all P < 0.001). Delta cTnI (change from baseline to peak level) (1.00 ± 1.34 vs. 2.25 ± 2.59), delta CK-MB (4.54 ± 5.89 vs. 10.68 ± 9.95), and delta BNP (120.41 ± 172.48 vs. 449.23 ± 790.95) all P < 0.001 were also significantly lower in the loaded group. Those loaded with rosuvastatin had lower inotrope duration (22.9 ± 23.33 vs. 31.26 ± 25.39 h, P = 0.04) and ventilator support time (16.94 ± 6.78 vs. 23.8 ± 20.53 h, P = 0.03). Conclusion: In patients undergoing off-pump CABG, statin reload can "recapture" cardioprotection in patients already on statins with favorable effect on release kinetics of biomarkers and postoperative outcomes.

Effects of Food and Gender on Pharmacokinetics of Rosuvastatin in a Chinese Population Based on 4 Bioequivalence Studies.

The effects of food and gender on the pharmacokinetics of rosuvastatin in healthy Chinese subjects were investigated from 4 bioequivalence studies. These studies were designed as randomized, open-label, and 2-period crossover in both fasting and fed states. A total of 204 subjects were enrolled, 134 men and 70 women. These subjects received a single oral 10-mg dose of rosuvastatin with a 7-day washout between 2 periods. The plasma concentrations were determined using a validated liquid chromatography tandem mass spectrometry method, and pharmacokinetic parameters were calculated by noncompartmental methods. Compared with the fasting condition, administration after a high-fat and high-calorie meal resulted in an approximately 40% reduction of rosuvastatin exposure and a near 50% decrease in absorption rate. Moreover, the apparent clearance was significantly greater in the fed state than that in the fasting state. It was noted that the adverse events incidence is increased by approximately 30% in the fasting state; however, no serious adverse events were observed. Additionally, small differences in pharmacokinetic characteristics were found between male and female subjects. Food effect might be considered for optimal effectiveness and safety of rosuvastatin therapy.

Influence of OATP1B1 and BCRP polymorphisms on the pharmacokinetics and pharmacodynamics of rosuvastatin in elderly and young Korean subjects.

A lack of information regarding whether genetic polymorphisms of SLCO1B1 and ABCG2 affect the pharmacokinetics (PKs)/pharmacodynamics (PDs) of rosuvastatin in elderly subjects prevents optimal individualized pharmacotherapy of rosuvastatin in clinical settings. This study aimed to investigate the effect of age and genetic polymorphisms and possible differences in genetic effects on the PKs/PDs of rosuvastatin between elderly and young subjects. Two separate clinical studies designed as open-label, one-sequence studies with multiple-dose administration for elderly (n = 20) and young (n = 32) subjects were conducted. All subjects received 20 mg of rosuvastatin once daily for 21 days. The exposure to rosuvastatin, characterized by the area under the time curve (AUC), increased by 23% in the elderly subjects compared with that of young subjects, which was not significant. When compared to the subjects with breast cancer resistance protein (BCRP) normal function, the exposure to rosuvastatin increased by 44% in young subjects (p = 0.0021) with BCRP intermediate function (IF) and by 35% and 59% (p > 0.05 for both) in elderly subjects with BCRP IF and low function, respectively. SLCO1B1 521T > C was also partially associated with a higher AUC of rosuvastatin in young subjects and a less pronounced increasing trend in elderly subjects (p > 0.05 for both). The lipid-lowering effect of rosuvastatin was less pronounced in the elderly subjects than in the young subjects, and genetic polymorphisms of neither SLCO1B1 nor ABCG2 significantly affected the PDs of rosuvastatin. The ABCG2 421C > A polymorphism was associated with the PKs of rosuvastatin and was identified as a more important determinant than the SLCO1B1 521T > C polymorphism in both elderly and young subjects.

Pharmacokinetic interactions between telmisartan/amlodipine and rosuvastatin after multiple oral administrations in healthy Korean male subjects.

PURPOSE: Hypertension and dyslipidemia are major risk factors for cardiovascular diseases, and reduction of cardiovascular risks can be achieved by combining antihypertensive therapy with statins. The objective of this study was to evaluate the pharmacokinetic interaction between telmisartan/amlodipine fixed dose combination and rosuvastatin in healthy Korean male volunteers. PATIENTS AND METHODS: An open-label, two-cohort, multiple-dose, single-sequence crossover study was conducted in healthy male subjects. In Cohort 1, the subjects were administered one tablet of telmisartan/amlodipine 80 mg/5 mg once daily for 14 days with or without one tablet of rosuvastatin 20 mg once daily. In Cohort 2, the subjects were administered one tablet of rosuvastatin 20 mg once daily for 14 days with or without one tablet of telmisartan/amlodipine 80 mg/5 mg once daily. Serial blood samples were collected up to 24 hrs post-dose on the 9th and 14th days in Cohort 1 and on the 5th and 14th days in Cohort 2. Plasma drug concentrations were measured by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration versus time curve over dosing interval (AUCτ,ss), were determined by non-compartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% confidence intervals (CIs) of log-transformed Cmax,ss and AUCτ,ss for separate or concurrent therapy were calculated to evaluate pharmacokinetic interactions. RESULTS: Thirty-eight subjects from Cohort 1 and nineteen subjects from Cohort 2 completed the study. The GLSM ratios and 90% CIs of Cmax,ss and AUCτ,ss, were 0.9829 (0.8334-1.1590) and 1.0003 (0.9342-1.0710) for telmisartan; 0.9908 (0.9602-1.0223) and 1.0081 (0.9758-1.0413) for amlodipine; and 2.2762 (2.0113-2.5758) and 1.3261 (1.2385-1.4198) for rosuvastatin, respectively. CONCLUSION: The pharmacokinetic parameters of telmisartan/amlodipine, but not rosuvastatin, met the pharmacokinetic equivalent criteria. The increase in systemic exposure to rosuvastatin caused by telmisartan/amlodipine co-administration would not be clinically significant in practice. Nevertheless, an appropriately designed two-sequence crossover study is needed to confirm the results of this study.

UHPLC-MS/MS assay for simultaneous determination of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin with its active metabolites in human plasma, for population-scale drug-drug interactions studies in people living with HIV.

Thanks to highly active antiretroviral treatments, HIV infection is now considered as a chronic condition. Consequently, people living with HIV (PLWH) live longer and encounter more age-related chronic co-morbidities, notably cardiovascular diseases, leading to polypharmacy. As the management of drug-drug interactions (DDIs) constitutes a key aspect of the care of PLWH, the magnitude of pharmacokinetic DDIs between cardiovascular and anti-HIV drugs needs to be more thoroughly characterized. To that endeavour, an UHPLC-MS/MS bioanalytical method has been developed for the simultaneous determination in human plasma of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin and its active metabolites. Plasma samples were subjected to protein precipitation with methanol, followed by evaporation at room temperature under nitrogen of the supernatant, allowing to attain measurable plasma concentrations down to sub-nanogram per milliliter levels. Stable isotope-labelled analytes were used as internal standards. The five drugs and two metabolites were analyzed using a 6-min liquid chromatographic run coupled to electrospray triple quadrupole mass spectrometry detection. The method was validated over the clinically relevant concentrations ranging from 0.3 to 480 ng/mL for amlodipine, atorvastatin and p-OH-atorvastatin, and 0.4 to 480 ng/mL for pravastatin, 0.5 to 480 ng/mL for rosuvastatin and o-OH-atorvastatin, and 3 to 4800 ng/mL for metoprolol. Validation performances such as trueness (95.4-110.8%), repeatability (1.5-13.4%) and intermediate precision (3.6-14.5%) were in agreement with current international recommendations. Accuracy profiles (total error approach) were lying within the limits of ±30% accepted in bioanalysis. This rapid and robust UHPLC-MS/MS assay allows the simultaneous quantification in plasma of the major currently used cardiovascular drugs and offers an efficient analytical tool for clinical pharmacokinetics as well as DDIs studies.

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.

Defining the process parameters affecting the fabrication of rosuvastatin calcium nanoparticles by planetary ball mill.

PURPOSE: Rosuvastatin calcium (ROSCa) nanoparticles were fabricated by planetary ball mill to enhance ROSCa dissolution rate and bioavailability. METHODS: Milling time factors (milling cycle time and number as well as pause time) were explored. The effect of different milling ball size, speed, and solid-to-solvent ratio were also studied using Box-Behnken factorial design. The fabricated nanoparticles were evaluated in term of physicochemical properties and long-term stability. RESULTS: The obtained data revealed that the integrated formulation and process factors should be monitored to obtain desirable nanoparticle attributes in terms of particle size, zeta potential, dissolution rate, and bioavailability. The optimized ROSCa nanoparticles prepared by milling technique showed a significant enhancement in the dissolution rate by 1.3-fold and the plasma concentration increased by 2-fold (P<0.05). Moreover, stability study showed that the optimized formula of ROSCa nanoparticles exhibits higher stability in long-term stability conditions at 30°C with humidity of 60%. CONCLUSION: Formulation of ROSCa as nanoparticles using milling technique showed a significant enhancement in both dissolution rate and plasma concentration as well as stability compared with untreated drug.

An LC-MS/MS spectrometry method for the simultaneous determination of Rosuvastatin and Irbesartan in rat plasma: Insight into pharmacokinetic and drug-drug interaction studies.

The synergistic vascular protective effect of statins and angiotensin receptor blockers (ARBs) is well known, however, the pharmacokinetic interaction among these classes is yet to be understood and the necessity of developing analytical methods for their determination in vivo is gradually increased. Herein, first chromatographic separation coupled tandem mass spectrometric was developed and fully validated for simultaneous measurement of rosuvastatin (ROS) and irbesartan (IRB) in rat plasma after oral administration. The two analytes were extracted from plasma sample using acetonitrile-induced protein precipitation then separated on an Agilent Eclipse Plus ODS (4.6 × 100 mm, 3.5 µm) column by gradient elution using 6 mM ammonium formate/0.1% formic acid and ACN at a flow rate 0.4 mL min-1. Multiple reaction monitoring in positive ion mode was used for quantification of precursor to production at m/z 492.1 → 206.9 for IRB, 482.1 → 258.1 for ROS, and 409.2 → 238.2 for the internal standard, amlodipine (AML). Linearity was obeyed in the range of 1-10000 ng mL-1 and 1-5000 ng mL-1 with detection limits (S/N of 3) of 0.05 and 0.07 ng mL-1 for IRB and ROS, respectively. The current method was validated in terms of selectivity, recovery, accuracy, precision, matrix effects, and stability as per US-FDA bioanalytical guidelines. The application of our method reported her is the first to study pharmacokinetic interaction of IRB and ROS in rat plasma after a single oral dose. The area under the concentration-time curve (AUC), peak plasma concentrations (Cmax), half-life time (t1/2), and volume of distribution (Vd) of ROS and IRB were affected when the two drugs were co-administering. The current study provided a valuable tool for studying drug-drug interaction and might be useful for therapeutic drug monitoring and bioequivalence studies.

No Effect of Digoxin on Rosuvastatin Pharmacokinetics in Healthy Subjects: Utility of Oita Combination for Clinical Drug-Drug Interaction Study.

This study evaluated the utility of combination of digoxin (0.25 mg) and rosuvastatin (5 mg) as a new transporter (P-glycoprotein/breast cancer resistance protein/organic anion-transporting polypeptide (OATP)1B1/OATP1B3) probe cocktail (Oita combination) for drug-drug interaction (DDI) studies by demonstrating lack of DDI of digoxin on the pharmacokinetics (PKs) of rosuvastatin, as it was already known that rosuvastatin did not affect digoxin PK. This was an open-label, two-period study in which the primary end points were the geometric mean ratio (GMR) of the area under the plasma rosuvastatin concentration-time curve from time zero to last (AUClast ) after rosuvastatin administration combined with digoxin to that after rosuvastatin administration alone and its 90% confidence interval (CI). As the GMR of AUClast was 0.974 and its 90% CI was 0.911-1.042, it was judged that digoxin does not affect rosuvastatin PK. Results of this study have rationalized utility of the Oita combination as a transporter probe cocktail for clinical DDI studies.

Pharmacokinetic comparison of a fixed-dose combination versus concomitant administration of amlodipine, olmesartan, and rosuvastatin in healthy adult subjects.

Objective: The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of a fixed dose combination (FDC) formulation and co-administration of amlodipine, olmesartan, and rosuvastatin. Materials and methods: This study was an open-label, randomized, cross-over design conducted in healthy male volunteers. All subjects received either a single FDC tablet containing amlodipine 10 mg/olmesartan 40 mg/rosuvastatin 20 mg, or were co-administered an FDC tablet containing amlodipine 10 mg/olmesartan 40 mg and a tablet containing rosuvastatin 20 mg, for each period, with 14-day washout periods. Plasma concentrations of amlodipine, olmesartan, and rosuvastatin were measured by liquid chromatography tandem mass spectrometry. Safety was evaluated by measuring vital signs, clinical laboratory parameters, physical examinations, and medical interviews. Results: Sixty-four subjects were enrolled, and 54 completed the study. The geometric mean ratios and 90% CI for the maximum plasma concentration (Cmax) and area under the curve from time zero to the last sampling time (AUCt) were 1.0716 (1.0369,1.1074) and 1.0497 (1.0243,1.0757) for amlodipine, 1.0396 (0.9818,1.1009) and 1.0138 (0.9716,1.0578) for olmesartan, and 1.0257 (0.9433,1.1152) and 1.0043 (0.9453,1.0669) for rosuvastatin. Fourteen cases of adverse events occurred in 12 subjects. There was no statistically significant clinical difference between the formulation groups. Conclusion: The 90% CI of the primary PK parameters were within the acceptance bioequivalence criteria, which is ln (0.8) and ln (1.25). These results indicate that the FDC formulation and co-administration of amlodipine, olmesartan and rosuvastatin are pharmacokinetically bioequivalent and have similar safety profiles.

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.

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.

A Fixed-Dose Combination Of Gemigliptin And Rosuvastatin Exhibits Similar Pharmacokinetics, Pharmacodynamics, And Safety Compared To That Of A Loose Combination In Healthy Subjects.

PURPOSE: Fixed-dose combination (FDC) of gemigliptin and rosuvastatin may improve medication compliance of patients with comorbid type 2 diabetes and dyslipidemia. Pharmacokinetics (PK), pharmacodynamics (PD), and safety of gemigliptin/rosuvastatin 50/20 mg FDC was compared with a loose combination of individual tablets in healthy subjects. PATIENTS AND METHODS: A randomized, open-label, single-dose, two-period, two-sequence, two-treatment crossover study was conducted. Subjects received FDC or a loose combination of gemigliptin (50 mg) and rosuvastatin (20 mg) during each period, with a 14-day washout. Serial blood samples were collected up to 72 hrs after dosing to measure plasma concentrations of gemigliptin, its active metabolite LC15-0636, and rosuvastatin for PK assessment, and DPP-4 activity for PD assessment. PK and PD parameters were calculated using a non-compartmental method. Safety profiles were evaluated throughout the study. RESULTS: Thirty-seven subjects completed the study. The concentration-time profiles of gemigliptin, LC15-0636, and rosuvastatin were similar between FDC and loose combination, respectively. For each of the three compounds, the geometric mean ratios (90% confidence interval) of FDC to loose combination for Cmax and AUClast fell within the bioequivalence range of 0.8-1.25. Inhibition of DPP-4 activity-time profiles after administration of FDC and loose combination was overlapping, and Imax and AUEClast were similar. Both FDC and the loose combination were well tolerated. CONCLUSION: PK, PD, and safety profiles of gemigliptin, its metabolite, and rosuvastatin were similar between FDC and loose combination. The FDC of gemigliptin (50 mg) and rosuvastatin (20 mg) can be used as an alternative to a loose combination, which is expected to improve patient compliance.

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.