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Evaluation of the Effects of Repeat-Dose Dabrafenib on the Single-Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate).
Nebot, N, Won, CS, Moreno, V, Muñoz-Couselo, E, Lee, DY, Gasal, E, Bouillaud, E
Clinical pharmacology in drug development. 2021;(9):1054-1063
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Abstract
Dabrafenib is an oral BRAF kinase inhibitor approved for the treatment of various BRAF V600 mutation-positive solid tumors. In vitro observations suggesting cytochrome P450 (CYP) 3A induction and organic anion transporting polypeptide (OATP) inhibition prompted us to evaluate the effect of dabrafenib 150 mg twice daily on the pharmacokinetics of midazolam 3 mg (CYP3A substrate) and rosuvastatin 10 mg (OATP1B1/1B3 substrate) in a clinical phase 1, open-label, fixed-sequence study in patients with BRAF V600 mutation-positive tumors. Repeat dabrafenib dosing resulted in a 2.56-fold increase in rosuvastatin maximum observed concentration (Cmax ), an earlier time to Cmax , but only a 7% increase in area under the concentration-time curve from time 0 (predose) extrapolated to infinite time. Midazolam Cmax and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to Cmax . No new safety findings were reported. Exposure of drugs that are CYP3A4 substrates is likely to decrease when coadministered with dabrafenib. Concentrations of medicinal products that are sensitive OATP1B1/1B3 substrates may increase during the absorption phase.
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Effect of Upadacitinib on the Pharmacokinetics of Rosuvastatin or Atorvastatin in Healthy Subjects.
Mohamed, MF, Coppola, S, Feng, T, Camp, HS, Kim, E, Othman, AA
Clinical pharmacology in drug development. 2021;(11):1335-1344
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Abstract
This phase 1, 2-part, 2-period, open-label, drug-drug interaction study evaluated the potential for pharmacokinetic interactions between upadacitinib and rosuvastatin, an organic anion transporting polypeptide (OATP) 1B1 and breast cancer resistance protein substrate, or atorvastatin, a cytochrome P450 3A, OATP1B1, and OATP1B3 substrate, in 36 healthy volunteers. During period 1, a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered on day 1, followed by a washout period of 5 days. During period 2, once-daily doses of upadacitinib extended-release (30 mg) were administered on days 1 to 10, and a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered 1 hour after the upadacitinib dose on day 7. Serial blood samples were collected for assays of drug concentrations. In Part 1, rosuvastatin maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity (AUCinf ) were 23% and 33% lower, respectively, when administered with upadacitinib relative to when administered alone. In part 2, atorvastatin Cmax and AUCinf was 11% and 23% lower, respectively, when administered with upadacitinib relative to when administered alone. The Cmax and AUCinf of the active metabolite ortho-hydroxyatorvastatin remained unchanged. Administration of a single 5-mg dose of rosuvastatin or a single 10-mg dose of atorvastatin had no relevant effect on upadacitinib Cmax or area under the plasma concentration-time curve. These results demonstrated that upadacitinib has no clinically relevant effect on the pharmacokinetics of rosuvastatin and atorvastatin or on substrates transported by OATP1B or breast cancer resistance protein.
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A randomized, double-blind clinical trial to evaluate the efficacy and safety of a fixed-dose combination of amlodipine/rosuvastatin in patients with dyslipidemia and hypertension.
Kim, W, Chang, K, Cho, EJ, Ahn, JC, Yu, CW, Cho, KI, Kim, YJ, Kang, DH, Kim, SY, Lee, SH, et al
Journal of clinical hypertension (Greenwich, Conn.). 2020;(2):261-269
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Abstract
This multicenter, randomized, double-blind, parallel-group phase III clinical trial aimed to investigate the efficacy and safety of a rosuvastatin + amlodipine combination compared with that of rosuvastatin or amlodipine monotherapy in hypertensive patients with dyslipidemia. A total of 106 patients of 15 institutions in Korea were randomly assigned to 1 of 3 treatment groups: rosuvastatin 20 mg + amlodipine 10 mg, amlodipine 10 mg, or rosuvastatin 20 mg. After 8 weeks of treatment, the mean ± SD of change in mean sitting systolic blood pressure (msSBP) was -22.82 ± 12.99 mm Hg in the rosuvastatin + amlodipine group, the most decreased among the treatment groups. The percentage of patients whose msSBP decreased ≥20 mm Hg or msDBP decreased ≥10 mm Hg was also highest in this group (74.29%). The mean ± SD percentage change in low-density lipoprotein cholesterol (LDL-C) level from baseline after 8 weeks was -52.53% ± 11.21% in the rosuvastatin + amlodipine group, the most decreased among the treatment groups. More patients in the rosuvastatin + amlodipine group achieved their target LDL-C goal at 8 weeks, compared with the other treatment groups (97.14%). No serious adverse events or adverse drug reactions were observed in all groups. In hypertensive patients with dyslipidemia, combination treatment with rosuvastatin 20 mg + amlodipine 10 mg effectively reduced blood pressure and LDL-C levels while maintaining safety.
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Positron Emission Tomography Imaging of [11 C]Rosuvastatin Hepatic Concentrations and Hepatobiliary Transport in Humans in the Absence and Presence of Cyclosporin A.
Billington, S, Shoner, S, Lee, S, Clark-Snustad, K, Pennington, M, Lewis, D, Muzi, M, Rene, S, Lee, J, Nguyen, TB, et al
Clinical pharmacology and therapeutics. 2019;(5):1056-1066
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Abstract
Using positron emission tomography imaging, we determined the hepatic concentrations and hepatobiliary transport of [11 C]rosuvastatin (RSV; i.v. injection) in the absence (n = 6) and presence (n = 4 of 6) of cyclosporin A (CsA; i.v. infusion) following a therapeutic dose of unlabeled RSV (5 mg, p.o.) in healthy human volunteers. The sinusoidal uptake, sinusoidal efflux, and biliary efflux clearance (CL; mL/minute) of [11 C]RSV, estimated through compartment modeling were 1,205.6 ± 384.8, 16.2 ± 11.2, and 5.1 ± 1.8, respectively (n = 6). CsA (blood concentration: 2.77 ± 0.24 μM), an organic-anion-transporting polypeptide, Na+ -taurocholate cotransporting polypeptide, and breast cancer resistance protein inhibitor increased [11 C]RSV systemic blood exposure (45%; P < 0.05), reduced its biliary efflux CL (52%; P < 0.05) and hepatic uptake (25%; P > 0.05) but did not affect its distribution into the kidneys. CsA increased plasma concentrations of coproporphyrin I and III and total bilirubin by 297 ± 69%, 384 ± 102%, and 81 ± 39%, respectively (P < 0.05). These data can be used in the future to verify predictions of hepatic concentrations and hepatobiliary transport of RSV.
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Evaluation of Clinically Relevant Drug-Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial.
Shore, N, Zurth, C, Fricke, R, Gieschen, H, Graudenz, K, Koskinen, M, Ploeger, B, Moss, J, Prien, O, Borghesi, G, et al
Targeted oncology. 2019;(5):527-539
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Abstract
BACKGROUND Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metastasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug-drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential-other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected. OBJECTIVE Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC. PATIENTS AND METHODS Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted. RESULTS Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one comedication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of comedications with DDI potential, no significant effects on darolutamide pharmacokinetics were identified. Comedications included lipid-modifying agents (34.5%), β-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses. CONCLUSIONS These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614.
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Effect of Rosuvastatin on Cholesterol Efflux Capacity and Endothelial Function in Type 2 Diabetes Mellitus and Dyslipidemia.
Jung, KY, Kim, KM, Han, SK, Yun, HM, Oh, TJ, Choi, SH, Park, KS, Jang, HC, Lim, S
Circulation journal : official journal of the Japanese Circulation Society. 2018;(5):1387-1395
Abstract
BACKGROUND Quality and quantity of high-density lipoprotein cholesterol (HDL-C) may be associated with cardiovascular risk. We investigated the effect of rosuvastatin on cholesterol efflux (CE) for HDL function and vascular health.Methods and Results:We enrolled 30 dyslipidemic patients with type 2 diabetes mellitus and 20 healthy subjects as controls. Vascular health was assessed on flow-medicated dilation (FMD), nitroglycerin-induced dilatation of the brachial artery and carotid artery intima-media thickness (cIMT). These parameters were compared between patients and controls, and between baseline and at 12 weeks of treatment with rosuvastatin 20 mg. Age and body mass index were 49.8±11.3 years and 25.8±3.7 kg/m2in the patients, and 28.8±3.2 years and 22.4±2.4 kg/m2in the controls, respectively. The biomarkers related to lipid and glucose metabolism and lipoprotein (a), high-sensitivity C-reactive protein, and cIMT were significantly higher, and CE and FMD were significantly lower in the patients than in the controls. In the patients, rosuvastatin 20 mg decreased low-density lipoprotein cholesterol by 54.1% and increased HDL-C by 4.8%. The CE increased significantly after rosuvastatin treatment (12.26±2.72% vs. 14.05±4.14%). FMD also increased, and lipoprotein (a) and cIMT decreased significantly and were associated with changes of CE. CONCLUSIONS Rosuvastatin-induced changes in HDL function are significantly associated with cardiovascular benefit.
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A Phase III, Multicenter, Randomized, Double-blind, Active Comparator Clinical Trial to Compare the Efficacy and Safety of Combination Therapy With Ezetimibe and Rosuvastatin Versus Rosuvastatin Monotherapy in Patients With Hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial.
Hong, SJ, Jeong, HS, Ahn, JC, Cha, DH, Won, KH, Kim, W, Cho, SK, Kim, SY, Yoo, BS, Sung, KC, et al
Clinical therapeutics. 2018;(2):226-241.e4
Abstract
PURPOSE Combination therapy with ezetimibe and statins is recommended in cases of statin intolerance or insufficiency. The objective of this study was to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus those of rosuvastatin monotherapy in patients with hypercholesterolemia. METHODS I-ROSETTE (Ildong ROSuvastatin & ezETimibe for hypercholesTElolemia) was an 8-week, double-blind, multicenter, Phase III randomized controlled trial conducted at 20 hospitals in the Republic of Korea. Patients with hypercholesterolemia who required medical treatment according to National Cholesterol Education Program Adult Treatment Panel III guidelines were eligible for participation in the study. Patients were randomly assigned to receive ezetimibe 10 mg/rosuvastatin 20 mg, ezetimibe 10 mg/rosuvastatin 10 mg, ezetimibe 10 mg/rosuvastatin 5 mg, rosuvastatin 20 mg, rosuvastatin 10 mg, or rosuvastatin 5 mg in a 1:1:1:1:1:1 ratio. The primary end point was the difference in the mean percent change from baseline in LDL-C level after 8 weeks of treatment between the ezetimibe/rosuvastatin and rosuvastatin treatment groups. All patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. FINDINGS Of 396 patients, 389 with efficacy data were analyzed. Baseline characteristics among 6 groups were similar. After 8 weeks of double-blind treatment, the percent changes in adjusted mean LDL-C levels at week 8 compared with baseline values were -57.0% (2.1%) and -44.4% (2.1%) in the total ezetimibe/rosuvastatin and total rosuvastatin groups, respectively (P < 0.001). The LDL-C-lowering efficacy of each of the ezetimibe/rosuvastatin combinations was superior to that of each of the respective doses of rosuvastatin. The mean percent change in LDL-C level in all ezetimibe/rosuvastatin combination groups was >50%. The number of patients who achieved target LDL-C levels at week 8 was significantly greater in the ezetimibe/rosuvastatin group (180 [92.3%] of 195 patients) than in the rosuvastatin monotherapy group (155 [79.9%] of 194 patients) (P < 0.001). There were no significant differences in the incidence of overall AEs, adverse drug reactions, and serious AEs; laboratory findings, including liver function test results and creatinine kinase levels, were comparable between groups. IMPLICATIONS Fixed-dose combinations of ezetimibe/rosuvastatin significantly improved lipid profiles in patients with hypercholesterolemia compared with rosuvastatin monotherapy. All groups treated with rosuvastatin and ezetimibe reported a decrease in mean LDL-C level >50%. The safety and tolerability of ezetimibe/rosuvastatin therapy were comparable with those of rosuvastatin monotherapy. ClinicalTrials.gov identifier: NCT02749994.
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Low YKL-40 in chronic heart failure may predict beneficial effects of statins: analysis from the controlled rosuvastatin multinational trial in heart failure (CORONA).
Arain, F, Gullestad, L, Nymo, S, Kjekshus, J, Cleland, JG, Michelsen, A, McMurray, JJ, Wikstrand, J, Aukrust, P, Ueland, T
Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals. 2017;(3-4):261-267
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CONTEXT AND OBJECTIVE To evaluate if YKL-40 can provide prognostic information in patients with ischemic heart failure (HF) and identify patients who may benefit from statin therapy. MATERIALS AND METHODS The association between serum YKL-40 and predefined outcome was evaluated in 1344 HF patients assigned to rosuvastatin or placebo. RESULTS YKL-40 was not associated with outcome in adjusted analysis. In YKL-40 tertile 1, an effect on the primary outcome (HR 0.50, p = 0.006) and CV death (HR 0.54, p = 0.040) was seen by rosuvastatin in adjusted analysis. CONCLUSIONS A beneficial modification of outcome was observed with statin therapy in patients with low YKL-40 levels.
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Rosuvastatin Pharmacokinetics in Asian and White Subjects Wild Type for Both OATP1B1 and BCRP Under Control and Inhibited Conditions.
Wu, HF, Hristeva, N, Chang, J, Liang, X, Li, R, Frassetto, L, Benet, LZ
Journal of pharmaceutical sciences. 2017;(9):2751-2757
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The Food and Drug Administration recommends rosuvastatin dosage reductions in Asian patients because pharmacokinetic studies have demonstrated an approximate 2-fold increase in median exposure to rosuvastatin in Asian subjects compared with Caucasian controls. Yet, no explanation for this ethnic difference has been confirmed. Here we show that rosuvastatin exposure in Asians and Whites does not differ significantly when all subjects are wild-type carriers for both solute carrier organic anion transporter 1B1 *1a and ATP-binding cassette subfamily G member 2 c.421 transporters in a 2-arm, randomized, cross-over rosuvastatin pharmacokinetics study in healthy white and Asian volunteers. For single rosuvastatin doses, AUC0-48 were 92.5 (±36.2) and 83.5 (±32.2) ng/mL × h and Cmax were 10.0 (±4.1) and 7.6 (±3.0) ng/mL for Asians and Whites, respectively. When transporters were inhibited by intravenous rifampin, rosuvastatin AUC0-48 and Cmax also showed no ethnic differences. Our study suggests that both SLCO1B1 and ABCG2 polymorphisms are better predictors of rosuvastatin exposure than ethnicity alone and could be considered in precision medicine dosing of rosuvastatin.
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Sustained Improvement of Arterial Stiffness and Blood Pressure after Long-Term Rosuvastatin Treatment in Patients with Inflammatory Joint Diseases: Results from the RORA-AS Study.
Ikdahl, E, Rollefstad, S, Hisdal, J, Olsen, IC, Pedersen, TR, Kvien, TK, Semb, AG
PloS one. 2016;(4):e0153440
Abstract
OBJECTIVE Patients with inflammatory joint diseases (IJD) have a high prevalence of hypertension and increased arterial stiffness. The aim of the present study was to evaluate the effect of long-term rosuvastatin treatment on arterial stiffness, measured by augmentation index (AIx) and aortic pulse wave velocity (aPWV), and blood pressure (BP) in IJD patients with established atherosclerosis. METHODS Eighty-nine statin naïve IJD patients with carotid atherosclerotic plaque(s) (rheumatoid arthritis n = 55, ankylosing spondylitis n = 23, psoriatic arthritis n = 11) received rosuvastatin for 18 months to achieve low-density lipoprotein cholesterol goal ≤1.8 mmol/L. Change in AIx (ΔAIx), aPWV (ΔaPWV), systolic BP (ΔsBP) and diastolic BP (ΔdBP) from baseline to study end was assessed by paired samples t-tests. Linear regression was applied to evaluate associations between cardiovascular disease (CVD) risk factors, rheumatic disease specific variables and medication, and ΔAIx, ΔaPWV, ΔsBP and ΔdBP. RESULTS AIx, aPWV, sBP and dBP were significantly reduced from baseline to study end. The mean (95%CI) changes were: ΔAIx: -0.34 (-0.03, -0.65)% (p = 0.03), ΔaPWV: -1.69 (-0.21, -3.17) m/s2 (p = 0.03), ΔsBP: -5.27 (-1.61, -8.93) mmHg (p = 0.004) and ΔdBP -2.93 (-0.86, -5.00) mmHg (p = 0.01). In linear regression models, ∆aPWV was significantly correlated with ΔsBP and ΔdBP (for all: p<0.001). CONCLUSIONS There is an unmet need of studies evaluating CVD prevention in IJD patients. We have shown for the first time that long-term intensive lipid lowering with rosuvastatin improved arterial stiffness and induced a clinically significant BP reduction in patients with IJD. These improvements were linearly correlated and may represent novel insight into the pleiotropic effects by statins. TRIAL REGISTRATION ClinicalTrials.gov NCT01389388.