A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects

Drug Design, Development and Therapy, Mar 2015

A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects Jin Ah Jung,1 Soo-Yun Lee,2 Jung-Ryul Kim,1 Jae-Wook Ko,1,2 Seong Bok Jang,3 Su Youn Nam,3 Wooseong Huh1,41Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, 2Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, 3Yuhan Research Institute, Yuhan Corporation, 4Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, KoreaPurpose: Valsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects. Subjects and methods: Thirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment.Results: For rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873-0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632-0.9701) for area under the concentration–time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946-1.0884) and 1.0072 (0.8893-1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events.Conclusion: The pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their individual pharmacokinetics were not affected by their coadministration. No dose adjustment was required and the results are supportive of a study in a larger patient population.Keywords: pharmacokinetics, pharmacodynamics, hypertension, dyslipidemia

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A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects

Drug Design, Development and Therapy a pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects Jung-ryul Kim 2 3 Jae-Wook Ko 1 2 3 0 Yuhan r esearch institute, Yuhan corporation 1 Department of health sciences and Technology, s amsung a dvanced institute for health sciences and Technology, sungkyunkwan University 2 Wooseong huh 3 Department of clinical Pharmacology and Therapeutics, s amsung Medical center 4 Department of internal Medicine, samsung Medical center, s ungkyunkwan University s chool of Medicine , seoul , Korea 8 1 0 2 - l u J - 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s e r p e v o .dw l.y from rsoe PowerdbyTCPDF(ww.tcpdf.org) soo-Yun lee 2 seong Bok Jang 3 su Youn n am3 Purpose: Valsartan, an angiotensin-receptor blocker, and rosuvastatin, a competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are frequently coadministered to treat patients with hypertension and dyslipidemia. The study reported here sought to evaluate the pharmacokinetic and pharmacodynamic interactions between rosuvastatin and valsartan in healthy Korean subjects. Subjects and methods: Thirty healthy male Korean subjects were administered with rosuvastatin (20 mg/day), valsartan (160 mg/day), and both drugs concomitantly for 4 days in a randomized, open-label, multiple-dose, three-treatment, three-period crossover study. Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and valsartan were determined using validated high-performance liquid chromatography with tandem mass spectrometry. Lipid profiles and vital signs (systolic and diastolic blood pressure and pulse rate) were measured for the pharmacodynamic assessment. Results: For rosuvastatin, the geometric mean ratios (90% confidence intervals [CIs]) of coadministration to mono-administration were 0.8809 (0.7873−0.9857) for maximum plasma concentration at steady state and 0.9151 (0.8632−0.9701) for area under the concentration-time curve (AUC) over a dosing interval at steady state. For valsartan, the geometric mean ratios (90% CIs) of those were 0.9300 (0.7946−1.0884) and 1.0072 (0.8893−1.1406), respectively. There were no significant differences in the metabolic ratio of N-desmethyl rosuvastatin AUC to rosuvastatin AUC between coadministration and rosuvastatin alone. No interaction was found in terms of systolic or diastolic blood pressure or lipid profiles. Combined treatment with valsartan and rosuvastatin was generally well tolerated without serious adverse events. Conclusion: The pharmacokinetic profiles of rosuvastatin and valsartan in combination were comparable with those of rosuvastatin and valsartan administered individually, suggesting that their individual pharmacokinetics were not affected by their coadministration. No dose adjustment was required and the results are supportive of a study in a larger patient population. pharmacokinetics; pharmacodynamics; hypertension; dyslipidemia - deda ropF open access to scientific and medical research O r i g i n a l r e s e a r c h Introduction Valsartan is one of the most commonly prescribed angiotensin II type 1 receptor blockers (ARBs) for the management of hypertension. Valsartan lowers blood pressure (BP) by antagonizing the renin–angiotensin–aldosterone system and competes with angiotensin II for interaction with the angiotensin II type 1 receptor, lowering BP by increasing the effects of angiotensin II. Valsartan is administered at a starting dose of 80 mg or 160 mg once daily and is titrated to a higher dose of 320 mg daily as required.1 Following oral administration, peak plasma concentrations of valsartan are reached in 2–4 hours and mean absolute oral bioavailability of valsartan is 23%.2 Valsartan is primarily eliminated largely unchanged by biliary excretion in feces and renally in the urine, and exhibits dose-linear pharmacokinetics within the clinical dosing range. Valsartan exhibits little accumulation in plasma following repeated administrations (accumulation ratio of 1.2 in healthy subjects),2 and its pharmacokinetics do not to 081 differ significantly between males and females and dosage l-2u adjustments based on age are not necessary.3 -J31 Rosuvastatin is a competitive inhibitor of 3-hydroxy-3no methylglutaryl coenzyme A (HMG-CoA) reductase, a rate.702 limiting enzyme that converts HMG-CoA to mevalonate (a .946 precursor for cholesterol), and is used in the treatment of .735 hyperlipidemia and mixed dyslipidemia.4 The usual starting /yb dose of rosuvastatin is 10–20 mg once daily, adjusted to com 40 mg in accordance with lipid levels.5 Peak plasma concen.sse trations of rosuvastatin are reached approximately 3–5 hours .rvpeodw l.y farfotemr oarpaplraodxmi minaistetrlaytio1n3 atnod2t1heheoluimrsi.n6aRtioosnuhvaalsft-alitfien riasngneost /ww no metabolized extensively and is primarily excreted in the feces :/ttsp lseu (90%). Little accumulation of rosuvastatin was observed after h na repeated, once-daily dosing; the accumulation ratio was 1.05 from rsoe in healthy subjects and 1.37 in patients with end-stage renal deda ropF disease on dialysis.7 No effect of age, sex, or administration lon time on rosuvastatin pharmacokinetics has been observed.8,9 dow Due to the fact that hypertension and hyperlipidemia frerypa quently coexist in the same patients and are responsible for an ehT increased risk of cardiovascular events, the coadministration dan of valsartan and rosuvastatin is desirable in such patients. ten However, to our knowledge, there has been no report of any pom study on the interaction between valsartan and rosuvastatin. lvee These two drugs share the same transporter proteins that are ,nD responsible for the hepatic uptake (organic anion-transporting iseg polypeptide 1B1 and 1B3) and biliary excretion (multidrug gD resistance-associated protein 2).10,11 Through the inhibition ruD of transporters, combination of rosuvastatin and telmisartan increased the peak plasma concentration (Cmax) of rosuvastatin and telmisartan by 2.01- and 1.35-fold, respectively.12 Hence, evaluation of drug–drug interactions is needed to ensure drug efficacy and the safety of patients for the combination therapy. Therefore, the aim of the study reported here (NCT01609907) was to evaluate potential interactions between valsartan and rosuvastatin after coadministration in a clinically relevant multiple-dose setting. Subjects and methods The Institutional Review Board of the Samsung Medical Center, Seoul, Korea, approved the protocol, and the study submit your manuscript | www.dovepress.com Dovepress was conducted in accordance with the principles outlined in the Good Clinical Practice standard and the Declaration of Helsinki.13 All subjects provided written informed consent before their enrollment in the study. subjects Thirty healthy male volunteers were enrolled between November 20 11 and February 2012 . Screening assessments included medical history, physical examination, 12-lead electrocardiogram (ECG), and standard laboratory tests including hematology, blood chemistry, urinalysis, and urine drug screening. Healthy male volunteers aged between 20 and 50 years with a body mass index of 19–27 kg/m2 were included in the trial. Volunteers who experienced hypersensitivity or allergy to any medication including statins or ARBs, had any other disease or abnormality of clinical relevance, or were positive in serology test (hepatitis C virus, hepatitis B virus, or HIV) were excluded from the trial. Volunteers were required to abstain from smoking, drinking alcohol, consuming caffeinecontaining drinks, and undertaking strenuous activity from midnight before dosing until 72 hours after dosing. study design This study was a randomized, open-label, six-sequence, three-period, three-treatment, multiple-dose crossover study in healthy male subjects. The number of subjects used in this study allowed for the detection of a 20% difference in area under the concentration–time curve (AUC) between the two drugs at a significance level of 0.05 with 80% power. Subjects received a different treatment in each period: 20 mg rosuvastatin (Crestor®, AstraZeneca plc, London, UK) alone once daily, 160 mg valsartan (Diovan®, Novartis International AG, Basel, Switzerland) alone once daily, and coadministration of 20 mg rosuvastatin or 160 mg valsartan once daily in an assigned order, with a 1-week washout period (Figure 1). To ensure compliance, study drugs were administered by the investigator at the Clinical Trial Center, Samsung Medical Center (Seoul, Korea). Subjects in a fasted state received study drugs with 240 mL of water every morning for 4 days to reach steady state, determined by the known pharmacokinetic characteristics of each drug. Subjects were admitted to the Clinical Trial Center 12 hours before the last dosing in each treatment period and were confined until 24 hours after dosing. Additional 48- and 72-hour visits were made for pharmacokinetic sampling. The same procedure was repeated during each period for pharmacokinetic, pharmacodynamic, and safety-profile assessments. 8 1 0 2 l u J 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s e r p e v o .dw l.y Determination of plasma rosuvastatin, N-desmethyl rosuvastatin, and valsartan To evaluate drug–drug interactions between rosuvastatin and valsartan, plasma concentrations of rosuvastatin and valsartan were analyzed. Valsartan is metabolized to a pharmacologically inactive metabolite, albeit slowly, by the action of cytochrome P450 2C9 (CYP2C9).14–16 N-desmethyl rosuvastatin, a pharmacologically active metabolite, is formed primarily by CYP2C9.17 Thus, the N-desmethyl metabolite was also measured. The plasma concentrations were measured by BioCore (Seoul, South Korea), which is certified to the Good Laboratory Practice standard by the Ministry of Food and Drug Safety, Seoul, South Korea. The analytes were measured using high-performance liquid chromatography with tandem mass-spectrometric detection. For rosuvastatin and N-desmethyl rosuvastatin, the extracted upper organic phase of samples was filtered with a 0.2 µm filter and evaporated. Valsartan and the corresponding internal standard (valsartan-d3) were extracted from human plasma by protein precipitation. The analytes were chromatographically separated with a Unison UK-C18 column (2.0×75.0 mm, 3 µm; Imtakt Corporation, Tokyo, Japan) with a flow rate of 200 µL/min. The calibration curves for the three analytes were linear (r0.990) over the concentration range of 0.15–150.00 µg/L for rosuvastatin, 0.1–50.00 µg/L for N-desmethyl rosuvastatin, and 40.00–20,000.00 µg/L for valsartan. Intra- and inter-assay accuracy and precision for the three analytes were within 15% of the theoretical values and stability was confirmed according to standard operating procedures and Ministry of Food and Drug Safety guidelines for bioanalytical method validation.18 Pharmacokinetic assessments The primary pharmacokinetic endpoints were the AUC over a dosing interval τ at steady state (AUCτ) and maximum plasma concentration at steady state (Cmax,ss). The secondary pharmacokinetic endpoints were time from last dosing to maximum plasma concentration at steady state (Tmax,ss), terminal elimination half-life at steady state (t½,ss), and minimum plasma concentration at steady state (Cmin,ss). Additionally, metabolic ratio was calculated as N-desmethyl rosuvastatin AUC/rosuvastatin AUC. All pharmacokinetic variables were calculated using Phoenix WinNonlin (v 6.1; Pharsight Corporation, Cary, CA, USA). Pharmacodynamic assessments Lipid profiles and BP were measured to evaluate the pharmacodynamic effect of the drugs. To determine lipid profiles, fasting blood samples were drawn before the first dosing and 24 hours after the last dosing in each period. All lipid parameters, including serum total cholesterol, triglycerides, high- and low-density lipoprotein cholesterol (HDL-C and LDL-C, respectively), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB) were measured using a Roche Modular P chemistry analyzer (Roche Diagnostics, Basel, Switzerland). Systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate (PR) were measured using a YM1000 Vital Signs Monitor (Mediana Technologies, San Antonio, TX, USA) after at least a 5-minute rest. Measurements were made from the same upper arm of each subject before the administration of daily dosing, then at 1 hour and 2, 4, 6, 12, 24, and 48 hours after the last dosing. safety assessments Safety was evaluated based on physical examination, monitoring of vital signs, 12-lead ECGs, adverse events (AEs), and clinical laboratory tests. AEs were monitored throughout the study. Their severity (mild, moderate, or severe) and relationship to the study drug (definite, probable, possible, probably not, definitely not, or nonassessable/unclassifiable) was assessed and recorded by the investigator. AEs were coded by using the Medical Dictionary for Drug Regulatory Activities (MedDRA; v 12.0). with a mean (standard deviation) age of 32 (7) years and body mass index of 23.0 (2.0) kg/m2. Demographic characteristics were comparable across the six sequence groups. Pharmacokinetics The trough plasma concentrations of these two agents confirmed that a steady state was reached after administration of rosuvastatin and valsartan for 4 consecutive days. The mean plasma concentration–time curves after coadministration of rosuvastatin and valsartan, and administration of each drug alone are shown in Figures 2 and 3. Pharmacokinetic variables for rosuvastatin, N-desmethyl rosuvastatin, and valsartan are summarized in Table 1. The Tmax,ss, Cmin,ss, and t½ of rosuvastatin and valsartan were not affected by their coadministration. Peak exposure to rosuvastatin and valsartan was 12% and 7% lower, respectively, when the drugs were coadministered, than when they were administered alone. However, this decrease was not clinically significant. For rosuvastatin, the 90% CI for the GMR was 0.7873–0.9857 for Cmax,ss and 0.8632–0.9701 for the AUCτ (Table 2). For valsartan, the 90% CI for the GMR was 0.7946–1.0884 for Cmax,ss and 0.8893–1.1406 for the AUCτ (Table 2). Pharmacodynamics Mean changes in SBP, DBP, and PR from baseline following oral administrations of rosuvastatin and valsartan alone and in combination are presented in Table 3. SBP, DBP, and PR were significantly decreased following multiple oral administration of valsartan compared with rosuvastatin alone. There was no significant difference in changes of SBP, DBP, and PR between administration of valsartan alone and valsartan submit your manuscript | www.dovepress.com Dovepress 8 1 0 2 l u J 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s e r p e v o .dw l.y /ww no / e :s s ttp lu h na from rsoe deda ropF o l n w o d y p a r e h T d n a t n e m p o l e v e D , n g i s e D g u r D with rosuvastatin. Changes in BP recovered to baseline levels 24–48 hours after the last dosing. Maximum changes in BP were observed on average 6 hours after dosing with a compensatory PR increase. However, maximum changes of SBP, DBP, and PR were not altered by coadministration of valsartan and rosuvastatin (Table 3). Mean changes from baseline in lipid profiles are summarized in Table 4. Total cholesterol, LDL-C, and ApoB/ ApoA1 decreased significantly following coadministration of valsartan and rosuvastatin compared with valsartan alone (P0.001). However, differences between rosuvastatin alone and in combination with valsartan were not significant. safety There were no serious AEs during the study. Two subjects dropped out of the study because their blood creatine phosphokinase (CPK) levels increased (10 times the upper limit of normal) accompanied by hepatic enzyme level increases without any symptoms. These AEs occurred 10 days after the most recent administration of valsartan, and these subjects reported a history of intense exercise. Thirty-five AEs were reported in 18 subjects (nine [29.6%] with rosuvastatin, twelve [32.1%] with valsartan, and 14 [32.1%] with coadministration). There were five cases of drug-related AEs after rosuvastatin administration (14.8%), six cases after valsartan administration (21.4%), and six cases after coadministration of both drugs (24.1%). The frequency of drug-related AEs between treatments was not statistically different (Table 5). Common drug-related AEs were hemoglobin decreased (16.7%), asthenia (10.0%), and hypotension (10.0%). Other AEs (fatigue, nasopharyngitis, blood bilirubin increase, blood CPK increase, headache, and pruritus) were reported in one or two subjects (10%). All drug-related AEs were mild in severity and subjects recovered without any medication. There were no clinically significant findings on physical examination or 12-lead ECGs. Discussion In the present study, we explored the pharmacokinetic interaction between rosuvastatin and valsartan in healthy male subjects. Peak and systemic exposure of rosuvastatin and valsartan at steady state was compared between administration of each drug alone and coadministration of both drugs. Rosuvastatin can be administered with or without a meal because food does not affect the AUC of rosuvastatin, whereas, food has been reported to decrease valsartan’s AUC by approximately 40% and its Cmax by approximately 50%.1,4,19 Therefore, this study was conducted under fasting conditions to avoid the effect of food on metabolizing enzymes and transporters.20 submit your manuscript | www.dovepress.com Dovepress 749 8 1 0 2 l u J 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s e r p e v o .dw l.y Variable Rosuvastatin c max,ss, µg/l aUc τ, µg⋅h/l Valsartan c max,ss, µg/l aUc τ, µg⋅h/l 8 1 0 2 l u J 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s e r p e v o .dw l.y from rsoe deda ropF o l n w o d y p a r e h T d n a t n e m p o l e v e D , n g i s e D g u r D Observed pharmacokinetic parameters for valsartan were rosuvastatin and valsartan for the treatment of hypertension in agreement with those reported in the literature.21 As shown in and hyperlipidemia. However, this study was conducted in a previous study, the Cmax,ss of rosuvastatin is increased in Asian subjects compared with in Caucasian subjects.22 In this a small cohort of healthy male Korean subjects, which limits its application, and the statistical analyses were powered for study, the 90% CI for coadministered/individually adminispharmacokinetic interactions only, not pharmacodynamic tered AUCτ ratios indicated that no interaction criteria were fulfilled.20 The 90% CI in the Cmax,ss of valsartan and rosuvastatin fell slightly outside of the range of 0.80–1.25. However, this study was not sufficiently powered to demonstrate drug interaction based on Cmax using the strict criteria of 90% CIs falling in the range 0.80–1.25. Considering high intra-subject variability of Cmax and the wide therapeutic range of valsartan and rosuvastatin, a CI range from 0.75 to 1.34 is acceptable for Cmax.23–25 Therefore, the observed 12% decreases in Cmax,ss ratios are not clinically relevant. The median Tmax of valsartan and rosuvastatin was not changed after coadministration of valsartan and rosuvastatin. interactions. To generalize the result clinically, studies in hypertensive patients with hyperlipidemia or mixed dyslipidemia are necessary. Conclusion The pharmacokinetic profiles of rosuvastatin and valsartan when coadministered were comparable with those when the drugs were administered alone, suggesting that the pharmacokinetic interaction between valsartan and rosuvastatin was not significant in the healthy volunteers used in this study. Acknowledgments Valsartan is excreted largely unchanged as the parent comThe authors are grateful to all study participants and volunteer pound into the feces via bile and into the urine.16 An inhibitory subjects. This study was supported by a grant from the Yuhan or induction effect of valsartan on cytochrome P450 enzymes Corporation, Seoul, Korea. has not been observed. Rosuvastatin is also mainly excreted unchanged into the feces via bile and into the urine and only Disclosure about 10% of rosuvastatin is metabolized by CYP2C9.4 In SY Nam and SB Jang disclose that they are employees of the present study, the Cmax of two drugs was only influenced by the combination, although the two drugs share the sample Yuhan Corporation. These two authors participated in the manuscript review. All other authors declare no conflicts of transporter proteins. This result is similar to those found with interest in this work. the of combination of rosuvastatin and olmesartan.26 Also, no clinically significant pharmacokinetic interactions have been reported between valsartan and other HMG-CoA reductase inhibitors such as simvastatin and pitavastatin.23,27 Multiple doses of valsartan and rosuvastatin, whether administered alone or coadministered, were generally well tolerated in this study. The frequency of AEs was similar whether the drugs were administered alone or coadministered. The observed AEs following administration of valsartan and rosuvastatin were not unexpected. No safety issues were reported, except in two subjects who dropped out because of an asymptomatic CPK increase related to intense exercise. The most important AEs associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently.28 Thus, frequency of these AEs with combination therapy should be evaluated on a long-term basis. Comparable beneficial effects on both lipids (decrease in total cholesterol and LDL-C) and BP (decrease of SBP and DBP) were observed with combined drug treatment. It is conceivable that the lack of pharmacokinetic interaction enabled each drug to maintain its own pharmacodynamic effect. The results of the present study support the combined use of submit your manuscript | www.dovepress.com Dovepress 751 8 1 0 2 l u J 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s e r p e v o .d . w ly ww no / / e :s s ttp lu h na from rsoe deda ropF o l n w o d y p a r e h T d n a t n e m p o l e v e D , n g i s e D g u r D Publish your work in this journal Drug Design, Development and Therapy is an international, peerreviewed open-access journal that spans the spectrum of drug design and development through to clinical applications. Clinical outcomes, patient safety, and programs for the development and effective, safe, and sustained use of medicines are a feature of the journal, which 1. Diovan (valsartan) tablets [prescribing information] . East Hanover , NJ: Novartis Pharmaceuticals Corporation; 2014 . Available from: http:// www.accessdata.fda.gov/drugsatfda_docs/label/2014/021283s044lbl. pdf. Accessed November 21 , 2014 . 2. Flesch G , Müller P , Lloyd P . 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Identification of cytochrome P450 forms involved in the 4-hydroxylation of valsartan, a potent and specific angiotensin II receptor antagonist, in human liver microsomes . Xenobiotica . 2005 ; 35 ( 6 ): 589 - 602 . 16. Waldmeier F , Flesch G , Müller P , et al. Pharmacokinetics, disposition and biotransformation of [14C] -radiolabelled valsartan in healthy male volunteers after a single oral dose . Xenobiotica . 1997 ; 27 ( 1 ): 59 - 71 . 17. Lee HK , Ho CS , Hu M , Tomlinson B , Wong CK . Development and validation of a sensitive method for simultaneous determination of rosuvastatin and N-desmethyl rosuvastatin in human plasma using liquid chromatography/negative electrospray ionization/tandem mass spectrometry . Biomed Chromatogr . 2013 ; 27 ( 11 ): 1369 - 1374 . 18. Ministry of Food and Drug Safety. Guideline on Bioanalytical Method Validation . Korea: Ministry of Food and Drug Safety; 2013 . Available from: https://eirb2.ajoumc.or.kr/board/file/Notice/Notice_1055.pdf. 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Jin Ah Jung, Soo-Yun Lee, Jung-Ryul Kim, Jae-Wook Ko, Seong Bok Jang, Su Youn Nam, Wooseong Huh. A pharmacokinetic and pharmacodynamic drug interaction between rosuvastatin and valsartan in healthy subjects, Drug Design, Development and Therapy, 2015, 745-752, DOI: 10.2147/DDDT.S76942