Pharmacokinetic Interaction Between Rosuvastatin and Telmisartan in Healthy Korean Male Volunteers: A Randomized, Open-label, Two-period, Crossover, Multiple-dose Study

Clinical Therapeutics/Volume 36, Number 8, 2014

Pharmacokinetic Interaction Between Rosuvastatin and Telmisartan in Healthy Korean Male Volunteers: A Randomized, Open-label, Two-period, Crossover, Multiple-dose Study Mijeong Son, MD1,2; Yukyung Kim, MD1,2; Donghwan Lee, MD, PhD1,2; Hyerang Roh, BS1,2; Hankil Son, PhD1,2; Jinju Guk, BS1,2; Seong Bok Jang, PhD3; Su Youn Nam, MD, PhD3; and Kyungsoo Park, PhD, MD1 1

Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea; Brain Korea 21 Plus Project for Medical Science, Yonsei University, Seoul, Republic of Korea; and 3 Yuhan Research Institute, Yuhan Corporation, Seoul, Republic of Korea 2

ABSTRACT Purpose: Rosuvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, and telmisartan, an angiotensin receptor blocker, are commonly prescribed in combination for the treatment of dyslipidemia accompanied by hypertension. However, the nature of the pharmacokinetic interaction between the 2 drugs is not clearly understood. The goal of the present study was to investigate the pharmacokinetic drug–drug interaction between rosuvastatin and telmisartan in a healthy Korean population. Methods: This was a randomized, 2-part, openlabel, 2-period, crossover, multiple-dose study, with each part composed of different subjects between the ages of 20 and 55 years. In part 1, each subject received rosuvastatin 20 mg with and without telmisartan 80 mg once daily for 6 consecutive days. In part 2, each subject received telmisartan 80 mg with and without rosuvastatin 20 mg once daily for 6 consecutive days. In both parts, there was a 16-day washout period between mono- and coadministration. Blood samples were collected up to 72 hours after the last dose. Adverse events (AEs) were evaluated through interviews and physical examinations. Findings: In part 1, the 90% CIs of the geometric mean ratios for the primary pharmacokinetic parameters for coadministration of the 2 drugs to monoadministration of each drug were 1.0736–1.2932 for AUCτ and 1.7442–2.3229 for Cmax,ss for rosuvastatin and 0.9942– 1.1594 for AUCτ and 1.3593–1.7169 for Cmax,ss for N-desmethyl rosuvastatin, whereas in part 2, the CIs were 1.0834–1.2672 for AUCτ and 1.1534–1.5803

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for Cmax,ss for telmisartan. The most frequently noted AE was cough in part 1, which occurred in 2 subjects receiving the combination therapy, and oropharyngeal pain in part 2, which occurred in 3 subjects receiving the combination therapy. All reported AEs were mild or moderate, and there was no significant difference in incidence between the treatments. Implications: These findings demonstrated that rosuvastatin and telmisartan mutually affected each other’s pharmacokinetics, suggesting a possibility of drug–drug interaction. However, based on dose–response characteristics of the 2 drugs and previous results from other interaction studies, the degree of drug interaction observed in this study was not regarded as clinically significant. All treatments were well tolerated, with no serious AEs observed. ClinicalTrials.gov identifier: NCT01992601. (Clin Ther. 2014;36:1147–1158) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key words: drug–drug interaction, pharmacokinetics, rosuvastatin, telmisartan.

INTRODUCTION Cardiovascular disease (CVD) is one of the most common chronic diseases and causes a significant burden on society. According to a 2011 statistical report on the causes of death in Korea, the death rate of Accepted for publication June 4, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.06.007 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics cardiovascular disease was the second highest, and the rate appears to be increasing.1 In the United States, the total cost incurred by CVD and stroke in 2009 was estimated to be $313 billion, which is in excess of the estimate for all cancerous diseases.2 Hypertension and dyslipidemia are frequent comorbidities, and both are responsible for CVD.3. A retrospective study in a general veteran population in the United States found that 31% of the population had both hypertension and dyslipidemia.4 Because hypertension and dyslipidemia can exhibit strong synergistic effects on CVD when combined with other risk factors, treatment of these conditions is important to prevent CVD.5 Rosuvastatin, a selective inhibitor of 3-hydroxy-3methylglutaryl-coenyme A (HMG-CoA) reductase, exerts a cholesterol-lowering effect by blocking the cholesterol synthesis process. Relative to other statins, rosuvastatin has a high affinity with HMG-CoA reductase and is effective in reducing LDL cholesterol levels and increasing HDL cholesterol levels in the blood.6 Telmisartan, an angiotensin II type 1 (AT1) receptor blocker, has a high affinity for the AT1 receptor and a powerful antihypertensive effect. The long half-life of telmisartan (E24 hours) ensures that the drug provides effective reductions in blood pressure over the 24-hour dosing interval. In addition to its blood pressure–lowering effect, it was also found that telmisartan relates to the regulation of lipid metabolism by acting as a partial agonist of peroxisome proliferator–activated receptor-γ.7 Rizos et al8 reported that in Greek adults with impaired fasting glucose levels, hypertension, and mixed hyperlipidemia, the combination therapy with rosuvastatin and telmisartan was more effective than the other combinations when evaluated using a homeostasis model of insulin resistance, fasting serum insulin, and high-sensitivity C-reactive protein.8 These additional effects of telmisartan imply that coadministration of rosuvastatin and telmisartan may provide additional benefits to patients with hypertension and dyslipidemia. Moreover, a combination formulation of the 2 drugs, if developed, will further improve treatment effects due to increased patient compliance. Although rosuvastatin is known to be transported to the liver by organic anion-transporting polypeptide 1B1/1B3 (OATP1B1/1B3) and excreted to the bile by breast cancer resistance protein (BCRP), multidrug resistance protein 1 (MDR1), and multidrug resistance

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protein 2 (MRP2),9–12 it has been reported that OATP1B3 and MRP2 are also responsible for the hepatic uptake and biliary excretion of telmisartan, and BCRP, MDR1, and MRP2 for the biliary excretion of its metabolite, telmisartan acylglucuronide.12–15 Therefore, it is likely that there exists drug–drug interaction when the 2 drugs are coadministered. However, as far as the interaction between statins and telmisartan is concerned, the only information currently available is the interaction between simvastatin and telmisartan, which has been reported to be clinically insignificant,7,16 and no information is available on the interaction between rosuvastatin and telmisartan. In this regard, the aim of the present study was to investigate the pharmacokinetic drug–drug interaction between rosuvastatin and telmisartan in healthy Korean population.

SUBJECTS AND METHODS Subjects Eligible subjects were healthy male volunteers between 20 and 50 years of age and within 20% of their ideal body weight, with no congenital anomalies or chronic diseases. Key exclusion criteria included a history of biliary, cardiovascular, pulmonary, renal, endocrine, gastrointestinal, hematologic, neurologic, musculoskeletal, psychiatric, or cancerous disease; clinically significant findings on routine laboratory testing (serology, hematology, serum chemistry, and urinalysis) or 12-lead ECG; low blood pressure (systolic r90 mm Hg or diastolic r50 mm Hg) or high blood pressure (systolic Z150 mm Hg or diastolic Z95 mm Hg); history of hypersensitivity reaction to rosuvastatin or telmisartan; and the use of prescription drugs within 14 days before the study initiation that could potentially interact with the study medication. The study protocol was approved by the Institutional Review Board of Yonsei University Severance Hospital (Seoul, Republic of Korea), and all procedures were performed in accordance with the Korean Good Clinical Practice guidelines17 and principles outlined in the Declaration of Helsinki.18 All subjects provided written informed consent before enrollment.

Study Design This multiple-dose, randomized, open-label, 2period crossover study consisted of 2 parts; part 1

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M. Son et al. was designed to investigate the influence of telmisartan on rosuvastatin pharmacokinetics and part 2 investigated the influence of rosuvastatin on telmisartan pharmacokinetics. Each part recruited a separate group of subjects who were randomly assigned to 2 groups in a 1:1 ratio (part 1: groups 1 and 2; part 2: groups 3 and 4) by a computer-generated randomization scheme (Compaq Visual Fortran 11.1, IMSL Fortran library, Compaq Computer Corporation, Houston, Texas).

Part 1: Telmisartan’s Influence on Rosuvastatin Pharmacokinetics In part 1, group 1 received the monotreatment of rosuvastatin 20-mg tablet (Crestors*) once daily (QD) for 6 consecutive days (denoted by “R” hereafter) in period 1 and the combination treatment of rosuvastatin 20 mg tablet and telmisartan 80 mg tablet (Micardiss†) QD for 6 consecutive days (denoted by “R þ T” hereafter) in period 2, and group 2 vice versa.

Part 2: Rosuvastatin’s Influence on Telmisartan Pharmacokinetics In part 2, group 3 received the monotreatment of telmisartan 80-mg tablet once daily for 6 consecutive days (denoted by “T” hereafter) in period 1 and “R þ T” in period 2, and vice versa for group 4. Dosing scenarios for the 2 parts are illustrated in Table I. In both parts 1 and 2, for day 1 through day 5 of each period, the subjects visited the Clinical Trial Center at Severance Hospital at 8 AM every morning in a fasting state and received the assigned treatment orally with 240 mL of water. In the evening of day 5, the subjects were hospitalized, and at 8 AM on day 6 after a 10-hour overnight fast, they received the last dose of the same treatment with 240 mL of water, followed by intensive blood sampling. The subjects were prevented from drinking water for 2 hours before and after the dose. Standard meals containing  700 kcal (60% carbohydrate, 16% protein, and 24% fat) were provided for lunch and dinner at 4 and 10 hours after the last dose, respectively. The subjects were discharged at 8 AM on day 7 when the 24-hour blood sampling was completed, and on days 8 and 9, Trademark Crestors (AstraZeneca Inc, London, United Kingdom). † Trademark: Micardiss (Boehringer Ingelheim, Ingelheim, Germany). *

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Table I. Dosing scenario. Period 1 Part Group (Days 1–6) 1 2

1 2 3 4

R RþT T RþT

Period 2 (Days 22–27) 16-day washout

RþT R RþT T

R ¼ monoadministration of rosuvastatin 20 mg once daily for 6 days; T ¼ monoadministration of telmisartan 80 mg once daily for 6 days; R þ T ¼ coadministration of rosuvastatin 20 mg and telmisartan 80 mg once daily for 6 days.

they revisited the hospital at 8 AM in a fasting state for additional blood sampling. There was a 16-day washout period between the treatments.

Blood Sampling In each period, venous blood samples of 8 mL each for pharmacokinetic analysis were collected in heparinized tubes by an indwelling catheter inserted in the forearm at 0 hour (predose) for days 1 and 5, and 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 16, 24, 48, and 72 hours after the last dose on day 6. Before collecting each blood sample, 1 mL of blood was drawn from the catheter and discarded. After each blood sample was drawn, 1 mL of heparinized saline solution was injected in the catheter. Plasma samples were put on ice after collection and separated via centrifugation (1800g at 41C for 10 minutes) and stored at 701C until assayed.

Bioanalysis Plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin (a major metabolite of rosuvastatin), and telmisartan were analyzed by BioCore Co, Ltd (Seoul, Korea) using validated LC-MS/MS.19,20 For the detection of rosuvastatin and N-desmethyl rosuvastatin, a mixture of 0.1% (vol/vol) formic acid in deionized water and 0.1% (vol/vol) formic acid in acetonitrile (55:45 [vol:vol]) was used for the mobile phase with a flow rate of 0.2 mL/min. Detection was achieved using the multiple reaction monitoring mode of positive electrospray ionization set to transmit at mass/charge (m/z) 482.1 - 258.1 and 468.2 - 258.2

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Clinical Therapeutics for rosuvastatin and N-desmethyl rosuvastatin, respectively, at m/z 488.1 - 264.1 and 474.2 264.2 for rosuvastatin-d6 and N-desmethyl rosuvastatin-d6 (internal standards), respectively. The standard stock solutions of rosuvastatin and Ndesmethyl rosuvastatin were prepared at plasma concentrations of 0.15 to 150 ng/mL and 0.1 to 50 ng/mL, respectively. An aliquot of 300 μL of plasma was added to polypropylene tube containing 100 μL of 0.2 M sodium acetate (pH 4.0) and 20 μL of internal standard (25 ng/mL in 50% methanol). After vortexing for 15 seconds, a 2.5-mL aliquot of methyl tert-butyl ether was added. The sample was shaken for 20 minutes using a WiseShake SHR Digital Reciprocating Shaker (Daihan, Gangwon-do, Republic of Korea) and then centrifuged for 5 minutes at 3000 rpm using the Union 32R Plus centrifuge (Hanil, Incheon, Korea). The organic layer was transferred into a 10-mL glass test tube and evaporated at 401C under a stream of nitrogen. The dried extract was reconstituted in 150 μL of the mobile phase and filtered through a 0.2-μm filter. From these, a 5-μL aliquot was injected in the liquid chromatograph (Shimadzu UFLC, Shimadzu, Japan) MS/MS (API 5000, Ab Sciex, Framingham, Massachusetts). For the detection of telmisartan, a mixture of 0.1% (vol/vol) formic acid in 10 mM ammonium acetate and 0.1% (vol/vol) formic acid in methanol (15:85 [vol:vol]) was used for the mobile phase with a flow rate of 0.2 mL/min. Detection was achieved using the multiple reaction monitoring mode of positive electrospray ionization set to transmit at m/z 515.2 - 497.3 for telmisartan, at m/z 518.3 - 279.1 for telmisartand3 (internal standard). The standard stock solutions of telmisartan were prepared at plasma concentrations of 10 to 10,000 ng/mL. An aliquot of 200 μL of plasma was added to polypropylene tube containing 500 μL of acetonitrile and 10 μL of internal standard (5 μg/mL in 50% methanol). After vortexing for 1 minute, the sample was centrifuged for 5 minutes at 13,000 rpm using the Union 32R Plus centrifuge (Hanil). Supernatant (40 μL) was mixed with 400 μL of deionized water, methanol, and formic acid (50:50:0.1 [vol:vol]). From these, a 5-μL aliquot was injected in the LC (Shiseido Nanospace SI-2, Shiseido, Japan) MS/MS (Quantum Ultra, Thermo, Waltham, Massachusetts). Responses were determined as the concentration of internal standard multiplied by the ratio of the peak area of the sample to internal standard obtained from

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the chromatograph. The concentrations of rosuvastatin, N-desmethyl rosuvastatin, and telmisartan were calculated from each calibration curve. The calibration standards demonstrated acceptable linearity (correlation coefficient, r 4 0.9950) over each concentration range of 0.15 to 150, 0.1 to 50, and 10 to 10,000 ng/mL for rosuvastatin, N-desmethyl rosuvastatin and telmisartan, respectively, using a 1/x2weighted least-squares linear regression analysis. Acceptable intraday and interday precision (o15%) and accuracy (within 15%) were observed over the linear range of 0.45 to 120, 0.3 to 40, and 30 to 8000 ng/mL for rosuvastatin, N-desmethyl rosuvastatin, and telmisartan, respectively. The intraday and interday precision were o20% and the accuracy was within 20% at the lower limit of quantification for 3 compounds.

Pharmacokinetic Analysis The plasma concentration–time profiles of rosuvastatin and N-desmethyl rosuvastatin for part 1 and those of telmisartan for part 2 after the last dose in each treatment period for each subject were analyzed by a noncompartmental method using WinNonlin Version 6.3 (Pharsight Corporation, Mountain View, California). Pharmacokinetic parameters evaluated were Cmax,ss, AUCτ, AUClast,ss, AUCinf,ss, Cmin,ss, Tmax,ss, and t½ of rosuvastatin, N-desmethyl rosuvastatin and telmisartan, where AUCτ denotes AUC over the dosing interval at steady state. AUCτ and AUClast,ss were calculated using the linear trapezoidal rule, AUCinf,ss as AUClast,ss þ (Clast,ss /λz), where Clast,ss was the last quantifiable concentration, λz the terminal elimination rate constant, and t½ 0.693/λz. Cmax,ss, Cmin,ss, and Tmax,ss were determined directly from the observed values. The primary parameters of interest were Cmax,ss and AUCτ of rosuvastatin and telmisartan. All analyses were made using the actual sampling times rather than the scheduled times.

Tolerability Assessments Tolerability assessments were based on the evaluation of AEs and vital signs (blood pressure, body temperature, and pulse rate), laboratory tests (hematology, blood chemistry, and urinalysis), 12-lead ECG, and physical examination. Physical examinations were evaluated before every dose and at 24, 48. and 72 hours after the last dose of each treatment period and at follow-up visits, with vital signs being additionally

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M. Son et al. evaluated at 2, 4, and 8 hours after the last dose. Laboratory tests and electrocardiography were performed at baseline, before the last dose, after the last dose, and during follow-up visits. The hematology test evaluated white blood cells (WBC), red blood cells, hemoglobin, hematocrit, platelets, and differential count of WBCs (neutrophils, lymphocytes, monocytes, eosinophils, and basophils); the blood chemistry test evaluated calcium, inorganic phosphate, fasting glucose, blood urea nitrogen, creatinine, uric acid, cholesterol, total protein, albumin, total bilirubin, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, creatine kinase, triglyceride, sodium, potassium, and chloride; and the urinalysis evaluated specific gravity, pH, protein, glucose, ketone, bilirubin, blood, urobilinogen, nitrite, WBCs, color, turbidity, sediment, and microscopy. Based on subject interviews and physical examinations, any unfavorable signs (including any abnormal laboratory findings) or symptoms, regardless of whether they were causally related to the study medication, was defined as an AE and recorded on case report forms.

visiting the center on time (3 on day 5 of period 1 and the other on day 26 of period 2). All subjects who were administered the study drug were included in the tolerability assessments, and only the subjects who completed the blood sampling as scheduled were included in the pharmacokinetic analysis. Demographic characteristics of the enrolled subjects are summarized in Table II.

Pharmacokinetics Part 1: Telmisartan’s Influence on Rosuvastatin Pharmacokinetics The plasma concentration–time profiles of rosuvastatin and N-desmethyl rosuvastatin after monoadministration of rosuvastatin (R) and coadministration of rosuvastatin and telmisartan for 6 days (RþT) are depicted in Figure 1, and the pharmacokinetic parameters of rosuvastatin and N-desmethyl rosuvastatin between R and RþT are compared in Table III. When assessed by the primary pharmacokinetic parameters, R þ T gave significantly larger exposure values in both Cmax,ss (P o 0.0001) and

Statistical Analysis Comparative bioavailability and the associated drug–drug interaction was assessed based on the 90% CIs of geometric mean ratios (coadministration to monoadministration) for the primary pharmacokinetic parameters (Cmax,ss and AUCτ,ss) of rosuvastatin and telmisartan using bioequivalence and crossover tools available in WinNonlin Version 6.3. It was concluded that a significant pharmacokinetic interaction existed between the 2 drugs if the 90% CI values did not fall within the range of 0.80–1.25.

RESULTS Study Population A total of 48 healthy male subjects, with 24 for each part, were enrolled in the study. Mean age, weight, and height of the subjects were 28.3 year, 72.6 kg, and 174.4 cm for part 1 and 26.3 years, 71.3 kg, and 173.4 cm for part 2. In part 1, 21 subjects completed the study, with 2 withdrawing consent (1 on day 17 of period 1 and the other on day 25 of period 2) and 1 dropping out of the study on day 2 of period 1 due to not following the requirement of overnight fasting before dosing. In part 2, 19 subjects completed the study, with 1 withdrawing consent on day 25 of period 2 and 4 dropping out due to not

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Table II. Demographic characteristics of the subjects. Characteristics

Part 1 (n ¼ 24)

Part 2 (n ¼ 24)

Age, y Mean (SD) 28.3 (5.4) 26.3 (4.0) Range 22–39 20–39 Weight, kg Mean (SD) 72.6 (9.3) 71.3 (8.0) Range 49.5–88.2 53.9–86.0 Height, cm Mean (SD) 174.4 (5.8) 173.4 (5.6) Range 160.0–184.1 161.8–185.4 Smoking, no. (%) Smoker 9 (37.5) 8 (33) Nonsmoker 15 (62.5) 16 (67) Alcohol drinking, no. (%) Drinker 18 (75) 18 (75) Nondrinker 6 (25) 6 (25) Caffeine user, no. (%) Yes 14 (58) 16 (67) No 10 (42) 8 (33)

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Clinical Therapeutics

Rosuvastatin

Plasma Concentration (ng/mL)

120 100

R R+T

80 60 40 20 0 120

128

136

168 144 152 160 Time after first dose (hr)

176

184

192

N-desmethyl rosuvastatin 10

Plasma Concentration (ng/mL)

9 8

R

7

R+T

6 5 4 3 2 1 0 120

128

136

144 152 160 168 Time after first dose (hr)

176

184

192

Figure 1. Mean (SD) plasma concentration–time profiles of rosuvastatin (A) and N-desmethyl rosuvastatin (B) observed during monoadministration of rosuvastatin 20 mg once daily for 6 days (R) and coadministration of rosuvastatin 20 mg and telmisartan 80 mg once daily for 6 days (R þ T): part 1.

AUCτ (P ¼ 0.0066) of rosuvastatin compared with R, yielding the geometric mean ratios (90% CI) of 2.0128 (1.7442–2.3229) and 1.1783 (1.0736–1.2932) for Cmax,ss and AUCτ, respectively. For secondary pharmacokinetic parameters when evaluated at the significance level of α ¼ 0.05, AUClast,ss, and AUCinf,ss of rosuvastatin and Cmax,ss of N-desmethyl rosuvastatin significantly increased and Tmax,ss of rosuvastatin and N-desmethyl rosuvastatin and t½ of N-desmethyl rosuvastatin significantly

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decreased, where the degree of significance was the highest in Cmax,ss of N-desmethyl rosuvastatin (P o 0.0001), followed by Tmax,ss of rosuvastatin and Ndesmethyl rosuvastatin (P ¼ 0.0001 and 0.0002, respectively).

Part 2: Rosuvastatin’s Influence on Telmisartan Pharmacokinetics The plasma concentration–time profiles of telmisartan after monoadministration of telmisartan (T)

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M. Son et al.

Table

III. Pharmacokinetic comparison of rosuvastatin and N-desmethyl rosuvastatin after monoadministration of rosuvastatin 20 mg once daily for 6 days (R) and coadministration of rosuvastatin 20 mg and telmisartan 80 mg once daily for 6 days (R þ T)* : part 1. Geometric Mean Ratio (R þ T)/R

Geometric Mean PK parameter Rosuvastatin Cmax,ss (ng/mL)† AUCτ (ng  h/mL)† AUClast,ss (ng  h/mL)† AUCinf,ss (ng  h/mL)† Cmin,ss (ng/mL)† Tmax,ss (h)‡ t½ (h)† N-desmethyl rosuvastatin Cmax,ss (ng/mL)† AUCτ (ng  h/mL)† AUClast,ss (ng  h/mL)† AUCinf,ss (ng  h/mL) † Cmin,ss (ng/mL)† Tmax,ss (h) ‡ t½ (h)†

RþT (n ¼ 21)

R (n ¼ 21)

Ratio

90% CI

P

56.00 269.95 309.25 316.15 2.11 0.75 11.32

27.82 229.10 274.47 281.80 1.90 5.00 12.63

2.0128 1.1783 1.1267 1.1219 1.1136 –3.1250 0.8960

1.7442–2.3229 1.0736 to 1.2932 1.0314 to 1.2309 1.0321 to 1.2196 0.9651 to 1.2348 –3.5000 to –2.3750 0.8064 to 0.9955

o0.0001 0.0066 0.0308 0.0278 0.2092 0.0001 0.0873

5.59 35.55 38.03 42.32 0.33 1.00 8.90

3.66 33.11 36.49 41.64 0.30 4.00 12.29

1.5277 1.0736 1.0424 1.0163 1.1094 –2.3750 0.7240

1.3593 to 1.7169 0.9942 to 1.1594 0.9578 to 1.1345 0.9469 to 1.0908 0.9644 to 1.2762 –3.0000 to –1.7500 0.5777 to 0.9073

o0.0001 0.1267 0.4064 0.6969 0.2151 0.0002 0.0230

PK ¼ pharmacokinetic. * Subjects who withdrew were excluded from the analysis. † WinNonlin bioequivalence test. ‡ WinNonlin crossover object where values are median.

and coadministration of rosuvastatin and telmisartan for 6 days (R þ T) are depicted in Figure 2, and the pharmacokinetic parameters of telmisartan between T and R þ T are compared in Table IV. With regard to primary pharmacokinetic parameters, similar to part 1, coadministration of the 2 drugs significantly increased both Cmax,ss (P ¼ 0.0041) and AUCτ (P ¼ 0.0026) of telmisartan. For secondary pharmacokinetic parameters, coadministration significantly increased AUClast,ss of telmisartan (P ¼ 0.0024), with no other parameter being significantly influenced.

Tolerability During the study, all 3 treatments were well tolerated in all subjects, and no serious AEs or drug reactions occurred. In part 1, cough was the most frequently noted AE, occurring in 2 subjects with

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combination therapy. The other AEs were constipation, dysuria, and toothache (each occurring in 1 subject receiving R), and oropharyngeal pain and neck pain (each occurring in 1 subject receiving R þ T). In part 2, the most common AEs were oropharyngeal pain (3 receiving R þ T), cough (2 receiving R þ T and 1 receiving T), and headache (2 receiving T and 1 receiving R þ T), followed by rhinorrhea (1 receiving T and 1 receiving R þ T). The other AEs occurred in 1 subject each, with epistaxis, arthralgia, and constipation occurring in subjects receiving T, and ear infection, chilling, catheter site edema, myalgia, dyspepsia, sputum, pyrexia, diarrhea, and acute sinusitis occurring in subjects receiving R þ T. All AEs were mild or moderate, and most of the subjects who reported having an AE recovered spontaneously. During the study, substantial decreases in blood pressure were observed in the subjects receiving T or

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Clinical Therapeutics

Telmisartan

Plasma Concentration (ng/mL)

2500

2000

T R+T

1500

1000

500

0 120

128

136

144 152 160 168 Time after first dose (hr)

176

184

192

Figure 2. Mean (SD) plasma concentration–time profile of telmisartan observed during monoadministration of telmisartan 80 mg once daily for 6 days (T) and coadministration of rosuvastatin 20 mg and telmisartan 80 mg once daily for 6 days (R þ T): part 2.

R þ T, yielding 9.19 mm Hg (from 118.90 to 109.71 mm Hg) for systolic blood pressure (SBP) and 18.19 mm Hg (from 77.57 to 59.38 mm Hg) for diastolic blood pressure (DBP) in R þ T of part 1, 13.85 mm Hg (from 124.55 to 110.70 mm Hg) for SBP and

12.20 mm Hg (from 77.25 to 65.05 mm Hg) for DBP in T of part 2, and 8.55 mm Hg (from 120.95 to 112.40 mm Hg) for SBP and 14.50 mm Hg (from 77.00 to 62.50 mm Hg) for DBP in R þ T of part 2, as measured by the mean change from the baseline level

Table IV. Pharmacokinetic comparison of telmisartan after monoadministration of telmisartan 80 mg once daily for 6 days (T) and coadministration of rosuvastatin 20 mg and telmisartan 80 mg once daily for 6 days (RþT)*: Part 2. Geometric Mean

Geometric Mean Ratio (RþT)/T

PK Parameter

RþT (n ¼ 19)

T (n ¼ 19)

Ratio

90% CI

P

Cmax,ss (ng/mL)† AUCτ (ng  h/mL)† AUClast,ss (ng  h/mL)† AUCinf,ss (ng  h/mL) † Cmin,ss (ng/mL)† Tmax,ss (h)‡ t½ (h)†

1304.52 3726.68 4580.54 5212.04 39.11 0.75 15.10

966.25 3180.55 3853.73 4567.98 34.89 0.75 14.81

1.3501 1.1717 1.1886 1.1410 1.1208 –0.125 1.0195

1.1534–1.5803 1.0834–1.2672 1.0923–1.2932 0.9932–1.3108 0.9735–1.2904 –0.25 to 0.125 0.7113–1.4612

0.0041 0.0026 0.0024 0.1165 0.1768 0.3109 0.9267

PK ¼ pharmacokinetic. * Subjects who withdrew were excluded from the analysis. † WinNonlin bioequivalence test. ‡ WinNonlin crossover object where values are in median.

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M. Son et al. observed before the first dose to the maximal effect observed after the last dose. These decreases in blood pressure were all statistically significant (P o 0.05) There were no clinically significant changes in physical examinations, vital signs, laboratory tests, or ECGs.

Assessment of Reaching Steady-State Concentrations To ensure that the study duration was adequate to reach steady state, the trough plasma concentrations of rosuvastatin, N-desmethyl rosuvastatin, and telmisartan on days 5 and 6 were compared (Table V). There were no significant differences between days 5 and 6 in any treatment, indicating that steady state had been reached.

DISCUSSION This study was undertaken to investigate the pharmacokinetic drug–drug interaction between rosuvastatin and telmisartan in a healthy Korean population. Pharmacokinetic analyses revealed the possibility that both rosuvastatin and telmisartan were mutually influenced by pharmacokinetic interactions when the 2 drugs were coadministered. Both drugs were administered for 6 consecutive days at high doses to maximize the possibility of drug interactions.

Table V. Comparison of trough plasma concentrations of the 3 drug substances between 96 hours (day 5) and 120 hours (day 6) after the first dose. Substance Rosuvastatin N-desmethyl rosuvastatin Telmisartan

Formulation

P*

R RþT R RþT T RþT

0.8265 0.5026 0.4270 0.0687 0.9911 0.6584

R ¼ monoadministration of rosuvastatin 20 mg once daily for 6 days; R þ T ¼ coadministration of rosuvastatin 20 mg and telmisartan 80 mg once daily for 6 days; T ¼ monoadministration of telmisartan 80 mg once daily for 6 days. * Paired t test

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In part 1, telmisartan had a significant effect on pharmacokinetic exposures of rosuvastatin, yielding increases in AUCτ and Cmax,ss of rosuvastatin by 1.1783- and 2.0123-fold, respectively, when coadministered with telmisartan. This can be explained by the pharmacokinetic characteristics of the 2 drugs, in that they share the same transporter proteins in hepatic uptake and biliary excretion. As described in the Introduction, rosuvastatin is transported to the liver by OATP1B1/1B3 and excreted to the bile by BCRP, MDR1, and MRP2, of which OATP1B3 and MRP2 are also responsible for the hepatic uptake and biliary excretion of telmisartan, and BCRP, MDR1, and MRP2 for the biliary excretion of its metabolite, telmisartan acylglucuronide. Therefore, it was surmised that telmisartan and its metabolite competitively inhibit the binding between rosuvastatin and OATP1B3, BCRP, MDR1, and MRP2 and thus reduced rosuvastatin’s influx into the liver and efflux into the bile, leading to increases in rosuvastatin concentrations in the blood.21–23 Given that Tmax is influenced by both absorption and elimination rates for an orally administered drug, the significant decrease in rosuvastatin’s Tmax during coadministration might be explained by its reduced biliary excretion caused by telmisartan. One interesting finding here is that Tmax,ss of rosuvastatin for coadministration, which is 0.75 hour, exactly matched that of telmisartan. Considering that Tmax,ss is the time to the peak plasma concentration of a drug, this finding indicates that the interaction between the 2 drugs was maximal when the plasma concentration of telmisartan was the highest. As for N-desmethyl rosuvastatin, similar to rosuvastatin, Cmax,ss significantly increased and Tmax,ss significantly decreased. This significant change in Cmax,ss and Tmax,ss of N-desmethyl rosuvastatin can be explained as follows: N-desmethyl rosuvastatin, the major metabolite of rosuvastatin, is formed by cytochrome P-450 2C9 in the liver and also primarily excreted via the biliary route,9 where transporter proteins associated with the latter process also relate to the biliary excretion of telmisartan and its metabolite, as explained previously. Because coadministration of rosuvastatin and telmisartan would reduce the hepatic uptake of rosuvastatin, which in turn would reduce the formation of Ndesmethyl rosuvastatin in the liver, it can be conjectured that the increased Cmax,ss of N-desmethyl

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Clinical Therapeutics rosuvastatin would be attributed to telmisartan’s inhibitory effect on the biliary excretion of Ndesmethyl rosuvastatin being sufficiently large enough to exceed the effect of decreased formation of Ndesmethyl rosuvastatin. The result that Tmax,ss for Ndesmethyl rosuvastatin decreased to 1.0 hour, close to that for telmisartan, can be similarly explained as in rosuvastatin by the maximal inhibition between the 2 drugs occurring near or at Tmax,ss of telmisartan. In contrast, AUCτ of N-desmethyl rosuvastatin did not significantly increase. The reason might be that the increased Cmax,ss of N-desmethyl rosuvastatin was compensated by decreased concentrations of N-desmethyl rosuvastatin at later time points, which were lower than those in monoadministration. This would make sense considering that the interaction between telimsartan and N-desmethyl rosuvastatin would become weaker as the plasma concentration of telmisartan quickly drops after Tmax,ss, as seen in Figure 2. The reason that AUCτ of rosuvastatin significantly increased would be that the increase in Cmax,ss of rosuvastatin was large enough to overcome such compensation effect. In part 2, AUCτ and Cmax,ss of telmisartan increased by 1.1717- and 1.3501-fold, respectively, when coadministered with rosuvastatin. Due to the fact that telmisartan is predominantly (497%) eliminated unchanged in the feces via biliary excretion, these findings can be explained by transporters.16 As mentioned previously, the hepatic uptake and biliary excretion of telmisartan is mediated by OATP1B3 and MRP2, which are also involved in the transport of rosuvastatin. Therefore, as discussed in part 1, sharing of the same transporters was thought to be a possible reason that the pharmacokinetic exposure of telmisartan increased when coadministered with rosuvastatin. However, unlike for rosuvastatin and N-desmethyl rosuvastatin, Tmax,ss of telmisartan did not change significantly when coadministered with rosuvastatin. The reason for this insignificant change might be that when rosuvastatin and N-desmethyl rosuvastatin reached their peak plasma concentrations, which occurred 5 and 4 hours after dosing, respectively, the plasma concentration of telmisartan already decreased close to the trough level, with the chances of maximal inhibition becoming low. However, the nature of drug– drug interaction between the 2 drugs is still not definitively understood, and further studies are needed to better elucidate the underlying mechanisms.

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Other examples of drug–-drug interaction that can be similarly explained by drug transporters in this study are found elsewhere. For rosuvastatin, its pharmacokinetic exposure was reported to increase in combination with cyclosporine through the inhibition of rosuvastatin hepatic uptake mediated by OATP-C.24 It was also reported that rosuvastatin concentration increased in combination with lopinavir/ ritonavir, probably mediated by the inhibition of OATP1B1 or BCRP.25 For telmisartan, its AUCss was reported to be increased by nisoldipine-induced inhibition of MDR1.26 It has been reported that rosuvastatin and telmisartan are characterized by flat dose–response curve at high doses27,28 and thus a moderate degree of pharmacokinetic interaction, although statistically significant, can be regarded not to have clinical significance. For example, the prescription information for rosuvastatin states that the influence of coadministered dronedarone or itraconazole on rosuvastatin is clinically insignificant with no dose adjustment recommended, although these drugs can increase the AUC of rosuvastatin by 1.4-fold when coadministered.29 This increase in rosuvastatin’s AUC was larger than that observed in our case, and we concluded that the pharmacokinetic changes in rosuvastatin and telmisartan arising from coadministration of the 2 drugs, although statistically significant, had no clinical influence. AEs were mild to moderate, with no serious AEs reported. None of the withdrawals from the study were considered by the investigators to be related to the study medication, and the incidence was not significantly different between mono- and coadministration treatments. The study power was 480% for all primary pharmacokinetic parameters except for Cmax,ss of telmisartan, which was 76%. However, given that this study was not designed to test the bioequivalence of 2 different modes of administration, which requires power 480%, the slightly lower power obtained for Cmax,ss of telmisartan would not affect the overall study results. Our claim is also based on the US Food and Drug Administration Guidance on Drug Interaction Studies, which does not require the power analysis in sample size determination.30 We note that a limitation of our study is that it was conducted with a small number of healthy male subjects selected with very narrow inclusion and exclusion criteria and may therefore be difficult to

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M. Son et al. generalize. Further studies with a wider range of subjects may be needed, including dyslipidemia and hypertension patients.

5.

CONCLUSIONS Our results demonstrated that both rosuvastatin and telmisartan were influenced by pharmacokinetic interactions between the 2 drugs. The systemic exposures of rosuvastatin and telmisartan significantly increased during coadministration, which could be explained by the drug transporter proteins shared by the 2 drugs. These pharmacokinetic changes, however, were not regarded as clinically significant based on dose– response characteristics of the 2 drugs and previous results from other interaction studies. All treatments were well tolerated, with no serious AEs observed.

6.

7. 8.

9.

ACKNOWLEDGMENTS This study was supported and monitored by Yuhan Corporation. Mijeong Son was supported by the Brain Korea 21 Plus Project for Medical Science, Yonsei University. Mijeong Son contributed to the study design, study conduct, data collection, data interpretation, literature search, figure creation, and writing. Yukyung Kim and Donghwan Lee contributed to the study design, study conduct, and data collection. Hyerang Roh contributed to the study conduct. Hankil Son and Jinju Guk contributed to the data interpretation. Seong Bok Jang and Su Youn Nam contributed to the study design and data interpretation. Kyungsoo Park contributed to coordinating the entire process of the study.

CONFLICTS OF INTEREST

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11. 12.

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14.

15.

The authors have indicated that they have no conflicts of interest regarding the content of this article.

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30. US Food and Drug Administration Center for Drug Evaluation and Research, Guidance for Industry: Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations, 2012. http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegula toryInformation/Guidances/ucm2 92362.pdf Accessed April 27, 2014.

Address correspondence to: Kyungsoo Park, PhD, MD, Department of Pharmacology, Yonsei University College of Medicine, 134 Shinchondong, Seodaemun-gu, Seoul 120-752, Republic of Korea. E-mail: kspark@yuhs. ac

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