Pharmacokinetic Interactions of Valsartan and Hydrochlorothiazide: An Open-Label, Randomized, 4-Period Crossover Study in Healthy Egyptian Male Volunteers

Clinical Therapeutics/Volume 35, Number 6, 2013

Pharmacokinetic Interactions of Valsartan and Hydrochlorothiazide: An Open-Label, Randomized, 4-Period Crossover Study in Healthy Egyptian Male Volunteers Mohsen A. Hedaya, PharmD, PhD1; and Sally A. Helmy, PhD, CPHQ2 1

Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, Kuwait; and 2Department of Pharmaceutics, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt

ABSTRACT Background: Co-administration of valsartan (VAL) and hydrochlorothiazide (HCT) has been used to regulate blood pressure. Compliance with a multiple medication regimen can be difficult for some patients; therefore, a combination of VAL þ HCT tablets may be a suitable alternative. Objective: This study was conducted to compare the rate and extent of absorption of VAL and HCT after oral administration as a fixed-dose combination (FDC) tablet and concomitant administration of the individual drugs under fasting conditions in healthy Egyptian subjects. The study was extended to investigate any potential interaction between VAL and HCT. Methods: This study was conducted as an openlabel, randomized study with 2 parts (parts I and II), with each part consisting of 4 single-dose treatment periods with a crossover design and 2-week washout periods. Blood samples were collected up to 48 hours postdose, and plasma was analyzed for VAL and HCT concentrations by using HPLC. The pharmacokinetic properties of each drug after co-administration of VAL and HCT were compared with those of each drug administered alone. Tolerability was assessed by physical examination and verbally questioning subjects regarding their well-being and any feelings of discomfort. All events reported by the subjects were recorded in adverse-event forms. Results: Forty-eight healthy subjects were enrolled (24 in each part), and all subjects completed the study. None of the participants showed any sign of adverse drug reactions during or after the completion of the study. Statistical analysis confirmed that the 90% CIs for AUC and Cmax of VAL/HCT FDC and VAL þ HCT were within the commonly accepted bioequivalence range of 0.8 to 1.25. As a result, from an in vivo pharmacokinetic perspective, 1 FDC tablet could be considered interchangeable in medical practice with

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the 2 individual reference tablets. However, the 90% CIs between VAL alone and when administered with HCT, either as FDC or concomitantly, indicated the presence of an interaction between VAL and HCT, which would significantly decrease the systemic exposure and intensity of VAL absorption. The coadministration of HCT with VAL decreased the AUC and Cmax of HCT nonsignificantly compared with administration of HCT alone. Conclusions: Both VAL/HCT FDC and VAL þ HCT were well tolerated. The safety/efficacy profile of VAL þ HCT co-administration therapy could be extended to the VAL/HCT FDC tablet. The interaction of HCT with other angiotensin-receptor blockers should be investigated to determine whether this interaction is limited to VAL or if other angiotensinreceptor blockers have the same pharmacokinetic interactions. Further studies are necessary to determine the role of efflux and influx transporters on VAL and HCT disposition and pharmacokinetics. (Clin Ther. 2013;35:846–861) & 2013 Elsevier HS Journals, Inc. All rights reserved. Key words: fixed-dose combination, hydrochlorothiazide, pharmacokinetics, valsartan.

INTRODUCTION Current US and European hypertension treatment guidelines recommend first-line combination therapy with 2 antihypertensive agents in patients with systolic blood pressure (BP) 420 mm Hg or diastolic BP 410 mm Hg above goal levels.1,2 Single-pill combinations have been shown to enable more rapid and effective Accepted for publication April 30, 2013. http://dx.doi.org/10.1016/j.clinthera.2013.04.014 0149-2918/$ - see front matter & 2013 Elsevier HS Journals, Inc. All rights reserved.

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M.A. Hedaya and S.A. Helmy achievement of BP goals. These combinations resulted in a reduction in cardiovascular events in patients with substantially elevated BP (systolic BP ≥160 mm Hg) and a history of cardiovascular disease, stroke, or diabetes mellitus.3,4 Valsartan (VAL) is an angiotensin-receptor blocker (ARB) that can be used to treat a variety of cardiac conditions, including hypertension, diabetic nephropathy, and heart failure.5–7 VAL lowers BP by antagonizing the renin-angiotensin system. It is a potent and highly selective angiotensin II receptor type I antagonist that lowers BP in patients with hypertension. Unlike angiotensin-converting enzyme (ACE) inhibitors, ARBs do not have the adverse effect of dry cough8 and have no effect on pulse rate.9 The mean reduction in diastolic and systolic BP is 6 to 9 mm Hg and 3 to 6 mm Hg, respectively, after a single oral administration of VAL 80 to 320 mg.9 Over the last 5 years, interest in VAL increased after Wang et al10 discovered that it significantly reduced the risk of Alzheimer disease, even when delivered at a dose lower than that used for hypertension treatment in humans. VAL is rapidly absorbed from the gastrointestinal tract, with a peak plasma concentration reached 2 to 4 hours after oral administration.11,12 Absolute bioavailability for VAL is 25% (range, 10%–35%).11 It can be administered with or without food and demonstrates antihypertensive effects for  24 hours. The pharmacokinetics of VAL are linear and dose proportional across a wide dose range (80–320 mg).13 Plasma values decrease mostly in the unchanged form,14 with a t1/2 of 7 to 14 hours.11 VAL is eliminated predominantly via bile (o80%) and urine (o20%). It is minimally ( 9%) metabolized via cytochrome P450 2C9,14 which is the only form responsible for 4-hydroxylation of VAL in human liver microsomes.15 Hydrochlorothiazide (HCT) is a thiazide diuretic used alone or with other medicines to treat hypertension. It enhances the action of other antihypertensive drugs and prevents the development of resistance to various adrenergic blocking and vasodilator agents used for treating patients with hypertension.16 It is used to reduce the amount of water in the body by increasing the flow of urine and removal of salts, such as potassium and sodium, from the blood into urine.17 Although the mechanism of the antihypertensive effect of thiazides is not fully understood,16 they seem to

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have an important direct vasodilator effect. HCT is incompletely but fairly rapidly absorbed from the gastrointestinal tract.18 Peak plasma concentrations occur between 60 and 120 minutes. It is not metabolized and is excreted into urine without being changed. HCT reportedly has a bioavailability of 65% to 70%, and the serum t1/2 is estimated to be in the range of 5 to 15 hours.17–21 A combination of an ARB, such as VAL, with a thiazide diuretic, such as HCT,22,23 is a widely used approach that provides complementary modes of action for the treatment of edema and hypertension.24 The combined use of VAL and HCT is an effective and well-tolerated therapy for the treatment of hypertension because of the agents’ additive effect on lowering BP. HCT lowers BP by directly reducing sodium and water retention; indirectly, the diuretic action of HCT reduces plasma volume, with consequent increases in plasma renin activity.25 This action limits the antihypertensive effect of diuretics; hence, co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics24 and is considered a logical step for additional BP reduction.23 Furthermore, the inhibition of the renin-angiotensin system provides additional renoprotective effects that are independent of BP lowering.26–28 Clinical studies of VAL/HCT suggest that this combination is clinically effective with a favorable safety profile.29–32 VAL/HCT provided consistent BP lowering and tolerability regardless of age, obesity, and prevalence of type 2 diabetes and greater efficacy in patients with high cardiovascular risk. Fixed-dose combination (FDC) tablets offer a simpler treatment regimen than taking the individual drugs in free combination.33 VAL/HC FDC tablets at doses of 160/12.5 and 160/25 mg are approved in the European Union and the United States for the treatment of essential hypertension in patients whose goal BP is not achieved with either VAL or HCT alone and who likely need multiple drugs for managing uncontrolled hypertension. Bioequivalence is achieved if the 90% CIs for the log-transformed geometric mean ratio (FDC tablets/coadministration) of AUC0–∞ and Cmax of both VAL and HCT fall within the prespecified bioequivalence range (0.8–1.25), according to international guidelines.34,35 Few data have been reported for the bioavailability of VAL and HCT taken concomitantly or in FDC. One

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Clinical Therapeutics available article is in Chinese.36 It is therefore important to demonstrate that the formulation of the VAL/HCT FDC tablets does not affect the bioavailability of the component agents and to confirm that patients already taking the combination of VAL and HCT can switch to the FDC tablet. Drug–drug interactions (DDIs) have focused on inhibition or induction of drug-metabolizing enzymes, most notably those of the CYP families.37 However, it has become evident that significant DDIs may result from inhibition and probably also from induction of transporter function.38 A potential for interactions with these enzymes or transporters exists with ACE inhibitors and ARBs but not with diuretic antihypertensive agents, such as HCT, which are renally eliminated and more vulnerable to drug interactions that occur in the kidney.19 In addition, Nakashima et al15 emphasized that although CYP2C9 was involved in VAL metabolism, CYP-mediated DDI between VAL and other co-administered drugs would be negligible. The available data regarding the pharmacokinetic (PK) interaction between VAL and HCT are rare and contradict each other. For example, according to the manufacturer’s prescribing information,24 the systemic availability of HCT was reduced by 30% when co-administered with VAL. In addition, coadministration of HCT decreased peak concentrations of VAL by 13% and the systemic exposure of VAL by 17%. This observed interaction had no impact on the combined use of VAL and HCT because controlled clinical trials had shown a clear antihypertensive effect, greater than that obtained with either drug administered alone or placebo.24 Conversely, Jiang et al39 confirmed that VAL greatly increased the concentration of HCT in plasma during coadministration in which concomitant administration of VAL with HCT led to a significant increase ( 1.5fold) in Cmax and AUC0–48 of plasma HCT even without dose normalizing. Accordingly, evaluating the PK interaction between VAL and HCT was a prerequisite in the current study. The aim of the current study was to compare the PKs of VAL/HCT 160/12.5-mg and 320/25-mg FDC tablets and co-administration of corresponding doses of VAL and HCT as individual tablets (VAL þ HCT) and to discuss if there is any potential PK interaction between VAL and HCT compared with each drug administered alone in healthy, normotensive adult Egyptian subjects.

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SUBJECTS AND METHODS This study was monitored in accordance with the International Conference on Harmonisation guidance regarding general considerations for clinical trials.40 The protocol was approved by the ethical committee of Tanta University Hospital. All subjects provided written informed consent to participate in the study after they had been informed of the study objectives, methods, and possible risks.

Study Design The study doses of VAL and HCT were determined based on dosage regimens of FDC required for patients with hypertension (VAL, 80, 160, or 320 mg once daily; HCT, 12.5 or 25 mg once daily). To maximize the possibility of finding DDIs, 160 and 320 mg of VAL and 12.5 or 25 mg of HCT were used. These are the maximum doses according to the terms of safety and therapeutic efficacy. This study was conducted as an open-label, randomized study with 2 parts (parts I and II), with each part consisting of 4 single-dose treatment periods with a crossover design. The overall study design is illustrated in Figure 1. Subjects were randomized (1:1) to participate in 1 part of the study (i.e., I or II only), during which they received a single oral dose of 4 treatments separated by a 2-week washout period. Each dose administration was followed by 240 mL of water after a 12-hour overnight fast. Participants continued fasting for another 4 hours after drug administration. Part I consisted of treatments A (VAL 160 mg alone), B (HCT 12.5 mg alone), C (VAL 160 mg þ HCT 12.5 mg), and D (VAL/HCT 160 mg/12.5 mg). Part II consisted of treatments E (VAL 320 mg alone), F (HCT 25 mg alone), G (VAL 320 mg þ HCT 25 mg), and H (VAL/HCT 320 mg/25 mg). The order in which each subject received treatments was randomly assigned. Volunteers received standardized meals 4 and 9 hours after the last dosing. After discharge, they visited the center for the assessment of tolerability and PK properties of the study drugs. After a 2-week washout period to ensure complete elimination of the first dose (5-fold the t1/2 of VAL and HCT),11,17,20,21 the same procedure was repeated with the other treatments until the last follow-up visit for safety profile assessment. All dietary, smoking, and drug/ herbal product restrictions were maintained throughout the study period.

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Figure 1. (A) Volunteer enrollment. (B) Design of comparative bioavailability study in healthy male Egyptian volunteers. HCT ¼ hydrochlorothiazide; VAL ¼ valsartan. Treatment A ━ (VAL 160 mg); Treatment B ╍ (HCT 12.5 mg); Treatment C ┄ (VAL 160 mg þ HCT12.5 mg); Treatment D — (VAL/HCT 160 mg/12.5 mg); Treatment E ━ (VAL 320 mg); Treatment F ╍ (HCT 25 mg); Treatment G ┄ (VAL 320 mg þ HCT 25 mg); Treatment H — (VAL/HCT 320 mg/25 mg).

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Subjects Healthy volunteers were recruited (through advertisements posted around the medical center) and assessed for inclusion in the study. Volunteers were selected randomly from a volunteer database and underwent a standardized screening procedure 14 days before admission. Eligible volunteers were Egyptian men aged between 18 and 33 years, with a weight 460 kg and a body mass index between 20 and 26 kg/m2. Forty-eight healthy Egyptian male volunteers who met the following inclusion criteria were recruited to this study34,35: (1) at least 18 years and not more than 45 years old; (2) actual weight no more than ⫾30% from ideal weight based on sex, height, and body frame; (3) had passed all the screening parameters; (4) free of any drug exposure known to interfere with the PKs or assay of VAL and HCT for at least 10 days before the study; and (5) were able to communicate effectively with study personnel, be literate, and able to give consent. Subjects were selected for study after clinical assessment of their health status according to medical

history (including the recording of any illnesses, allergies, consumption of tobacco, alcohol, drugs of abuse, and concomitant medication), physical examination, body temperature measurement, weight, height measurements, and electrocardiography. After a physical examination (to exclude any abnormality of the cardiovascular, respiratory, abdominal, or central nervous system), BP and heart rate were measured and a general examination of the subject was conducted to exclude any illness or abnormality (e.g., anemia, cyanosis, clubbing, jaundice, lymphadenopathy). Resting BP was recorded by using a sphygmomanometer while the subject was in a sitting position. Blood samples (10 mL) were collected for full blood cell count, urea, electrolytes, liver function tests, renal function tests, and random blood glucose. Serologic tests were conducted for the presence of hepatitis B surface antigen, hepatitis C virus antibody, and HIV antibodies. Urine samples were also collected for microscopic examination analysis. Subjects were

Table I. Demographic characteristics and baseline data of hematologic and biochemical parameters of healthy Egyptian subjects in the pharmacokinetic studies. Values are given as mean (SD) [range]. Characteristic

Part I*

Part II†

Age, y 23.9 (3.9) [18–31] 26.1 (5.1) [21–33] Weight, kg 72.2 (7.6) [60–86] 75.9 (6.1) [63–84] Height, cm 171.4 (5.6] [163–184] 176.4 (7.0) [160–180] 2 22.5 (1.8) [21.2–26] 23.9 (4.1) [20.7–24.1] BMI, kg/m Systolic BP, mm Hg 121.3 (5.3) [110–125] 124.1 (7.1) [110–125] Diastolic BP, mm Hg 77.3 (4.1) [73–80] 80.5 (8.0) [78–80] Pulse, beats/min 76.1 (4.4) [70–81] 75.4 (7.2) [70–78] Creatinine, mg/dL 0.86 (5.1) [0.8–1.2] 0.89 (4.7) [0.8–1.1] Alkaline phosphatase, UI 65.4 (8.9) [42–95] 61.1 (5.1) [42–95] Glucose, mg/dL 83.2 (5.2) [80–95] 81.3 (3.2) [82–90] Uremia, mg/dL 22.0 (7.0) [0–25] 12.0 (4.0) [0–20] AST, UI 22.3 (5.1) [10–35] 20.7 (6.1) [8–22] ALT, UI 19.7 (6.9) [8–40] 18.6 (3.0) [8–40] Hematocrit 41.8 (4.1) [40–56] 42.6 (3.2) [40–48] 6600.7 (999.1) [5000–8500] 6904.7 (1200.1) [5000–9000] Leukocytes, /mm3 Hemoglobin, mg/dL 14.8 (2.7) [13–15] 13.9 (4.1) [13–15] Total bilirubin, mg/dL 0.82 (6.1) [0.3–1.1] 0.75 (5.4) [0.5–1.2]

Normal Range NA NA NA 18–30 120 80 70–80 0.8–1.5 38.0–126.0 60.0–100.0 0.0–50.0 5.0–40.0 7.0–56.0 40.0–54.0 5000–10,000 13.0–16.0 0.2–1.3

NA ¼ not applicable; BMI ¼ body mass index; BP ¼ blood pressure; AST ¼ aspartate aminotransferase; ALT ¼ alanine aminotransferase. * Part I involved the lowest dose of individual tablets (160-mg VAL or 12.5-mg HCT), concomitant administration (160-mg VAL+ 12.5-mg HCT) and FDC (160/12.5-mg VAL/HCT). † Part II involved the maximum dose of individual tablets (320-mg VAL or 25-mg HCT), concomitant administration (320mg VAL+ 25-mg HCT) and FDC (320/25-mg VAL/HCT).

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M.A. Hedaya and S.A. Helmy admitted to the study after a review of pathology reports, medical history, and confirmation that they met all the study inclusion and exclusion criteria. The demographic characteristics and baseline data of hematologic and biochemical parameters of the participants are summarized in Table I. On completion of study, the physical examination and clinical laboratory measurements were repeated. Blood samples were drawn from each subject at study end for assessment of all laboratory parameters as mentioned here, except for serologic tests, which were not redone. The subjects were instructed to abstain from taking any medication for at least 10 days before and during the study period. They were also prohibited from consuming caffeinated beverages within 3 days of the first dosing administration and until completion of the study. The use of drugs or caffeinated beverages was identified by self-report and medical history taken by the study investigator. During the studies, strenuous physical exercise, as well as intake of xanthine-containing food or beverages and alcohol, was not permitted. Subjects were excluded if they had any of the following: (1) a clinically significant abnormal physical examination, medical history, or laboratory test results; (2) if they had a sitting systolic BP Z140 or o100 mm Hg, diastolic BP Z90 or o60 mm Hg, or a pulse rate Z95 beats/min or o50 beats/min at screening; (3) a history of serious intolerance, allergy, or sensitivity to VAL or HCT; (4) the use of any prescription drug within the previous month or use of any over-thecounter medication (with the exception of acetaminophen) within the last 10 days; (5) a history of blood dyscrasias; (6) a history of alcohol or drug abuse; (7) donation of blood during the 8 weeks before the study or plans to donate blood during or within 8 weeks of completing the study; (8) unable to tolerate vein puncture and multiple blood samplings; (9) any surgical/medical condition that might alter drug absorption, distribution, metabolism, or excretion; or (10) could not follow instructions, in the investigator's opinion.

Sample Collection On the day of PK evaluation, blood samples (5 mL) were collected from an indwelling intravenous cannula inserted into the antecubital vein of the forearm of each volunteer before drug administration (blank); samples (5-mL each) were then obtained at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, and 48

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hours after drug administration in heparinized tubes (a total of 16 blood samples). Normal saline was used to flush the cannula between sampling. The first 0.5 mL of blood was discarded before the 5-mL sample was collected. The first 1 mL of blood drawn at each sampling time was discarded. Blood samples were centrifuged, and the plasma was harvested and stored at 801C until assay for both VAL and HCT by using a validated HPLC method.

Tolerability Assessment Throughout the study, the subjects were questioned and examined for the presence of adverse drug reactions (ADRs). Tolerability was assessed based on changes in vital signs (temperature, BP, pulse, and heart rate) and laboratory tests (hematology, biochemistry, liver function, and urinalysis). The vital signs were measured before dosing in each period and approximately every 4 hours thereafter; laboratory tests were performed at baseline and at the end of the study. In addition, a physician questioned volunteers about any adverse events occurring during the study, addressed them as required, and recorded them on the appropriate form. This physician was not blinded to treatment but had no involvement in the study.

Bioanalytic Assessments The plasma levels of VAL and HCT concentrations were determined by using a validated HPLC assay method. The HPLC was equipped with fluorescence or ultraviolet detectors for the determination and quantification of VAL and HCT, respectively. For VAL, the mobile phase comprised 20 mM of ammonium dihydrogen orthophosphate (pH was adjusted to 3.2 by phosphoric acid) and acetonitrile (40:60, vol/vol). The analysis was run at a flow rate of 1.7 mL/min on a Hypersil C18 column (250 mm  4.6 mm, 5 μm; Thermo Fisher Scientific, Waltham, Massachusetts). The effluent was monitored by using a model RF-10A XL Shimadzu fluorescence detector (Shimadzu Scientific Instruments, Kyoto, Japan) set at 255 nm for excitation and 370 for emission for VAL and the internal standard (IS; etodolac). For HCT, the mobile phase comprised 0.05% hexane sulfonate in 0.6% acetic acid and acetonitrile (83:17, vol/vol). The analysis was run at a flow rate of 1.7 mL/min on a Hypersil C18 column (250 mm  4.6 mm, 5 μm; Thermo Fisher Scientific). The effluent was monitored by using a model SPD-10AVP Shimadzu

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UV-VIS detector set (Shimadzu Scientific Instruments) at 271 nm for HCT and the internal standard (tinidazole). The peak areas for VAL and HCT were integrated electronically by using the Class-VP data analysis program (Shimadzu Scientific Instruments) and used to calculate the peak area ratio of the drug and IS. The calibration standards of VAL were prepared by transferring 25 μL from each working solution and IS (etodolac) to a set of test tubes. The solvent was evaporated, and 0.25 mL of blank plasma was added to each tube to form a set of calibration standards with concentrations of 0.01, 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 5, and 10 mg/mL. The sample was vortexed and then 0.5 mL of methanol was added, shaken for 1 minute, and centrifuged at 3000 rpm for 7 minutes. The supernatant was separated, and 25 μL was injected into the HPLC. For the analysis of the study samples, 0.25 mL of each was transferred to a clean test tube. The study samples were treated as the calibration standards after addition of the IS (etodolac). Under the chromatographic condition described earlier, the mean retention time of VAL and IS was 2.9 (0.2) minutes and 4.1 (0.1) minutes, respectively (Figure 2). For HCT, the calibration standards were prepared by transferring 50 μL from each working solution and IS (tinidazole) to a set of test tubes. The solvent was evaporated, and 0.5 mL of blank plasma was added to each tube to form a set of calibration standards with concentrations of 1, 2, 5, 10, 20, 50, 100, 200, and 500 ng/mL. The sample was vortexed and then the calibration standards were extracted by adding 5 mL of diethyl ether and shaken for 1 minute. They were then centrifuged at 3000 rpm for 7 minutes. The diethyl ether layer was transferred to clean test tubes and evaporated in a water bath at 601C under nitrogen flow, then reconstituted with 250 μL of the mixture (methanol:0.05% hexane sulfonate in 0.6% acetic acid [1:1]). The resulting solution was transferred to clean HPLC vials, and 50 μL was injected into the HPLC. For the analysis of the study samples, 0.5 mL of each was transferred to a clean test tube. The study samples were treated as the calibration standards after addition of the IS (tinidazole). Under the chromatographic condition described earlier, the retention time of HCT and IS was 4.3 (0.2) and 5.2 (0.1) minutes, respectively (Figure 3). The method was developed and validated in terms of selectivity, linearity, precision, accuracy, sensitivity, recovery, lower limit of quantitation (LLOQ), and stability

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Figure 2. Representative chromatograms for (A) blank plasma sample, (B) blank plasma spiked with valsartan (VAL) to produce a drug concentration of 5 mg/mL and internal standard (IS), and (C) plasma sample that was obtained after administration of VAL to a volunteer.

according to the US Food and Drug Administration guideline for bioanalytical method validation.41 The linearity of the calibration curve in human plasma was confirmed by plotting the peak-area ratios of (drug/IS) versus the corresponding VAL and HCT concentrations with least squares linear regression analysis. The calibration curves were linear, with a correlation coefficient 40.999 throughout the course of the assay (0.01–10 mg/mL) and for VAL and HCT (1–500 ng/mL), respectively. The LLOQ was 0.01 mg/ mL for VAL and 1 ng/mL for HCT. Quality control samples were analyzed to assess the accuracy and precision of the method. The concentrations of the quality control samples were 5, 0.5, and 0.05 μg/mL and 200, 20, and 2 ng/mL for VAL and HCT,

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curves. Values for t1/2 were calculated as 0.693 divided by ke. The AUC0–t was calculated by using the linear trapezoidal rule. AUC0–∞ was calculated as AUC0–∞ (AUC0–t þ C/ke), where C is the last measured concentration.42,43 Cmax and Tmax were obtained directly from the individual plasma concentration–time curve. CL/F was calculated as dose/ AUC0–∞. Vd/F was estimated as oral clearance/ke relative to the bioavailability of each drug. The area under the first moment curve (AUMC) was calculated by trapezoidal integration and extrapolation to infinity. MRT was calculated as the ratio (AUMC)/ (AUC0–∞).42,43

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Figure 3. Representative chromatograms for (A) blank plasma sample, (B) blank plasma spiked with hydrochlorothiazide (HCT) to produce a drug concentration of 150 ng/mL and internal standard (IS), and (C) plasma sample that was obtained after administration of HCT to a volunteer.

respectively. The within-day %CV ranged from 1.5% to 8.1% and 1.7% to 12.6 % for VAL and HCT, respectively; the between-day %CV ranged from 1.7% to 9.1% and 2.7% to 11.6 % for VAL and HCT. Results of stability testing showed that both VAL and HCT are stable in plasma for at least 24 hours at room temperature and for 3 months in frozen plasma at –801C.

PK Analysis The following PK parameters were measured for VAL and HCT: AUC0–∞, Cmax, Tmax, t1/2, mean residence time (MRT), Cl/F, and Vd/F. A noncompartmental PK analysis was performed on plasma drug concentration–time data; ke was estimated by least squares regression of plasma concentration–time data points in the terminal log-linear region of the

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The sample size of this study was calculated based on the number estimated to provide Z80% power at a significance level of 0.05.44 It was calculated by using the intrasubject %CVs for AUC0–∞ and Cmax parameters of 25% and 30%, respectively, with an expected ratio between 0.90 and 1.05. Statistical comparisons between phases were made with a 1way analysis of variance model by using the Minitab Statistical Package version 13 (Minitab, State College, Pennsylvania) on an IBM PC for crossover design.45 AUC0–t, AUC0–∞, and Cmax were evaluated after logarithmic transformation according to international guidelines,34,35 providing point estimates and 90% CIs46,47 for the T/R ratio. A P value of ≤0.05 and 90% CIs fell away from the specified limit of 80% to 125% and were taken as the level of significance.

RESULTS Baseline Characteristics Forty-eight male volunteers (age range, 18–33 years; weight range, 60–86 kg; height range, 160– 184 cm) were chosen to participate, and they all completed the study. The demographic characteristics of volunteers are depicted in Table I. The baseline characteristics of the 2 treatment groups were not significantly different in either study part. In study part I, 24 healthy male volunteers (mean [SD] age, 23.9 [3.9] years; weight, 72.2 [7.6] kg; height, 171.4 [5.6] cm) were enrolled and completed the study. In study part II, 24 healthy male volunteers (mean age, 26.1 [5.1] years; weight, 75.9 [6.1] kg; height, 176.4 [7.0] cm) were enrolled and completed the study. Safety profiles and PK characteristics were

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The mean plasma concentration–time curves of VAL and HCT administered orally on different occasions as a single dose are represented in Figures 4 and 5. Both VAL and HCT were readily absorbed from the gastrointestinal tract, and they were measurable at the first sampling time (0.25 hour) in almost all volunteers. The mean PK parameters of VAL with HCT are summarized in Table II. The PK parameters of VAL and HCT were similar in case of FDC and concomitant administration. The co-administration of VAL with HCT significantly decreased the systemic absorption represented by AUC ( 26%–34%) and the intensity of absorption represented by Cmax ( 22%–28%) of VAL compared with the administration of VAL alone. However, the co-administration of HCT with VAL decreased the AUC ( 3%–14%) and Cmax (  6%–7%) of HCT nonsignificantly compared with the administration of HCT alone. Concerning the rate of absorption, the Tmax of both VAL and HCT showed a nonsignificant increase when administered concomitantly or as a FDC compared with the administration of each drug alone.

DISCUSSION The majority of patients with hypertension require combination therapy to achieve their BP goal. Studies have consistently shown that polypharmacy and complex treatment regimens have a detrimental effect on treatment compliance and adherence.48 A combination of ARBs and diuretics is a preferred treatment option for managing uncontrolled hypertension in high-risk patients with chronic kidney disease, diabetes, or heart failure because ARBs provide cardiorenal benefits in addition to lowering BP.26–28,48 The use of once-daily single-pill combination therapy with effective and well-tolerated agents will reduce pill burden, lower medical cost, simplify treatment regimens, and improve patient compliance and treatment adherence.48 This, in turn, will help patients reach and maintain their BP target and achieve the short- and long-term treatment goal while mitigating the risks of treatment-related adverse events.11,48

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FDC tablet 160 mg/12.5 mg

VAL Plasma Concentration (µg/mL)

PK Characteristics

4 3.5

Individual tablets 160 mg + 12.5 mg Val 160 mg alone

3 2.5 2 1.5 1 0.5 0 0

10

80 HCT Plasma Concentration (ng/mL)

assessed in all 48 volunteers who completed the 2 parts of the study. All enrolled volunteers were healthy, and none of the participants showed any signs of ADRs during or after completion of the study.

20 30 Time (h)

40

50

FDC tablet 160 mg/12.5 mg Individual tablets 160 mg + 12.5 mg HCT 12.5 mg alone

70 60 50 40 30 20 10 0 0

10

20 30 Time (h)

40

50

Figure 4. In study part I, mean (SE) plasma concentration–time profiles of (A) valsartan (VAL) and (B) hydrochlorothiazide (HCT) after a single dose of VAL/HCT fixed-dose combination (FDC) 160 mg/12.5 mg (●), concomitantly administered VAL 160 mg þ HCT 12.5 mg (○), HCT 12.5 mg alone (▲), and VAL 160 mg alone (Δ). n ¼ 24.

The PKs of VAL and HCT when given alone were in good agreement with findings from previous investigations,49–54 which emphasize the validity of the current results. VAL and HCT were rapidly absorbed after oral administration. Measurable concentrations (ie, those above the LLOQ) were observed 15 to 30 minutes after dosing in cases of VAL administration and 15 to 60 minutes in cases of HCT administration. Peak plasma levels were reached 2 to 4 hours after oral administration of VAL and HCT, then declined with a terminal t1/2

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M.A. Hedaya and S.A. Helmy

VAL Plasma Concentration (µg/mL)

8 FDC tablet 320 mg/25 mg

7

Individual tablets 320 mg + 25 mg Val 320 mg alone

6 5 4 3 2 1 0 0

10

20 30 Time (h)

40

50

HCT Plasma Concentration (ng/mL)

160 FDC tablet 320 mg/25 mg Individual tablets 320 mg + 25 mg HCT 25 mg alone

140 120 100 80 60 40 20 0 0

10

20 30 Time (h)

40

50

Figure 5. In study part II, mean (SE) plasma concentration–time profiles of (A) valsartan (VAL) and (B) hydrochlorothiazide (HCT) after a single dose of VAL/ HCT FDC 320 mg/25 mg (●), concomitantly administered VAL 320 mg þ HCT 25 mg (○), HCT 25 mg alone (▲), and VAL 320 mg alone (Δ). n ¼ 24.

ranging from 6 to 13 hours. VAL and HCT plasma concentrations increased in a nearly proportional manner with dose. In case of VAL, a high intersubject variability in Cmax (%CV, 30.9%–34.9%) and AUC (%CV, 30.1%–39.4%) was observed (Table II), which was in good agreement with previously published data.55,56 The 90% CIs were calculated for the difference between the log-transformed values of mean ratio (T/R) for VAL and HCT PK parameters estimated when they were administered alone, concomitantly, and as an FDC (Table II). In case of co-administration

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of VAL and HCT, the results indicated the similarity of PK parameters of VAL and HCT when given in FDC or concomitantly. This finding was supported by the 90% CIs of log-transformed values of Cmax, AUC0–t, and AUC0–∞, which were always between 80% and 125% for concomitant administration and FDC. The 90% CIs between VAL alone and when administered with HCT, either as FDC or concomitantly, indicated the presence of a DDI between VAL and HCT. This DDI could significantly decrease the systemic exposure and intensity of VAL absorption without any significant effect on the rate of absorption or elimination of VAL, even when the dose of VAL and HCT was doubled. Conversely, the systemic exposure and intensity of HCT were slightly decreased when co-administered with VAL. The previous results commensurate to a great extent with the FDC prescribing information.24 However, the exact mechanism of this DDI is unknown. In general, any drug is eliminated from the body by metabolism, which occurs mainly in the liver and by excretion into bile or urine.57 During these PK processes, a drug molecule passes through several biological membranes. The extent of drug movement through these membranes is generally affected by the physicochemical properties of a drug such as size, lipophilicity, and charge (or degree of ionization). In addition, membrane transporters have a significant role in facilitating or preventing drug movement.38 As a result, in this study, different mechanisms could have been involved in the decreased extent of VAL absorption. Potential explanations are: (1) CYPmediated DDI; (2) displacement of VAL from its protein-binding sites; or (3) effect of efflux and influx transporters. Concerning CYP-mediated DDI, although CYP2C9 was involved in VAL metabolism,14 the DDI between VAL and other co-administered drugs was unlikely to occur because of the low extent of VAL metabolism, in which 85% of orally administered VAL was excreted into bile in unchanged form.14,58 In addition, the CYP was not involved in HCT metabolism (because it was excreted unchanged in urine).19 As a result, CYP-mediated DDI could be ruled out as a reason for the significant decrease in the systemic exposure and intensity of absorption of VAL. Displacement interactions involving plasma or tissuebinding sites could be implicated as 1 of the causative

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Table II. Pharmacokinetic variables presented as mean (%CV) of valsartan (VAL) with hydrochlorothiazide (HCT) after the administration of each drug alone, concomitant administration, and the fixed-dose combination (FDC) in 48 healthy volunteers participated in study parts I and II.

Variable Part I VAL 160 mg Cmax, mg/mL Tmax, h AUC0–t, mg  h/mL AUC0–∞, mg  h/mL t ½, h MRT, h CL/F, L/h Vd/F, L HCT 12.5 mg Cmax, ng/mL Tmax, h AUC0–t , ng  h/mL AUC0–∞, ng  h/mL t ½, h MRT, h CL/F, L/h Vd/F, L Part II VAL 320 mg Cmax, mg/mL Tmax, h AUC0–t, mg  h/mL AUC0–∞, mg  h/mL t ½, h MRT, h CL/F, L/h Vd/F, L HCT 25 mg Cmax, ng/mL Tmax, h AUC0–t, ng  h/mL AUC0–∞, ng  h/mL t ½, h MRT, h CL/F, L/h Vd/F, L

VAL Alone

4.1 3.4 41.2 43.1 11.8 8.4 4.4 36.9

HCT Alone

(34.9) (30.6) (39.4) (38.9) (20.6) (19.7) (36.5) (33.1)

3.1 3.6 28.8 30.3 11.8 8.7 5.8 42.9 77.9 2.8 797.7 826.5 10.9 7.8 16.2 123.2

8.0 3.3 82.0 84.9 11.8 8.6 4.3 35.6

VAL þ HCT Concomitantly Administered

(31.4)* 0.73 (0.83–0.64) (41.1) (30.5)* 0.58 (0.49–0.67) (30.1)* 0.59 (0.48–0.7) (33.0) (18.8) (36.4) (40.0)

VAL/HCT FDC

3.2 3.6 30.6 32.2 12.0 8.6 5.6 45.0

Geometric Mean (90% CI)

(33.6)* 0.72 (0.63–0.81) (41.7) (36.3)* 0.62 (0.52–0.74) (35.8)* 0.63 (0.53–0.72) (32.3) (18.6) (38.5) (43.1)

(29.4) 72.8 (17.6) 1.02 (0.95–0.94) 72.9 (18.4) 1.01 (0.96–1.1) (31.4) 3.1 (38.4) 3.0 (37.1) (24.9) 780.2 (35.4) 0.99 (1.1–0.96) 771.1 (35.1) 1.04 (0.96–1.1) (24.9) 803.5 (34.8) 0.98 (0.88 –1.04) 795.1 (34.4) 0.93 (0.86–1.0) (16.3) 10.1 (21.3) 10.3 (21.8) (22.0) 7.8 (17.9) 7.9 (18.0) (31.6) 16.9 (27.6) 17.1 (27.0) (42.8) 129.5 (34.5) 131.9 (34.4)

(31.2) (29.1) (37.6) (36.9) (20.6) (20.6) (32.5) (29.7)

6.0 3.5 58.5 60.0 12.1 8.8 5.9 42.0 151.5 2.9 1716.8 1776.2 9.9 8.0 15.2 115.3

Geometric Mean (90% CI)

(21.1) (25.7) (31.1) (31.6) (19.6) (23.5) (27.0) (37.2)

141.8 3.1 1477.8 1526.4 9.8 7.8 17.4 131.0

(30.9)* 0.64 (0.58–0.72) (41.1) (31.1)* 0.53 (0.44–0.62) (30.8)* 0.62 (0.55–0.69) (31.0) (18.2) (36.4) (39.1)

5.8 3.5 54.2 56.5 11.9 8.7 6.37 44.1

(32.9)* 0.67 (0.54–0.81) (40.71) (33.0)* 0.55 (0.46–0.65) (32.5)* 0.63 (0.59–0.68) (31.7) (18.6) (42.0) (42.1)

(15.1) 1.01 (1.09–0.94) 142.7 (16.2) 1.06 (0.96–1.15) (34.4) 3.2 (32.4) (26.2) 0.94 (0.87–1.01) 1508.3 (24.4) 0.93 (0.86–1.0) (26.5) 0.95 (0.87–1.03) 1559.5 (24.8) 0.96 (0.9–1.02) (16.8) 10.1 (18.2) (24.8) 7.9 (23.1) (27.2) 16.3 (27.5) (32.6) 123.2 (35.3)

AUC0-N, area under the concentration-time curve from zero to infinity; AUC0-t, area under the concentration-time curve from zero to the last measurable plasma concentration; Cl/F, clearance; Cmax, peak plasma concentration; MRT, mean residence time; t1/2, elimination half-life; tmax, time to reach peak plasma concentration; Vd/F, volume of distribution. *Significant difference from either VAL or HCT alone at P o 0.05, one-way analysis of variance (ANOVA).

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M.A. Hedaya and S.A. Helmy mechanisms in many DDIs.59 Displacement of 1 drug by another from blood and/or tissue protein would alter the PK behavior of the displaced drug.60 A decrease in protein binding for a drug, such as VAL, can lead to an increase in its metabolic rate. However, VAL was reported to be 496% (2%)61 bound to plasma proteins, and displacement from its binding site required a drug with a higher affinity to plasma proteins. Because HCT was not highly bound to plasma protein (40%–68%),50 it is unlikely that it could displace VAL from its protein-binding sites, and this was evidenced by the values of Vd/F (Table II), which were nearly the same regardless of HCT coadministration. This finding is consistent with previously published reports that VAL was not displaced by HCT, diclofenac, furosemide, or warfarin.61 Another possible explanation was the effect of efflux and influx transporters. VAL and HCT have been identified as class III drugs (according to a biopharmaceutical classification system) that are characterized by a high solubility and poor permeability.62,63 As such, an absorptive transporter might be necessary to overcome the poor permeability characteristics of these drugs.57 Transporters can be classified as influx and efflux transporters, which are typically located either at the basolateral or apical membrane in polarized cells.38 The human organic anion transporters (hOAT) are classified within 2 superfamilies. One of them consists of organic anion transporting polypeptides (OATPs), whereas the other consists of organic anion transporters (OATs).64 Substrates of OATPs, such as VAL, are mainly large hydrophobic organic anions, and OATs transport smaller and more hydrophilic organic anions, such as HCT. OATP1B1 and 1B3 are mainly located at the sinusoidal membranes of human hepatocytes and mediate the influx of their substrates from blood into the hepatocytes. Thus, they might represent an important step preceding elimination of drugs by metabolism or biliary Accordingly, alteration of the excretion.38 transporter-mediated uptake of VAL into hepatocytes might be considered a potential mechanism underlying this DDI. Yamashiro et al65 reported that VAL was considered to be a substrate of OATP1B1 and 1B3. As a result, theoretically, co-administration of inducers of the uptake or efflux transporters would decrease the systemic exposure and increase the efflux of VAL.

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Thiazide and loop diuretics are secreted from the proximal tubule via the OAT system to reach their principal sites of action. 66 HCT is considered a substrate of the hepatic uptake transporters OAT1 and OAT3, which play a key role in renal secretion of HCT. 67 Because VAL and HCT are substrates to hOAT, co-administration of HCT might, therefore, result in the decreased absorption of VAL due to the competitive binding of HCT with OATs or other transporters present in the intestinal wall. The permeability of VAL was found to be consistent with carrier-mediated transport, and 2 transporters of VAL, OATP1B1 and OATP1B3, have been identified. 59 In contrast to the mechanism just described, the results of a literature review demonstrated the inhibitory effects of HCT (among other diuretics) on the organic anion uptake mediated by hOATs, especially hOAT1. 68 This effect would theoretically increase the systemic exposure of VAL by the inhibitory effect of HCT on OAT. All the previous explanations could lead to a decrease in VAL efflux, but the opposite happened. P-glycoprotein (P-gp) in the intestinal epithelium plays an important role in the extrusion of many drugs from the blood into the intestinal lumen and in preventing drugs in the intestinal lumen from entering the bloodstream.69 P-gp activity could, therefore, reduce the absorption and oral bioavailability of its substrates. Recently, Challa et al70 investigated whether VAL could be considered a substrate for P-gp. They reported that the transport of VAL from the serosal side to the mucosal side was decreased in the presence of quercetin, a P-gp inhibitor, leading to a significant increase in the intestinal absorption and decrease in the efflux of VAL. In addition, Liao et al71 indicated that the absorption of HCT in Caco-2 cell monolayer model could be due to a carrier-mediated active transport, along with the excretion action mediated by P-gp. Therefore, coadministration of HCT might decrease the systemic exposure and increase the efflux of VAL by competition on P-gp. Our results also revealed that the Tmax of both VAL and HCT exhibited nonsignificant increases, which might indicate that the co-administration of VAL and HCT could slightly decrease the rate of absorption for both agents due to the effect on OATs or other transporters that could mediate their absorption.

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Clinical Therapeutics Accordingly, the estimation of the role of a single transporter in the DDI might be challenging because many drugs could be substrates of 41 transporter and often subjected to metabolism by CYP enzymes.72 Therefore, additional studies are needed to gain more insight into the exact mechanism and the role of P-gp and OATs in this interaction. The findings from the current single-dose studies suggest that there is evidence of a significant PK DDI between VAL and HCT when co-administered in these selected cohorts of healthy male Egyptian volunteers, which coincided, to a great extent, with those results published earlier.24 Thus, these findings provide important information for further investigations of an FDC of VAL and HCT. All enrolled volunteers were healthy, and none of them exhibited any signs of ADRs during or after completion of the study. However, the BP measured after a single-dose treatment in these healthy volunteers might be different from that in hypertensive patients after long-term treatment. Therefore, further multipledose administration and long-term studies in hypertensive patients are needed to evaluate the clinical efficacy and the pharmacologic drug interactions of the combination therapy of VAL and HCT. These studies are necessary to discover whether the observed DDI has any impact on the combined use of VAL and HCT, as stated previously.24 The DDI of HCT with other ARBs members should be investigated to determine whether this DDI is limited to VAL or whether other ARBs may have the same PK interactions.

CONCLUSIONS Both VAL/HCT FDC and VAL þ HCT were well tolerated in this population of healthy male subjects. The prespecified bioequivalence bounds were met for Cmax, AUC0–t, and AUC0–∞ of VAL and HCT in case of concomitant administration and FDC. These results demonstrated that the lowest and highest dosage strengths of the VAL/HCT FDC tablet (160 mg/12.5 mg and 320 mg/25 mg) were bioequivalent to corresponding doses of VAL þ HCT co-administered as separate tablets. However, the co-administration of HCT decreased the Cmax and AUC of VAL significantly among this volunteer study cohort. In contrast, the co-administration of VAL decreased the Cmax and AUC of HCT nonsignificantly. Further studies are necessary to determine the role of efflux and influx transporters on VAL and HCT disposition.

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ACKNOWLEDGEMENTS The authors thank all the study subjects and medical staff for their contributions and efforts.

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

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Address correspondence to: Sally A. Helmy, PhD, CPHQ, Department of Pharmaceutics, Faculty of Pharmacy, Damanhour University, Damanhour, 22111, Egypt. E-mail: [email protected]

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