Evaluation of the relative bioavailability between two formulations of olmesartan medoxomil 40mg, in orodispersible tablet form and coated tablet form, in healthy participants of both sexesAbstract
The objective of this study was to verify whether the test formulation of olmesartan medoxomil, in orodispersible tablet form, administered with water (treatment B) and without water (treatment C), presents a rate and extent of absorption equivalent to the reference formulation, film-coated tablet form (treatment A). Study design was monocentric, open-label, crossover and randomized. Olmesartan medoxomil 40 mg was orally administered, under fasting conditions to healthy participants. Blood collections were carried out over a period of 72 hours. Olmesartan plasma concentrations were determined by liquid chromatography coupled to mass spectrometry detector techniques. Pharmacokinetic parameters Cmax, AUC0-t, AUC0-inf, Tmax, T1/2, Kel, %AUC_extrap were determined. Confidence intervals were constructed for the ratio of the geometric means between the test and comparator treatments (B/A and C/A) for Cmax and AUC(0-t), using ln-transformed data. Formulations were well tolerated, with no serious adverse events observed. The 90% CI for the B/A ratio was 89.50%-102.63% for the Cmax parameter and 89.72%-100.89% for the AUC(0-t) parameter, while for the C/A ratio it was 83.22%-95.40% for the Cmax parameter and 85.18%-95.77% for the AUC(0-t) parameter. In conclusion, the test formulation of olmesartan medoxomil, in orodispersible tablet form, administered with and without water, is bioequivalent to the reference formulation.
Keywords:
Olmesartan medoxomil; Relative bioavailability; Orodispersible tablet; Coated tablet; Liquid chromatography.
INTRODUCTION
Systemic Arterial Hypertension is the leading preventable risk factor for cardiovascular diseases such as coronary artery disease, congestive heart failure, cerebrovascular disease, peripheral arterial disease, aortic aneurysm, and chronic kidney disease (Mills, Stefanescu, He, 2020; Tackling, Borhade, 2023). In Brazil, the prevalence of self-reported hypertension in 2018 was 24.7% and it is estimated that 388 people die per day from hypertension (Ministério da Saúde, 2022). One of the most used classes of antihypertensive medications are renin-angiotensin system blockers, as they are capable of controlling high blood pressure, thus reducing morbidity and mortality associated with cardiovascular diseases (El-Gendy et al., 2017). Furthermore, the renin-angiotensin system blockers are considered one of the first-line treatments for arterial hypertension due to their effectiveness and high tolerability with less risk of withdrawals during the treatment because of adverse events (Gallo, Volpe, Rubattu, 2022).
Olmesartan medoxomil is a prodrug that is rapidly and completely de-esterified to the active metabolite olmesartan by both arylesterase and albumin during the gastrointestinal absorption process. The olmesartan acts through competitive and selective binding to Guilherme Guimarães de Souza, Iram Moreira Mundim, Franciely Jesus Gue-des, Laura Moreira Rezeck, Vanessa Martins Vilela, Karini Bruno Bellorio, Leonardo de Souza Teixeira, Rafael Paletta da Silva the angiotensin II receptor of the AT1 subtype and prevents the vasoconstrictive effects of angiotensin II, selectively blocking its binding to the AT1 receptor in vascular smooth muscle (Benicar® - Daiichi Sankyo Brasil Farmacêutica Ltda, 2023). In clinical studies, olmesartan showed superior efficacy compared to losartan, valsartan and irbesartan when administered at recommended doses and was more effective in reducing systolic blood pressure than telmisartan and losartan and has tolerability similar to placebo (Brunner, Laeis, 2003; Yoshihara et al., 2005; Kalikar et al., 2017).
There is evidence of the linear relationship, aftera single oral dose and multiple oral doses greater than therapeutic doses, between prodrug dosage and active metabolite (olmesartan) for Cmax and AUC, but not Tmax. Steady-state levels are reached after the first few doses, and no accumulation occurs in plasma with once-daily dosing. Following administration, the absolute bioavailability after a single oral dose of olmesartan medoxomil in healthy participants is 26%. The Cmax after oral administration occurs in approximately 2 hours (Tmax) and food does not affect the bioavailability of olmesartan. Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, the olmesartan is excreted without undergoing any further metabolism and no other metabolites of olmesartan have been identified in humans. Total plasma clearance is 1.3 L/h, with a renal clearance of 0.5-0.7 L/h. Approximately 30% to 50% of the absorbed dose is recovered in the urine, while the remainder is eliminated in the feces via the bile. The volume of distribution is 16-29 liters. It is highly bound to plasma proteins (99%) and does not penetrate red blood cells. Protein binding is constant even at plasma concentrations of olmesartan well above the range achieved with recommended doses. The olmesartan appears to be eliminated in a biphasic manner, with an elimination half-life of six to 15 hours and a duration of action of up to 24 hours. (Warner, Jarvis, 2002; Brousil, Burke, 2003; Benicar® - Daiichi Sankyo Brasil Farmacêutica Ltda, 2023). According to the United States Food and Drug Administration, orodispersible tablets are solid dosage forms which contains active pharmaceutical ingredients that disintegrates, within a matter of seconds, when placed upon the tongue. The advantages of this pharmaceutical form include easier way of administration for patients who have problem with swallowing drugs such as patients in shock state, stroke victim, bedridden patients, patients who are suffering from kidney failure, pediatric, geriatric patients. There is no risk of suffocation due to physical obstruction when swallowed, thus offers improved safety and has accurate dosing when compared to liquids. Meanwhile, the disadvantages are that sometimes orodispersible tablets are highly fragile and since they don’t have enough hardness they must be handled with great care (Vishali, Damodharan, 2020).
This study aimed to verify, through a single dose study, whether the test treatments of Olmesartan Medoxomil (treatment B: Olmesartan Medoxomil - 40 mg orodispersible tablet administered with water and treatment C: Olmesartan Medoxomil - 40 mg orodispersible tablet administered without water) has a rate and extent of absorption equivalent to the reference treatment (treatment A: Olmesartan Medoxomil - coated tablet) when administered under fasting conditions, to healthy adult participants of both sexes.
MATERIAL AND METHODS
Study population and Research Ethics Committee
This study was conducted in accordance with national and international guidelines and standards for research involving human beings (ICH, 2023; CNS, 1997; CNS, 2013; World Medical Association, 2013). The Principles of Good Laboratory Practices (Inmetro, 2019) were also followed. The protocol for the present study was approved together with the Free and Informed Consent Form by the Research Ethics Committee of the Instituto de Ciências Farmacêuticas de Estudos e Pesquisas (ICF; Aparecida de Goiânia, Goiás, Brazil), protocol number: 4.248.175. All participants were informed about the nature and objectives of this research, had their doubts clarified and decided to participate in the study voluntarily, signing the Free and Informed Consent Form before carrying out any procedure.
The sample size of a bioequivalence/relative bioavailability (BE/BD) study is determined by calculating the power function, which is based, among other factors, on an estimate of the intra-individual coefficient of variation (CVintra) obtained from data published in the literature or from previous experiences with the analyte.
Li and colleagues (2010) conducted a bioavailability study of olmesartan medoxil under experimental conditions similar to this study, and Rohatagi and colleagues (2008) described bioequivalence studies of the combination of amlodipine besylate + olmesartan medoxil compared with the isolated treatments administered concomitantly. Although neither study explicitly reported the estimated values for CVintra or test power, favorable results were reported. Furthermore, data from previous studies conducted in the ICF of olmesartan medoxil under a 2x2 crossover design and under fasting conditions suggest a maximum CVintra varying from 24% to 30% for the primary pharmacokinetic parameters.
Therefore, to define the total number of research participants required to conduct this study, the following assumptions were considered:
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a) The presence of normality on the individual difference of the primary pharmacokinetic parameters;
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b) A nominal significance level of 5.0%;
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c) A 6x3 crossover design (Williams, 3 treatments, 6 sequences, 3 periods);
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d) An equivalence range of 80-125% for the parameters determining bioequivalence;
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e) A maximum CVintra of 30% for the primary pharmacokinetic parameters;
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f) A population ratio for the means of the treatments ranging from 95% to 105%;
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g) A projected number of 12 research participants to compensate for possible losses due to withdrawals/ exclusions.
Therefore, a total sample of 72 healthy research participants would be sufficient to ensure that the null hypothesis of bioinequivalence (H0) is rejected with a minimum power of 90%, provided that the aforementioned assumptions are met.
All calculations were performed using R software, PowerTOST package (R version 3.1.2, The R Foundation for Statistical Computing, 2014).
According to the sample size calculations, 72 participants would be recruited (36 male and 36 female individuals) aged between 18 and 50 years old and with a Body Mass Index (BMI) ranging between 18.50 and 28.63 kg/m2. There were no restrictions regarding ethnic group.
Participants underwent clinical assessment and examinations before and after the study to ensure good health conditions. The medical history, stool examination, electrocardiogram (12 leads), and laboratory tests (hematological, biochemical, and urine type I) should be within normal limits or considered clinically irrelevant, in addition to negative tests for the detection test for drugs of abuse, serological tests (Hepatitis B, C and HIV), RT-qPCR (SARS-CoV-2) and pregnancy test for women. Some of the exclusion criteria considered were having hypersensitivity to any component of the medication formula, use of medication that interfered with the pharmacokinetics of olmesartan, history of gastrointestinal, neurological, pulmonary, renal, cardiovascular, or metabolic pathology, donation 450mL or more blood samples within the three months prior to the study, also history of drug and/or alcohol abuse.
Study design
The clinical phase was developed by the Instituto de Ciências Farmacêuticas de Estudos e Pesquisas. According to the approved protocol, the study design was monocentric, open-label, crossover (Williams 6x3), randomized, prospective, three treatments (A, B and C), three periods and six sequences (ABC, ACB, BAC, BCA, CAB, CBA). Participants were divided into two subgroups due to the logistics of confinement at the ICF. Each subgroup was composed of 36 healthy participants (18 male and 18 female individuals), equally distributed among six individuals per sequence. In each period, participants received the test formulation with water or, the test formulation without water, or the reference formulation, according to the protocol randomization list and under fasting conditions. The clinical, analytical and statistical stages were conducted between September 2020 and April 2021.
Study formulations
The reference formulation (treatment A) corresponds to the film-coated tablet of olmesartan medoxomil 40mg (Benicar® -Daiichi Sankyo Brasil Farmacêutica Ltda, batch: 200684, expire date: 05/2022). The test formulation corresponds to the orodispersible tablet of olmesartan medoxomil 40mg (Daiichi Sankyo Brasil Farmacêutica Ltda, batch: D08820, expire date: 07/2022) administered under different conditions, with water (treatment B) and without water (treatment C). Both formulations (test and reference) were administered in a single dose. Both reference and test formulations were manufactured and packaged under Good Manufacturing Practice conditions at Daiichi Sankyo Brasil manufacturing site located at Alameda Xingu, 766 Alphaville, Barueri, SP Brazil.
Drug administration
In each period, participants received, orally, a dose of 40mg of olmesartan medoxomil, corresponding to1 orodispersible tablet of the test drug administered with water, or 1 orodispersible tablet of the test drug administered without water, or 1 coated tablet of the reference drug, according to the randomization list and after a minimum period of 8 hours of fasting. The administration of drugs under fasting conditions was defined according to recommendations [List 1 - Form of administration (immediate release pharmaceutical forms)] (ANVISA, 2023).
The administration of the reference formulation (A) was carried out directly on the participants’ tongue, with 200mL of drinking water. The administration of the test formulation with water (B) and without water (C) was carried out directly on the participant's tongue, where it should be kept until it was completely disintegrated. Ingestion of 200mL of water after the tablet had completely disintegrated was only permitted for participants who received treatment B.
Participants remained without drinking liquids for 2 hours and without eating food for 4 hours after drug administration. As a precaution, participants remained lying down (45° plane) for four hours after administering the drugs. The interval between treatments (washout) was 14 days and the participants' confinement time was approximately 27 hours.
Safety and tolerability
Before each study period clinical tolerability was monitored and recorded through signs and symptoms and adverse events. Vital signs (blood pressure, temperature and pulse rate) were checked before and 1.0, 2.0, 3.0, 4.0, 8.0 and 12.0 hours after drug administration. Adverse events were monitored and recorded by ICF medical and nursing staff during the study. Adverse events were classified according to their nature (serious and non-serious), intensity (mild, moderate and severe) and relationship with the study medication (related and unrelated). The correlation between adverse events and the study medication was established based on a clinical assessment by the investigator of the adverse event after reviewing all available data, including the leaflet of the reference medication (Benicar® - Daiichi Sankyo Brasil Farmacêutica Ltda, 2023). Then, the clinical investigator judged whether, in his/her opinion, the adverse event was related to the study medication. During the confinement period, the questions asked to find out whether the research participant had any adverse events were limited to general questions, such as: How are you? Each research participant was instructed to report any symptoms of adverse reactions and when they occurred.
Blood collections and biological sample processing
In each study period blood samples (4.9mL) were collected from participants at the following times: predose (-0.5) and 0.17, 0.33, 0.50, 0.67, 0.83, 1.0, 1.25, 1.50, 1.75, 2.0, 2.33, 2.67, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0 and 72.0 hours after drug administration. Participants were released from confinement 12.0 hours after medication administration and returned for collections at 24.0, 36.0, 48.0 and 72.0 hours. All samples were stored in vacuum tubes containing the anticoagulant EDTA.
The samples were kept inside a thermal box containing rigid ice and with temperature control (2 - 8 °C) until transport to the Biological Sample Processing Laboratory, where the tubes were separated on racks and centrifuged at 3000rpm for 5 minutes, at approximately 4 °C. The plasma was separated into 2 cryogenic tubes with approximately 1.2mL of plasma in each and stored in a freezer (-20 °C) until analysis was carried out. According to the study protocol, the maximum time elapsed between blood collection and sample centrifugation did not exceed 60 minutes, and the time between sample centrifugation and storage did not exceed 60 minutes, with the exception of the predose sample.
Quantification of olmesartan in plasma and Bioanalytical method validation
The determination of olmesartan in human plasma was carried out using the high-performance liquid chromatography technique HPLC (ALC10) with the following components: pump, degasser, autoinjector with cooler and column oven, all in the Agilent 1200 Series model, coupled to a mass spectrometer API 3200 C MS/MS (AMS06).
Validation of the bioanalytical method was carried out in accordance with RDC nº27/2012 (ANVISA, 2012) ensuring, through experimental studies, that the method meets the requirements of analytical applications, ensuring the reliability of the results. To this end, the method presents precision, accuracy, linearity, residual effect, matrix effect, selectivity and stability according to the specifications of each test. Table I presents the description of the method used to analyze the samples.
Pharmacokinetic parameters and statistical analysis
The following pharmacokinetic parameters were determined from olmesartan plasma concentration:
Cmax: Maximum plasma concentration achieved after administration of each treatment (A, B and C).
AUC0-t: Area under the plasma concentration versus time curve, from time 0 (zero) to the last quantifiable concentration.
AUC0-inf: Area under the plasma concentration versus time curve, from time 0 (zero) to infinity (extrapolated).
Tmax: Time at which Cmax occurs.
%AUC_extrap: Percentage of AUC0-inf due to extrapolation of the last quantified collection time to infinity.
T½: Elimination half-life.
Kel: Elimination rate constant.
WinNonlinTM software and the Microsoft Office package were used to perform statistical analyses. To assess bioequivalence, predefined acceptance criteria were applied to the 90% confidence interval for the ratio between test and reference formulations (T/R) for the log-transformed data of Cmax and AUCs (AUC(0-t) and AUC(0-inf)), where the acceptance range must be between 80.00%-125.00%. An analysis of variance (ANOVA) test was performed to evaluate the effects of sequence, treatment and period on these parameters.
RESULTS
Research Participants
Initially, 72 healthy participants of both gender were selected, according to the inclusion and exclusion criteria determined in the protocol. However, due to withdrawals and exclusions that occurred before the first administration of the medication, there was a need to select 79 participants (38 male individuals and 41 female individuals), of which 71 participated.
The study was completed with 58 research participants, 29 male and 29 female, all of them were includes in the statistical analysis. Of the participants who did not complete the study, 12 were excluded (7 due to symptoms compatible with COVID-19 or a positive test for SARS-CoV-2; 2 due to a positive drug test, 2 due to the use of unauthorized medications and 1 due to an adverse event), while 2 dropped out for personal reasons. Table II presents the demographic characteristics of the study participants.
Safety and tolerability
During the study, some participants presented adverse events as reported in Table III. Some participants presented post-study exam values outside normal limits, these participants were evaluated by the doctor and, for those with changes considered clinically significant, there were clinical monitoring until normalization. In total, 21 adverse events were reported by 31 of a total of 71 study participants.
The events reported were for both the test and reference formulation. Eight of the reported events were classified as drug-related, while 13 were unrelated. Of the related events, headache was the most common, with a prevalence of 8.3%, followed by an increase in serum TGP with 5.5%. While for unrelated events, symptoms compatible with COVID-19 and leukocyturia associated with mild bacterial flora were the most prevalent (8.3%).
Pharmacokinetic parameters
Table IV and V present the geometric means, confidence intervals and p-values obtained in the analysis of variance of the olmesartan study. For the comparison of the test treatment administered with water, the results of the three parameters evaluated (Cmax, AUC(0-t) and AUC(0-inf)) were quite similar to each other. The ratios between treatment means were estimated at approximately 95% and the estimated values for the power of the test calculated via the TOST (Two One- Sided t-Tests) method were greater than 99%. For the comparison of the test treatment administered without water, the ratio between the geometric means of the Cmax parameter was estimated at 89% and the test power was greater than 83%. For the AUC0-t and AUC0-inf parameters, the ratios were estimated at 90% and 91%, respectively, and the estimated values for the power of the tests were greater than 96%.
Pharmacokinetic parameters of treatments A, B and C (olmesartan medoxomil) when administered on an empty stomach and in healthy patients (n = 58) Data expressed as mean (Standard Deviation)
Geometric means, confidence intervals and p-values obtained in the analysis of variance of the olmesartan study
As for general comparisons, the estimates obtained for the intra-individual coefficient of variation (CVintra) varied approximately between 19% and 22% for the three pharmacokinetic parameters evaluated. The ANOVA was tested only with the standard model for bioequivalence studies with sequence, period and treatment as fixed effects. In relation to the p-values obtained, no statistically relevant differences were evidenced for the sequence effect and for the period effect, at the 5% level of significance in any of the evaluated parameters. However, also at the 5% level of significance, the occurrence of a treatment effect was evidenced, indicating that at least one of the treatments presents a mean that is statistically different from the others. There was no adjustment for multiplicity and no other post hoc tests.
DISCUSSION
The present study was planned and carried out to evaluate the bioequivalence of the test formulation of olmesartan medoxomil 40mg (orodispersible tablet) administered with or without water, in relation to the reference formulation (olmesartan medoxomil 40mg; film-coated tablet) in order to provide supportive data for the NDA (new drug application) submission in Brazil. The three treatments, reference formulation (A), test formulation administered with water (B) and without water (C) showed results, T1/2[mean (SD)] = 10.565 (3.416), 10.76 (3.055) and 10.694 (4.232) hours; and Tmax[mean (SD)] = 2.376 (0.857), 2.338 (0.739) and 2.582 (0.895) hours for treatments A, B and C, respectively, which corroborate with the pharmacokinetics described In the Benicar® (T1/2 from 6 to 15 hours and the Tmax is approximately 2 hours).
Li and colleagues (2010) conducted a relative bioavailability study comparing three capsule and tablet formulations of olmesartan medoxomil 20 mg in healthy Chinese male volunteers (n = 21) in a single dose and under fasting conditions. The mean (SD) Cmax of olmesartan for the test tablet, test capsule, and reference tablet were 728.6 (139.3) ng/mL, 637.5 (120.7) ng/mL, and 638.7 (111.5) ng/mL respectively. The mean (SD) values for Tmax were 1.41 (0.34), 1.71 (0.44) and 1.83 (0.46) hours and the mean values for T1/2 were 7.42 (2.29), 7.18 (1.36) and 7.02 (1.50) hours, respectively. Although these values are slightly lower than those found in the present study due to the dose of the drug, the curve of olmesartan plasma concentration versus time presented a similar profile to our study.
From the results of the present study it is possible to observe that the bioavailability of the orodispersible tablet with and without water is similar to that of the immediate release tablet under fasting conditions. This provides a major advantage for patients with dysphagia, such as elderly patients, children, patients with mental retardation, uncooperative patients such as treatmentresistant psychiatric patients, patients with dysphagia associated with certain diseases (Parkinson's disease, AIDS, thyroidectomy, head and neck radiotherapy, cerebral palsy and other neurological disorders), patients with nausea or on a diet with reduced fluid intake, and patients who are on the move and have little access to water (Benicar® ODT - Daiichi Sankyo Brasil Farmacêutica Ltda, 2023).
In addition to comparing the relative bioavailability between two formulations of olmesartan medoxomil 40 mg (orodispersible tablet and film-coated tablet), the present study monitored the safety and tolerability of these medications under fasting conditions. Both formulations were also well tolerated and had no serious adverse events. The values found for the shortest confidence intervals for the geometric mean (90% CI) of the B/A ratio (test treatment administered with water) were 89.50%-102.63% for Cmax and 89.72%-100.89% for AUC(0-t), and C/A ratio (test treatment without water) was 83.22%-95.40% for Cmax and 85.18%-95.77% for AUC(0-t). These results are within the limit of 80.00% and 125.00% proposed by the national regulatory agency (ANVISA, 2022) to conclude bioequivalence between products.
From the results obtained with the present study, it is concluded that the test treatment: Olmesartan Medoxomil 40mg; orodispersible tablet; Daiichi Sankyo Brasil Farmacêutica Ltda., administered with or without water, and the reference/comparator treatment: Benicar® - Olmesartan Medoxomila 40mg; film-coated tablet; Daiichi Sankyo Brasil Farmacêutica Ltda. They are bioequivalent, that is, they have a similar rate and extent of absorption, under fasting conditions.
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ACKNOWLEDGMENTS
The present study was funded by Daiichi Sankyo Brasil Farmacêutica Ltda.
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Edited by
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Associated Editor:
Stephania Fleury
