Introduction/Study Objectives: A bioequivalence study was performed to compare the pharmacological profile of innovator etoricoxib (ETO) with a newly developed generic ETO, both in a 120 mg tablet formulation. A dissolution study was conducted to optimize the formulation process before evaluating physical changes in the active pharmaceutical ingredient and the formulated product.
Submitted: 19 May 2021; Revised: 26 August 2021; Accepted: 26 August 2021; Published online first: 8 September 2021
Etoricoxib (ETO), which has the chemical formula 5-chloro-6’-methyl-3-[4-(methylsulfonyl) phenyl]-2, 3’-bipyridine, see Figure 1, is a highly selective non-steroidal cyclooxygenase (COX)-2 inhibitor with a molecular weight of 358.84 g/mol. Cyclooxygenase catalyses the production of prostaglandins and exists in two isoforms, namely COX-1 and COX-2. Inhibition of COX-2 reduces the production of prostaglandins, leading to anti-inflammatory and analgesic effects. COX-2 also plays a role in ovulation, implantation and closure of the ductus arteriosus in newborns, and regulates certain functions of the renal and central nervous systems such as the induction of fever, perception of pain and cognition .
Figure 1 pending to upload
ETO has been shown to produce dose-dependent inhibition of COX-2 at doses up to 150 mg/day. However, it does not inhibit the synthesis of gastric prostaglandin or exert any effects on platelet function . Thus, it can be ingested orally to relieve the acute pain associated with rheumatoid arthritis, psoriatic arthritis, osteoarthritis, gout, back pain, headache, or inflammation secondary to dental surgery .
In terms of pharmacokinetics, ETO shows good oral absorption with an absolute bioavailability of approximately 100%. Peak plasma concentration, maximum concentration (Cmax), of 3.6 μg/mL was reached one hour after the administration of 120 mg ETO in fasting adults  with an area under curve (AUC) of 37.8 μg·hr/mL. Furthermore, the pharmacokinetics of ETO are linearly related to the clinical dose range . Onset of action of ETO can occur from 24 minutes after administration. Approximately 92% of administered ETO is bound to human plasma protein with a concentration range of 0.05 μg/mL–5 μg/mL. At steady state, the volume of distribution (Vdss) is approximately 120 L in humans.
ETO undergoes extensive metabolism; fewer than 1% is excreted as the parent compound in urine. ETO metabolism is catalysed by cytochrome P450 (CYP) enzymes before forming 6’-hydroxymethyl derivatives. Further oxidation of the 6’-hydroxymethyl derivative leads to the formation of the principal metabolites from ETO metabolism, i.e. the 6’-carboxylic acid derivatives of ETO. These principal metabolites act as weak COX-2 inhibitors with minimal or no measurable activity. None of the principal metabolites are COX-1 inhibitors.
A generic drug should have the same dosage, strength, route of administration, safety profile, quality, and performance characteristics as the innovator product . Generic versions of ETO are often preferable in view of their equivalence to the innovator and their availability at a lower cost. A bioequivalence (BE) study in compliance with the Association of Southeast Asian Nation (ASEAN) Guidelines is required to establish therapeutic equivalence between the generic and innovator formulations before any new generic products can be registered under the National Pharmaceutical Regulatory Agency in Malaysia. Therefore, this study aimed to determine the BE of a generic ETO (120 mg, tablet formulation) in comparison to the innovator product, Arcoxia® (120 mg, tablet formulation).
Subjects and study design
This was a randomized, open-label, balanced, two-treatment, two-period, two-sequence, single-dose, two-way crossover, truncated trial with a washout period of 10 days. The study recruited 26 healthy male volunteers aged between 18–45 years with a body weight of ≥ 45 kg and body mass index (BMI) ranging from 18.5 to 30.0 kgm-2. The mean age, height, weight, and BMI of the participants were 32.69 ± 6.30 years, 169.5 ± 6.74 cm, 71.07 ± 10.05 kg, and 24.7 ± 2.6 kg/m2, respectively. Researchers monitored contraindications, hypersensitivities and other potential risks of treatment among participants. Vital signs (blood pressure, pulse rate) were measured at pre-dose, 1.00, 3.00, 9.00, 25.00, 33.00 and 50.00 hours after dosing. Table 1 shows the demographic characteristics of the subjects, who were selected based on predetermined eligibility criteria. Subjects medical history was obtained and physical examination was performed to record blood pressure, radial pulse rate, body temperature and respiratory rate. Electrocardiogram and other clinical laboratory evaluations were carried out, including evaluations of HIV 1 and 2 antibody status, hepatitis B surface antigen, hepatitis C virus antibodies, tests for venereal disease, and tests for common drugs of abuse (amphetamine, barbiturates, benzodiazepines, morphine, tetrahydrocannabinols and cocaine) 21 days prior to the study commencing.
Table 1 pending to upload
This BE study number No. 152-18 (as referenced by the independent ethics committee) followed the International Conference on Harmonisation Good Clinical Practice and the ASEAN guidelines on the conduct of BE studies . All subjects were informed about the objectives, procedures, and potential risks of participation in the study and all subjects signed an informed consent form before enrolling in the study. The trial protocol received approval from the Maarg Independent Ethics Committee, an independent ethics committee regulated by the Indian Drug and Cosmetic Act and the 2008 Declaration of Helsinki. Analysis was performed by RA Chem Pharma Limited, Hyderabad, India (Clinical Research and Biosciences Division).
The test product, etoricoxib tablet 120 mg (Batch No.1908296PB) was manufactured by Duopharma Manufacturing Bangi Sdn Bhd, Malaysia. The reference product, Arcoxia® ETO tablet 120 mg (Lot No. 83882064) was manufactured by Frosst Iberica, SA, Spain.
A dissolution study was conducted to compare the test and reference products prior to the BE study. It was performed using the Electrolab dissolution test system, in accordance with United States Pharmacopeia (USP) general methods. A high-performance liquid chromatography system (Agilent, 1260 Infinity, India) equipped with model software was used to quantify the samples. The Metrohm model AG/913 (India) was used to determine the pH of all solutions with 0.45 μm nylon membranes procured from Millipore, India.
Treatment phase and blood sampling
Subjects underwent at least ten hours of fasting before sampling. A total of 23 sampling points were planned. A pre-dose sample was collected as the baseline. Subjects received either a single dose of test product or reference product along with 240 mL of water. Blood samples were collected at 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.25, 2.50, 2.75, 3.00, 3.50, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00 and 72.00 hours post-administration. The samples were centrifuged at 4,000 rpm for 10 minutes at 4°C. Plasma samples were transferred to the bioanalytical department in dry ice and stored at -80°C until analysis.
Analysis of drug concentration
Liquid chromatography tandem mass spectrometry (LC-MS/MS) was conducted to analyse the samples. The analyte ETO and its internal standard etoricoxib D4 were separated with the analytical column Phenomenex, C18, 50 x 4.6 mm, 5 μm. This method produced a linear response in the plasma ETO concentration in the K2EDTA blood tube over a concentration range of 10.28–5479.52 ng/mL. The method has been validated for its selectivity, intra-batch and inter-batch precision, accuracy, recovery, stability, linearity, and sensitivity. Liquid-liquid extraction was completed using Phenomenex, C18, 50 x 4.6 mm, 5 μm column to extract ETO from the plasma.
Statistical analysis was performed using SAS® software version 9.4 (SAS Institute Inc, Cary, NC, USA) using the non-compartmental method in Phoenix® WinNonlin (Version 8.0) to identify the pharmacokinetic values of Cmax and AUC of the drug. ANOVA analysis was performed on the Ln-transformed pharmacokinetic parameters using the General Linear Model (PROC GLM). The BE of the test formulation was established within a 90% CI such that the relative means of Cmax and AUC0-72 were expected to fall within 80%–125% of that of the reference formulation.
Comparative dissolution was conducted at pH 1.2, 4.5, and 6.8. At pH 1.2, more than 85% of the active ingredient dissolved within 15 minutes. At pH 4.5 and pH 6.8, the similarity factors were 43.8 and 50.8, respectively. The accepted similarity factor range is above 50 . At pH 4.5, the dissolution of the test formulation behaves differently due to its variation in excipient compositions compared to the reference. Tables 2 and 3 compare the dissolution profile of the test formulation against the reference formulation, whereas Figures 2, 3 and 4 show the dissolution profile of test formulation plotted against reference formulation.
Figure 2, 3 and 4 pending to upload
To determine the test and reference product’s comparative bioavailability, a BE study must be performed. We therefore recruited 26 healthy male subjects of South Asian heritage who fulfilled the inclusion criteria. All subjects received both the test and reference products and were included in the pharmacokinetic and safety analysis. No serious adverse events (SAEs) were reported. However, two adverse events (AEs) were reported: fever and headache not associated with nausea and vomiting during first phase (of the crossover) after the administration of reference product, and fever not associated with any other symptoms during the first phase after the administration of test product. Both AEs were categorised as mild. No clinical biochemistry values or vital signs met the predefined criteria of Potential Clinical Importance.
Table 4 shows the pharmacokinetic parameters for the test and reference products. In this study, the pharmacokinetic parameters of the ETO tablet were assessed based on the plasma concentrations of ETO. The T/R ratios of ETO were 104.36% (90% CI interval: 98.30%–110.80%) for AUC0-72 and 101.39% (92.15%–111.56%) for Cmax. The Tmax for the test and reference products were 1.063 and 1.156 hours, respectively. Furthermore, intra-subject variability was low for both Cmax and AUC0-72 as the CV (%) did not exceed 30% for any parameter. The AUC0-72 and Cmax of the test formulation passed the acceptance criteria for BE as the 90% CI of the AUC0-72 and Cmax of the test and reference formulations fell within the range of 80%–125% according to guidelines. The AUC0-72 and Cmax of ETO were also within an 80%–125% range.
Figure 5 shows the mean plasma concentration versus time after oral administration of 120 mg ETO tablet (both the test and reference products). The highest intra-subject coefficient of variation was found to be 15.3% for Cmax.
Table 4 pending to upload
Figure 5 pending to upload
A similar study was previously conducted in Saudi Arabia . In this study, the AUC0-72 for the test product was 23,067.30 ± 8,978.36 as compared to 23,478.20 ± 9,719.32 for the reference product. The Cmax was 1,923.90 ± 466.83 for the test product and 1,986.14 ± 614.41 for the reference product. As the BE was within a range of 80%–125%, the test product was deemed to be bioequivalent to the innovator . In comparison, our study reported that the 90% CI observed for Cmax was 92.15%–111.56%, higher than the 89.76%–106.81% reported in the Saudi Arabian study. Similarly, the AUC0-72 of 98.30%–110.80% in the current study is also slightly higher than the 95.72%–102.48% reported in the previous study . The difference could be due to the ETO formulations and study populations.
A further study administered a 60 mg formulation of ETO among healthy volunteers in Mexico . The geometric mean ratios of Cmax and truncated AUC0-72 were 99.55%–119.33% and 95.97%–103.06%, respectively. Thus, the test product was also deemed bioequivalent to the reference product in this study. Furthermore, a single dose study of ETO 60 mg was conducted in 24 healthy subjects in Bangladesh . In this study, the AUC0-120 reported was 85.37%–107.74% with a Cmax of 85.54%–111.98%, indicating that the test and reference formulation of ETO met the regulatory criteria for BE. Finally, a similar study comparing the reference product (Arcoxia) against a test product produced by PT Dexa Medica in 26 healthy subjects was conducted in Indonesia. The results also showed bioequivalence, with a AUC0-72 of 98.70%–108.32% and a Cmax of 100.18%–119.18%.
The current study had a sufficient number of subjects to ensure adequate statistical power to prove the equivalency of the test product to the reference product. However, the study has some limitations. Due to recruitment capacity, we could only include male volunteers. This is because the use of ETO is not recommended in women who are trying to conceive due to evidence of an increased risk of miscarriage, and no women who are unable to conceive, e.g. post hysterectomy, volunteered to participate in the study .
This study intended to assess the bioavailability of a newly developed etoricoxib (120 mg, tablet formulation) in comparison to the innovator preparation, Arcoxia® (120 mg, tablet formulation). Based on the study results, we conclude that the new etoricoxib 120 mg tablet meets bioequivalence guidelines.
This work was financially supported by a Duopharma R & D fund (Purchase Order No. 4100225052). Pharmacological evaluation support was provided by KL Tan, DPhil during an industrial internship, funded by Duopharma Biotech Berhad.
The study TCTR identification number is TCTR20210714009 (https://www.thaiclinicaltrials.org/show/TCTR20210714009).
This study received ethical approval from the independent ethics committee with permits from India Central Drugs Standard Control Organisation. Informed consent was obtained from all subjects.
Prior presentations: None.
Competing interest: This work was financially supported by the Duopharma R & D fund. KL Tan received a subsidy from Duopharma Biotech Berhad, Malaysia during an industrial internship at Universiti Sains Islam Malaysia (USIM) for a bioequivalence study of ETO.
Provenance and peer review: Not commissioned; externally peer reviewed.
1Outsource R&D, Duopharma Innovation Sdn Bhd, No. 2 Jalan Saudagar U1/16, Zon erindustrian Hicom Glenmarie, Seksyen U1, 40150 Shah Alam, Selangor, Malaysia
2Pharmacology Unit, Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia, Persiaran Ilmu, Putra Nilai, 71800 Nilai, Negeri Sembilan, Malaysia
3Formulation and R&D Technologies, Duopharma Innovation Sdn Bhd, No. 2 Jalan Saudagar U1/16, Zon Perindustrian Hicom Glenmarie, Seksyen U1, 40150 Shah Alam, Selangor, Malaysia
4RA Chem Pharma Limited, Clinical Research and Biosciences Division, Plot No. 26 & 27, Technocrat Industrial Estate (TIE), Balanagar, Hyderabad 500037, India
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Author for correspondence: Chuei Wuei Leong, PhD, Formulation and R&D Technologies, Duopharma Innovation Sdn Bhd, No. 2 Jalan Saudagar U1/16 Zon Perindustrian Hicom Glenmarie Seksyen, U1 Shah Alam, 40150 Shah Alam, Selangor, Malaysia
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