Bioequivalence Study of Eltrombopag 75 mg Film-coated Tablets under Fasting Conditions during the Covid-19 Pandemic in Healthy Caucasian Male Subjects

doi:10.21203/rs.3.rs-4950508/v1

This study aims to determine the bioequivalence of the reference preparation and the test preparation containing eltrombopag when both were given during the COVID-19 pandemic while fasting. Participants in the research were healthy male Caucasian subjects. One film-coated tablet of the test preparation or one film tablet of the reference preparation, equivalent to 75 mg of eltrombopag, was given to the participants in a randomized order throughout each treatment session. At pre determined blood sampling points, blood samples were taken to determine the pharmacokinetics of eltrombopag. Eltrombopag concentrations in the samples were determined using an LC-MS/MS technique verified using ESI(-). The study results were used to calculate the rate (the maximum plasma concentration, or C_max) and extent (area under the concentration-time curve of plasma, or AUC₍₀₋₇₂₎ and AUC_(0−t) of eltrombopag absorption from the test preparation and reference preparation. The 90% confidence intervals (CI) of the ln-transformed AUC₍₀₋₇₂₎, AUC_(0−t), and C_max of eltrombopag met the bioequivalence requirements of 80.00% -125.00%. Both trial preparations had a similar and very satisfactory safety profile.

Bioequivalence study

eltrombopag

pharmacokinetic

bioavailability

Bioequivalence of eltrombopag film-coated tablets
Safety evaluation of eltrombopag film-coated tablets

Eltrombopag is a tiny molecule medication taken orally that is an agonist of the thrombopoietin (TPO) receptor. It binds to the human TPO receptor's transmembrane domain, initiating signaling pathways that support the differentiation and multiplication of progenitor cells in the bone marrow.^1,2

When eltrombopag is given to healthy people at dosages ranging from 50 to 150 mg/day, there is a dose-proportional increase in exposure. The AUC Eltrombopag is about 1.7 times higher in patients with immune thrombocytopenic purpura (ITP). In chronic or persistent use, the AUC is about 2.8 times higher in patients with hepatitis C when compared with healthy subjects. At a dosage of 75 mg/day, the geometric mean accumulation ratio is 1.56 (90% CI 1.20, 1.63), which indicates that steady-state concentrations are usually attained after approximately one week of daily administration. Eltrombopag AUC is generally 3.2 times higher in patients with severe aplastic anemia who have not received definitive immunosuppressive therapy than in healthy subjects. It suggests that AUC in hepatitis C is more significant than in both healthy subjects and individuals with ITP. Moreover, eltrombopag oral suspension produces a plasma AUC_(0−∞) 22% greater than the tablet formulations.³

The plasma levels of eltrombopag increase linearly with the dose, and it takes two and a half to five hours to reach their highest concentration when taken at 75 mg orally.^3,4 A high-fat meal (876 calories, 52 grams of fat, 71 grams of carbs, 34 grams of protein, and 427 milligrams of calcium) was shown to considerably lower plasma eltrombopag AUC_(0−∞), C_max and time to achieve C_max (t_max). The increased calcium content is primarily responsible for this decrease in AUC_(0−∞), C_max and t_max. On the other hand, irrespective of the meal's calorie content and lipid composition, a low-calcium meal did not significantly influence plasma eltrombopag level.^5,6

A radiolabeled study found that the level of eltrombopag in blood cells is 50–79% compared to that in plasma. Based on in vitro investigations, eltrombopag binds to more than 99% of human plasma proteins.⁴ Eltrombopag has an elimination half-life in plasma of 21–32 hours in healthy subjects and 26–35 hours in ITP patients. After absorption, eltrombopag is extensively metabolized via oxidation, cleavage, and conjugation with cysteine, glutathione, or glucuronic acid. Eltrombopag's oxidative metabolism is linked to CYP1A2 and CYP2C8, whereas UGT1A1 and UGT1A3 cause glucuronidation. These findings are based on in vitro investigations.^7,8 Eltrombopag is mainly excreted in feces, where 59% of the dosage is eliminated, and 31% is eliminated in urine. The unaltered eltrombopag, which is undetectable in urine, is about 20% of the total dosage.⁷

Any product's efficacy and safety must be shown for registration. The marketing authorization procedure for a novel generic product includes establishing the bioequivalence with a market standard by comparing relative bioavailability or showing therapeutic equivalence. The therapeutic equivalence procedure needs many more patients and a long time to show the similarity between the test and reference drugs. The bioequivalence trial based on bioavailability is the most sensible option.^9,10

The present trial aims to investigate the bioequivalence between a test and a reference preparation, each containing eltrombopag, under fasting conditions during the COVID-19 pandemic. Revolade 75 mg Film Tablets, already registered and marketed for sale in Germany, are the reference medication used in this study. Fromer clinical trials have verified the safety and efficacy of this reference medication. Eltrombopag 75 mg Film-Coated Tablet, produced by İLKO Pharmaceuticals, Turkiye, has been used as the test drug.

Human Ethics and Consent to Participate declarations

The study was approved by an independent ethics committee-Ethics Committee for Bioavailability-Bioequivalence Trials of Erciyes University (date of approval: 15.06.2022; vote no: 2022/148) and the Turkish Medicines and Medical Devices Agency (TİTCK) of Turkish Ministry of Health, (date of approval: 01.07.2022, note no.: E-66175679-514.06.01-803603). Clinical trial number is not applicable.

The study was designed following the Turkish Pharmaceutical and Medical Preparations Law No. 1262, ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP), Turkish Regulations Regarding Clinical Trials of Drugs and Biologics and the Turkish Good Clinical Practice Guideline (13.11.2015).^11,12,13

The purpose of the investigation was fully disclosed to each subject in a written document and oral presentation by the principal investigator or one of the co-investigators. Then, each participant voluntarily signed the Informed Consent Form.

Study Design

This study was conducted in 48 healthy male individuals under fasting conditions. It was a single-dosage, mono-centric, randomized, open-label, two-period, crossover bioequivalence study. 68 Caucasian male subjects were screened between July 25, 2022, August 4, 2022, and August 15, 2022. After undergoing thorough physical examinations and clinical laboratory tests, 48 healthy male individuals were included in the research (Figure 1).

Figure 1. Schematic Study Design

Precautions for COVID-19

Before the subjects were accepted to the clinical unit, their body temperature was measured, and a SARS-CoV-2 Rapid Antigen Test was performed. If the body temperature was within normal ranges and the rapid antigen test showed negative results, then the subjects were accepted to the clinical unit for screening. A combined throat/nasal swab was collected for an additional real-time Reverse Transcription Polymerase Chain Reaction (RT – PCR) COVID-19 test during screening. If this test also showed negative results and the subjects were considered suitable for the study, they were confined to the clinical unit. An additional COVID-19 real-time RT – PCR test or a SARS CoV-2 Rapid Antigen Test was also performed before the second period. Participants who had two negative COVID-19 test results were hospitalized in the clinical unit in the evening before drug administration.

Drug administration, study requirements and blood sampling

After being hospitalized, participants were given a snack in the evening with a total caloric value of approximately 600 kcal, which they were required to finish by 9:00 pm. The Investigational Products were administered the following morning, and the subjects were discharged approximately twelve hours later. The subjects were invited to the clinical site for blood sampling at 24-, 36-, 48-, and 72 hours post-administration. The test and reference preparations, each containing 75 mg of eltrombopag, were administered orally with 240 mL of water after at least ten hours of overnight fasting. A second medical professional performed mouth and hand checks to ensure that the drug was taken wholly and correctly. After the drug administration, subjects were instructed not to lie down for the next two hours, except in cases of orthostatic discomfort.

Overnight fasting continued after four hours post-dosing, with fluid intake restricted to tap water, allowing a maximum of 1.5 liters on dosing days. Water was allowed one hour before and after the drug administration. A standard lunch (approximately 1,200 kcal) was provided at the end of the fasting period, followed by a standard dinner (approximately 1,200 kcal) 10 hours post-dose. Smoking was prohibited during blood sampling periods. Alcohol consumption was restricted from two days before each dosing until after the final blood sampling of each period. Furthermore, from two days before the dosing until the last blood sample, meals and drinks that included caffeine or other methylxanthines (such as coffee, tea, cola, and chocolate) and fruit juices were prohibited. Consumption of grapefruit and orange products was not allowed from seven days before the first dosing until the final blood sampling.

Subjects were instructed to avoid prescribed systemic or topical medications for two weeks before the study and to stop taking over-the-counter (OTC) medications, including herbal products, one week before the survey. The use of systemic or topical drugs, including herbal products, was not allowed during the study. Additionally, participants were prohibited from using investigational medicines (i.e., medications that are not yet licensed) within the 60 days before the trial. Between periods I and II, a 14-day wash-out period was provided. Subjects were permitted to leave the clinical center after the final examination.

Blood sampling was done before the dosing and 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 2 hours 20 minutes, 2 hours 40 minutes, 3 hours, 3 hours 20 minutes, 3 hours 40 minutes, 4 hours, 4 hours 30 minutes, 5 hours, 5 hours 30 minutes, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 36 hours, 48 hours, and 72 hours after the dosing. Blood sampling (22 per period) was done with a short intravenous catheter. Every sample (7 milliliters) was placed into tubes containing K₂-EDTA as an anticoagulant. Following centrifugation at 3,000 rpm, 4–7°C, for 10 minutes, the separated plasma was given into two 3.5 ml transparent polypropylene tubes, each containing at least 1.5 ml of plasma, and kept at <–70°C until it was transported to the analytical facility. After the trial was completed, one aliquot was sent to Analytisches Zentrum Biopharm GmbH, Berlin, Germany, via courier on dry ice (solid CO₂)

Study drugs

The test product, Eltrombopag 75 mg Film Coated Tablets (T), batch no: 2213819001, expiry date: 04.2024, was produced under Good Manufacturing Practices (GMP) conditions by İLKO İlaç Sanayi ve Ticaret A.Ş., Turkiye. The innovative product, Revolade 75 mg Filmtabletten (Film Tablets) (R), batch no: BALJ7X, which was acquired from the German market, served as the reference preparation.

Bioanalytical Method

Samples were analyzed for concentrations of eltrombopag with a validated LC-MS/MS method with ESI(-). Guidelines for Good Laboratory Practice (GLP) were used to perform the analytical procedures.^14,15 The lower limit of quantification (LLOQ) for eltrombopag was set at 0.150 μg/mL for plasma samples. The mean relative deviations of quality control (QC) samples, reflecting inter-assay accuracy (bias %), were as follows: 4.7% for high-quality control (HQC), 2.7% for medium-quality control (MQC), -6.2% for low-medium-quality control (LMQC), and 4.8% for low-quality control (LQC). The corresponding mean values for inter-assay precision (CV %) were 3.2% for HQC, 3.7% for MQC, 3.4% for LMQC, and 4.1% for LQC.

Assessment of Pharmacokinetics and Statistics

Eltrombopag's AUC_(0-72)and C_max, the primary target variables, were first estimated using pharmacokinetic values based on the literature indicating a long half-life of 21–32 hours. However, The study's findings showed that the half-lives of the reference and test items were around 18 hours. As a result, AUC_(0-72) could only be assessed for 16 subjects. Analysis of variance (ANOVA) and two one-sided t-tests were used to compute the 90%CI for the test/reference ratios of geometric means for the primary pharmacokinetic variables AUC_(0-72), C_max, and the additional variable AUC_(0-t), assuming a log-normal distribution of the data. This was done to assess the bioequivalence between the test and reference preparations.

In addition to AUC_(0-_¥₎, parameters such as t_max, t½_{(λz) ,} λ_z and AUC_%-extrapolwere also examined as auxiliary variables. To better approximate a normal distribution, AUC_(0-72), AUC_(0-_∞₎, AUC_(0-t), and C_max data were transformed logarithmically before analysis and then subjected to parametric testing using ANOVA. The 90% confidence interval for the test/reference ratio of geometric means was calculated by retransforming the log-transformed values. Bioequivalence was determined if the 90% CI fell within the 80.00% to 125.00% range for AUC_(0-72)and C_max, as specified in the study protocol, and also for AUC_(0-t), which was considered as an extrapolatory pharmacokinetic variable. t_max values were also statistically evaluated. Non-parametric analysis results (90% CI from two one-sided Wilcoxon tests) were used as supportive data and were not used for the primary bioequivalence assessment. Parameters of the individual estimate of the terminal elimination rate constant (λ_z) and half-life (t½_(λz)), along with AUC_%-extrapol, were tabulated with their descriptive statistics. Differences in t_max were assessed through non-parametric analysis (90% CI from two one-sided Wilcoxon tests) using Phoenix WinNonlin V8.3.5.340.3. For calculating λ_z [h-1], the slopes of the log-linear concentration/time curves were based on the last four data points above the LLOQ. The parameters AUC_(0-72), AUC_(0-_¥₎, AUC_(0-t), C_max, t_max, λ_z, t½_(λz)and AUC_%-extrapolof eltrombopag were determined with the program Phoenix WinNonlin V8.3.5.340.

Safety Assessment:

All adverse events (AEs) were recorded in Case Report Forms (CRF) for each subject. These AEs included those reported spontaneously by the participants, identified during regular questioning (upon admission to the clinical unit before the 1^st and 2^nd periods, and at study times of 0 hours (within 60 minutes before dosing), 1 hour and 6 hours, 12 hours, 24 hours, 36 hours, 48 hours and 72 hours during both periods). Additionally, any AEs observed by the investigator were also recorded.

Pharmacokinetic Results

Fourthy-eight healthy male Caucasian subjects were enrolled in the study after a comprehensive screening (including first medical examination, blood and urine laboratory tests, ECG and others). Out of these, 46 subjects, aged (18 - 50 years) with a Body Mass Index (BMI) between 18.7 to 29.7 kg/m², finished the study as planned. Two subjects withdrew from the study: the first left after period I for personal reasons, and the second before period II due to a medical issue (a positive RT-PCR COVID-19 test).

The subjects were hospitalised 12 hours before the medication was administered and discharged 12 hours after the administration. Eltrombopag concentrations were investigated using plasma samples from the 46 participants who completed the research. The average (± standard deviation) demographic data for these 46 subjects were 33.3 (± 9.4) years in age, 77.4 (± 12.1) kg in weight, 174 (± 7.4) cm in height, and a BMI of 25.6 (± 3.2) kg/m² (Table 1).

Table 1. Summary of the Subjects' Demographic Data

Summary Demographic Data	*Age[a]**	Weight* [kg]	Height* [cm]	BMI/* [kg/m²]
Mean	33.3	77.4	174	25.6
SD***	9.4	12.1	7.4	3.2
CV [%]****	28.1	15.6	4.2	12.5
Minimum	18	50.8	161	18.7
Maximum	50	99.0	192	29.7

*at the time of pre-study examination

**Body mass index should be in the range of 18.5 – 30 kg/m²

*** standard deviation

****Coefficient of variation

As a result of the blind review of analytical data, the pharmacokinetic data set (n = 46 subjects) represented all subjects who completed the study, all devoid of protocol violations, without violation of entry criteria and with all of the primary target variables available for measurement. There were noticeable similarities between the test and reference drugs when comparing pharmacokinetic data. Eltrombopag characteristics showed no significant differences, such as AUC_(0-72), AUC_(0-t), and C_max (Table 2).

Table 2. Results of Pharmacokinetic Testing (arithmetic mean±SD.; n = 46) of eltrombopag

Treatment

*AUC_(0-72)

[µg/mL*h]

Cmax [µg/mL]

AUC_(0-t)

[µg/mL*h]

tmax [h]

λz

[1/h]

t½( λz )

[h]

AUC(0-_¥)

[µg/mL*h]

AUC_%-extrapol

_[%]

T: Eltrombopag

75 mg Film Coated Tablets

batch no.: 2213819001

107.898

± 33.848

8.490

± 2.919

83.149

± 36.723

2.95

± 0.82

0.0462

±

0.0237

18.27

±

7.40

90.683

±

42.180

7.73

±

3.35

R: Revolade 75 mg Filmtabletten (Film Tablets)

batch no.: BALJ7X

110.488

± 26.191

7.534

± 2.517

75.512

± 34.810

3.33

±

0.90

0.0497

±

0.0249

17.14

±

7.52

82.982

±

39.997

8.55

±

3.46

*n = 16 subjects included for AUC_(0-72) evaluation

AUC: Area under the curve

C_max: The Maximum plasma concentration

t_max: Time to achieve C_max

λz : Individual estimate of the terminal elimination rate constant

t½: Half life

The comparative bioavailability of eltrombopag of the test drug, determined by comparing the geometric means of AUC(0-72), is 99.26 %, AUC(0-t) is 111.03 %, and Cmax is 111.79 % (ratio, i.e., point estimator of 90 % CI) (Table 3).

Table 3. Statistical results of eltrombopag (test vs reference); n = 46

Primary pharmacokinetic parameters			Intrasubject variability
^*AUC_(0-72)	85.58 % - 115.12 %	(ratio: 99.26 %)	22.34 %
^*AUC_(0-t)	98.76 % - 124.82 %	(ratio: 111.03 %)	34.38 %
^*C_max	100.69 % - 124.11 %	(ratio: 111.79 %)	30.53 %
Secondary pharmacokinetic parameters			Intrasubject variability
^*AUC_(0-_-_¥₎	98.35 % - 123.13 %	(ratio: 110.04 %)	32.90 %
^**t_max	0.00 h – 0.67 h	(median of difference reference-test: 0.34 ^h)

* two one-sided t-tests; ANOVA

** non-parametric analysis

h: hour

AUC: Area under the curve

C_max: The Maximum plasma concentration

t_max: Time to achieve C_max

For a more comprehensive evaluation, Figures 2a and 2b present mean plasma concentration-time profiles for eltrombopag across different time points and treatments. These graphical representations confirm the same pharmacokinetic characteristics between the test and reference products. In conclusion, the data from both tables and figures support the claim of bioequivalence between the test and reference products.

Figure 2a. Eltrombopag mean plasma concentration/time profiles - linear (±SEM) plot (n = 46)

Figure 2b. Eltrombopag mean plasma concentration/time profiles semilogarithmic plot (n = 46)

Safety Evaluation

Five out of the 48 subjects experienced seven adverse events during the study. Four adverse events occurred before dosing: three (3 x headaches) of them even before the first drug administration and one (1 x positive COVID-19 RT-PCR test) before the second drug administration (two weeks after the first treatment). So, these adverse events were evaluated to be “unlikely” drug-related. Two of the remaining treatment-emergent adverse events (2 x headaches) were mild, and one (1 x high blood glucose level) was of moderate intensity. Two headaches occurred in period II after the test preparation. High blood glucose was observed during the final examination. The last dose administered to this subject was the test preparation. The subject did not return to the clinical facility for the repeat tests. Both headaches were evaluated to be “possible” drug-related, whereas the high blood glucose level was assessed to be “unlikely” drug-related. Headaches seen pre-administration and one of the headaches seen during period II were treated with 500 mg paracetamol. All treatment-emergent adverse events recovered without sequelae, except for the high blood glucose level, for which the outcome is unknown as the subject refused to return to the clinical unit for the repeat measurement.

No severe adverse events were recorded. Table 4 summarizes the observed treatment-emergent adverse events.

Table 4. Number, type and qualification of adverse events observed

Relationship with the drug	Adverse Event (n)	Adverse Events by Treatment at Onset of AE
Relationship with the drug	Adverse Event (n)	Treatment T	Treatment R	Pre-dose
possible	headache (2)	2	0	0
unlikely	headache (3)	0	0	3
unlikely	high blood glucose (1)	1	0	0
unlikely	positive COVID-19 real-time PCR test (1)	0	0	1

n: Number

AE: Adverse events

T: Test

R: Reference

Bioavailability is the term used to describe the rate and extent of absorption and availability of the therapeutic moiety or active component in a pharmaceutical at the site of treatment action. The Guideline on the Investigation of Bioequivalence Committee for Medicinal Products for Human Use states that two medicinal products are bioequivalent if their bioavailabilities (rate and extent) after administration of the same molar dose are similar to such degree that their effects concerning both efficacy and safety will be essentially the same.¹³ This condition is met if the AUC-ratio and C_max-ratio's 90% confidence intervals fall between 80.00% and 125.00%. According to the above guidance, AUC_(0-72) may be used instead of AUC_(0-t)for comparing exposure duration since the absorption phase for immediate-release formulations is completed in 72 hours. Therefore, regardless of the drug's half-life, a sample duration greater than 72 hours is not required for any immediate-release formulation. When doing research with a 72-hour sample interval and measurable concentration at 72 hours, reporting AUC_(0-∞) and residual area is unnecessary; reporting AUC_(0-72) suffices.¹⁶ As eltrombopag was given in the literature data as a long half-life drug (21 – 32 hours), AUC_(0-72) was chosen as the primary pharmacokinetic parameter besides C_max. AUC_(0-t) was initially foreseen as an exploratory variable.³However, the long half-life given in the literature for eltrombopag was not confirmed by the study results, where the half-lives of both test and reference drugs were calculated to be about 18 hours. Consequently, AUC_(0-72) could only be evaluated for 16 subjects. Therefore, besides AUC_(0-72) and C_max, AUC_(0-t) was also treated as a primary target variable. According to the current study, the extent and rate of eltrombopag absorption from test and reference preparation are comparable. The 90% CI for the Test/Reference ratio of ln-transformed AUC_(0-72), AUC_(0-t), and C_maxof eltrombopag satisfies the 80.00% - 125.00% bioequivalence requirements.

The bioequivalence acceptance range includes the 90% CI of the ln-transformed data for eltrombopag's secondary pharmacokinetic target variable AUC(0-∞). Both study preparations have a very acceptable safety profile. There was no clinically significant variation in the therapies' safety and tolerability.

The clinical research area, except for COVID-19 research, was significantly interrupted, especially in the early period of the pandemic. In our GCP clinical facility, we started the clinical trial procedure by considering the risk of COVID-19 infection in our staff and subjects. The rationale for this action was to use a method that includes pre-study isolation of subjects and frequent checks for COVID-19 infection in our staff and subjects. While working with hotel isolation in the early days of the pandemic, we continued to work with measures such as the SARS Co-V-2 Rapid Antigen Test, RT- PCR tests, checking body temperature, and use of face masks. The significant contributions of this study are both indicating that clinical study can be done in periods of pandemics and showing that two eltrombopag products are bioequivalent.

Funding declaration

This study was supported by ILKO Pharmaceuticals, Türkiye

Conflicts of Interest

AI is the principal investigator at Hakan Cetinsaya GCP Center, and ZS and MM are co-investigators at Hakan Çetinsaya GCP Center. OP and BB are the sponsor representatives from ILKO Pharmaceuticals. MR is staff in Analytisches Zentrum Biopharm GmbH. WM is a staff member at Pharmakin Consulting Services UG. SAK is staff in IDEAL Biyolojik Ürünler ve İlaç Danışmanlık Eğitim Ltd. Şti.

Author Contribution

All authors contributed to the concept and design of the study. OP and BB took decisions in the name of the sponsor. SK prepared study documentation and carried out the necessary application and submissions for the study. AI carried out the clinical part as the principal investigator, ZS and MM as co-investigator. MR, performed Bioanalysis in plasma. WM performed the Pharmacokinetic analysis, statistics and reporting parts. AI and SK contributed to writing the manuscript. All authors approved the final version of the manuscript.

Acknowledgments

We would like to thank the Proofreading & Editing Office of the Dean for Research at Erciyes University for copyediting and proofreading service for this manuscript

Data Availability

The data are not publicly available due to compromise the privacy of study participants and due to the fact that trade secret. The data that are publicly available are shared in the article.

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No competing interests reported.

Bioequivalence Study of Eltrombopag 75 mg Film-coated Tablets under Fasting Conditions during the Covid-19 Pandemic in Healthy Caucasian Male Subjects

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Abstract

Figures

Key Points

1. Introduction

Methods

Results

Discussion

Conclusion

Declarations

Author Contribution

Acknowledgments

Data Availability

References

Additional Declarations

Status:

Journal Publication

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