Bioequivalence Acceptance Range Research Articles

Bioequivalence of Water-Soluble Progesterone Injection (GenSci070) in Healthy Chinese Postmenopausal Women Volunteers.

To study the pharmacokinetic characteristics of progesterone (GenSci070) in healthy Chinese postmenopausal women volunteers and to evaluate the bioequivalence and safety of GenSci070 and reference formulation. In this randomized, open-label, single-center, single-dose, 2-period, 2-sequence, 2-way crossover study, 50 postmenopausal healthy women were recruited and received a single subcutaneous injection of test (GenSci070) or reference formulation 25 mg, respectively. Plasma progesterone concentrations were measured using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were calculated by noncompartmental analysis method using Phoenix WinNonlin 8.3.1 software to evaluate the bioequivalence. The safety profile was evaluated by adverse events, physical examination, vital signs, laboratory tests, 12-lead ECG, etc. FINDINGS: The geometric mean ratios (90% CIs) for Cmax, AUC0-t, and AUC0-∞ of the test and reference formulations were 92.70% (87.29%-98.44%), 96.26% (94.02%-98.55%), and 95.46% (93.27%-97.71%), respectively. They were all within the acceptable bioequivalence range of 80% to 125%. Thirty-one treatment-emergent adverse events occurred in 22 participants (44.0%) who received test formulation and 21 treatment-emergent adverse events occurred in 16 participants (32.0%) who received reference formulation, all events were mild. The water-soluble progesterone injection (GenSci070) demonstrated bioequivalence to the marketed progesterone injection (Lubion) and exhibited a good safety profile in this study.

Bioequivalence Study of Bedaquiline Fumarate Tablets in Healthy Chinese Subjects.

Bedaquiline fumarate tablets are a novel oral antimycobacterial drug. This study assessed the bioequivalence of a generic bedaquiline fumarate tablet compared to a reference tablet under fasting (n=44) and fed (n=24) conditions. Conducted as a single-center, randomized, open-label, 2-sequence, crossover trial, 68 participants were randomly assigned to receive a 100-mg dose of either the test or reference tablet, with a 42-day washout period between doses. Blood samples were collected at prespecified time points from 0 hour (before administration) to 984 hours after administration. Plasma concentrations of bedaquiline were measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry method. Safety was monitored throughout the study. Key pharmacokinetic parameters included maximum plasma concentration, area under the plasma concentration-time curve (AUC) from 0 to 72 hours, AUC from time 0 to the last measurable concentration, AUC from 0 to 336 hours, and AUC from time 0 to infinity. The 90% confidence intervals for the geometric mean ratios of the test/reference formulations for maximum plasma concentration, AUC from 0 to 72 hours, AUC from 0 to 336 hours, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity fell within the bioequivalence acceptance range of 80%-125%. confirming bioequivalence between the 2 formulations in healthy Chinese volunteers. Moreover, a high-fat diet can significantly elevate the exposure of bedaquiline. No serious adverse events occurred, and both formulations were well tolerated across all participants.

Evaluating the pharmacokinetics and safety of blonanserin tablets and Lonasen®: a randomized, open-label, two-period, two-sequence, self-crossover phase I clinical trial

ObjectiveThis study evaluated the pharmacokinetic and safety profiles of generic and original blonanserin tablets under fasting and postprandial conditions, and the bioequivalence of two formulations to obtain sufficient evidence for abbreviated new drug application.MethodsA randomized, open-label, two-period, two-sequence, self-crossover bioequivalence study was conducted to assess the bioequivalence of the test and reference blonanserin tablets under fasting and postprandial conditions. Eligible healthy individuals received a single 4-mg dose of either the test or reference blonanserin tablet, followed by a wash out period of 14 days. Serial blood samples were collected for up to 72 h after administration during each period, and the plasma concentrations of blonanserin were determined using a validated method. The non-compartmental method was used to calculate the primary pharmacokinetic parameters, and the geometric mean ratios for the PK parameters of the test drug to those of the reference drug, along with the corresponding 90% confidence intervals, were obtained for bioequivalence analysis. Throughout the study, a safety evaluation was conducted.ResultsUnder both fasting and postprandial conditions, the pharmacokinetic parameters of the test drug were found to be similar to those of the reference drug. The 90% confidence intervals (CIs) of the geometric mean ratios of the test to reference formulations were 97.79%–118.28% for peak concentration (Cmax), 92.35%–111.78% for the area under the curve from zero to the last measurable concentration (AUC0-t) and 92.88%–111.91% for the AUC from zero to observed infinity (AUC0-∞) under fasting conditions, 88.65%–103.20% for Cmax, 95.89%–106.81% for AUC0-t and 96.02%–106.91% for AUC0-∞ under postprandial conditions, all of which were within the accepted bioequivalence range of 80.00%–125.00%. Both the test and reference formulations were well-tolerated, and no serious adverse events related to the study drug were reported during the study.ConclusionThe bioequivalence of blonanserin tablets, both test and reference, was confirmed in healthy Chinese subjects under fasting and postprandial conditions, meeting the predetermined regulatory criteria for both formulations. Both formulations were found to be safe and well tolerated.Clinical Trial Registrationhttp://www.chinadrugtrials.org.cn/index.html, identifier CTR20230703.

Lack of Clinically Meaningful Effect of Cariprazine on the Pharmacokinetics of a Combined Oral Contraceptive.

Cariprazine (CAR) is a potent dopamine receptor partial agonist antipsychotic approved by the EMA and the FDA. To address the uncertainty regarding the effectiveness of hormonal contraceptives during CAR co-administration and whether a second barrier method is necessary, a drug-drug interaction study with an oral contraceptive was conducted post-approval. The phaseI, fixed-sequence multicenter study involved two periods with 24 patients with schizophrenia, aiming to evaluate the effect of CAR on the pharmacokinetics (PK) of a combined oral contraceptive (COC) containing 30μg ethinylestradiol (EE) and 150μg levonorgestrel (LNG). In periodA, a single dose of COC alone was administered on day1. In periodB, the highest therapeutic dose of 6mg CAR was administered once daily from day4, and a second dose of COC was given concomitantly on day31. Overall, CAR had no clinically meaningful effect on the PK of the COC. The terminal half-life and the time of maximum plasma concentration of EE and LNG were not altered by CAR co-administration. The highest difference observed was a decrease of 14% in the maximum plasma concentration of EE, with only slight deviation of the 90% confidence interval (CI) of the test/reference ratio (77.09-96.81) from the generally accepted bioequivalence range of 80-125%, which is not considered clinically relevant. Confidence intervals of all other exposure measures were within the 80-125% range for both EE and LNG. According to these results, hormonal contraceptives can be considered effective during CAR treatment. Trial registration number (EudraCT) 2018-003722-80.

Pharmacokinetics and Bioequivalence of Vardenafil Hydrochloride in Healthy Chinese Volunteers.

Vardenafil hydrochloride tablet is an inhibitor of phosphodiesterase type 5, primarily for the treatment of erectile dysfunction. This postprandial study evaluated the pharmacokinetics and bioequivalence of the test and reference formulations of vardenafil hydrochloride tablets in healthy Chinese volunteers. An open, randomized, single-center, single-dose, 2-period, 2-sequence bioequivalence test was conducted on 66 healthy subjects under fed conditions. Subjects were randomly assigned to a 20-mg test or reference formulation with a 7-day washout period. Venous blood samples (4mL) were collected from each subject 25 times spanning predose (0hour) to 24hours after dosing. The plasma concentration of vardenafil was determined by high-performance liquid chromatography-tandem mass spectrometry. Sixty-two volunteers completed the study. Under fed conditions, the maximum plasma concentration was 29.1ng/mL, the area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration was 85.3ng•h/mL, and AUC from time 0 to infinity was 87.1ng•h/mL. The 90% confidence intervals of the geometric mean ratio of AUC time 0 to the time of the last measurable concentration and AUC from time 0 to infinity were within the bioequivalence acceptance range of 0.80-1.25. The test formulation was a bioequivalent alternative to the reference formulation when taken under fed conditions in healthy Chinese subjects.

Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm Phase I trial (VOLTAIRE-HCLF)

ABSTRACT Objective VOLTAIRE-HCLF compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. Methods Healthy volunteers (N = 200) aged 18–55 years and with body mass index of 18.5–29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. Results The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0–1344, AUC0–∞, and Cmax for both groups were entirely within the standard 80–125% bioequivalence acceptance range at 101.88% (93.31–111.23%), 105.38% (95.06–116.81%), and 91.29% (84.38–98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. Conclusions Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. Clinical trial registration NCT05203289

Apixaban Pharmacokinetics and Bioequivalence of Two Tablet Formulations: A Randomized, Open-Label, Crossover Study, Fasting Condition in Healthy Indonesian Volunteers.

The present study aimed to assess the bioequivalence of a new apixaban generic with reference formulation. Twenty-six healthy volunteers were recruited for an open-label, balanced, randomized, 2-treatment, 2-sequence, 2-period, single oral dose study. Following overnight fasting, each volunteer received 5mg of apixaban test and reference formulations as single doses, separated by a 1-week washout period. Twenty blood samples were collected at predose and multiple time points between 0.5 and 72 hours after dosing. A validated ultra-performance liquid chromatography-tandem mass spectrometry detection method following a protein precipitation step was implemented to determine apixaban concentrations. Noncompartmental analysis was used to derive the pharmacokinetic parameters, which were then compared between the test and reference products using a multivariate analysis of variance. The pharmacokinetic parameters of the test product were not statistically different from the reference product, and the 90% confidence intervals of apixaban natural log-transformed area under the concentration-time curve from time 0 to infinity, area under the concentration-time curve from time 0 to the last measurable concentration, and maximum concentration were within 80%-125% based on the bioequivalence acceptance range criteria. The test and reference formulations of apixaban are bioequivalent in healthy subjects under fasting conditions.

Pharmacokinetics and Bioequivalence of Two Combination Metformin/Glipizide Tablets under Fasting and Fed Conditions in Chinese Healthy Subjects: A Randomized, Open-Label, Crossover Study

Metformin/glipizide tablets are a compound formulation composed of metformin hydrochloride and glipizide. This study aimed to assess the pharmacokinetics and bioequivalence of two fixed-dose combination (FDC) tablets of metformin/glipizide (500 mg/2.5 mg) in healthy Chinese subjects. We conducted a single-center, open-label, randomized, two-way crossover study with a total of 48 subjects enrolled (24 in each dietary group). The test or reference formulations were given to the subjects at random at a ratio of 1 : 1, with a seven-day washout period. Blood samples, collected at prearranged intervals before and up to 24 hours after dosage, were analyzed using validated LC-MS/MS technology to ascertain plasma concentrations of metformin and glipizide. Finally, 23 subjects completed the fasting and fed studies, respectively. In both studies, the 90% confidence intervals for the geometric mean ratios (test/reference) of the Cmax, AUC0-t, and AUC0-∞ were all found to fall within the acceptable range for bioequivalence (80%–125%). The exposure of metformin/glipizide FDC tablets in vivo was not significantly affected by food. No serious adverse events were observed. In conclusion, this study demonstrated that both the test and reference metformin/glipizide tablets exhibited bioequivalence and were well tolerated under both fasting and fed conditions. This trial is registered with CTR202686.

Pharmacokinetic and pharmacodynamic evaluation study of etomidate: a randomized, open-label, 2-period crossover study in healthy Chinese subjects

Etomidate is a sedative and hypnotic drug through intravenous administration that act on the central nervous system through GABA (Gamma-Amino Butyric Acid) receptors, which is widely used in anesthesia induction and maintenance and long-term sedation in severe patients. The study aimed to evaluate the pharmacokinetic and pharmacodynamic properties of two etomidate fat emulsions after administration through the intravenous infusion pump in healthy Chinese subjects. A randomized, open-label, 2-period crossover study was performed in 52 healthy subjects. The wash-out period was 7 days. Blood samples and pharmacodynamic index values were collected at the specified time points. Etomidate concentrations were measured using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed using a non-compartment model method. Pharmacodynamic parameters were calculated using pharmacodynamic index values. The study also evaluated the safety of the etomidate. Both the pharmacokinetic parameters and pharmacodynamic parameters result of the test and reference formulation were very similar. The 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratios of the test to reference formulation were 91.33–104.96% for the maximum plasma concentration (Cmax), 97.21–102.03% for the area under the plasma concentration time curve from time 0 to the time of the last measurable concentration (AUC0–t), and 97.22–102.33% for the area under the plasma concentration time curve from time 0 to infinity (AUC0–∞). Meanwhile, the 90% CI of the GLSM ratios of the test to reference formulation were 102.28–110.69% for the minimal BIS value (BISmin), 99.23–101.17% for the area under the BIS time curve from time 0–60 min after administration (BISAUC0–60 min), respectively. The 90% CI of these pharmacokinetic and pharmacodynamic parameters all fall in the accepted bioequivalence range of 80.00–125.00%. No serious adverse events occurred during the study. This study has shown that the etomidate fat emulsion test and reference formulation had similar pharmacokinetic and pharmacodynamic characteristics in vivo. The two formulations exhibited good safety and well-tolerance.Clinical trials registration number:http://www.chinadrugtrials.org.cn/index.html. # CTR20191836.

(031) Bioequivalence Studies of Sildenafil Citrate Orodispersible Film Administered With and Without Water versus Viagra Film-Coated Tablets in Healthy Adult Male Volunteers

Abstract Introduction Orodispersible film (ODF) formulation offers ease of use, convenience of administration, and other advantages, especially for patients who have difficulty in swallowing or are on liquid restriction compared with conventional oral formulations for the treatment of erectile dysfunction. Objective These studies compared the bioequivalence of 50 mg sildenafil citrate ODF formulation (test drug) with the marketed 50 mg sildenafil citrate film-coated tablet (FCT) (Viagra; Pfizer, New York, NY) (reference drug), with and without water in 2 randomized cross-over studies. Methods Two randomized cross-over studies were conducted. The first study explored the bioequivalence of test drug administered with and without water compared with the reference drug with water. The second study investigated the bioequivalence of test drug, without water, compared with the reference drug with water. 42 healthy adult male volunteers started the first study and only 40 completed. While 80 subjects who were enrolled completed the second study. All the 120 subjects from both the studies were included for pharmacokinetic and bioequivalence analysis. All volunteers fasted for 10 hours pre-dose. A 1-day washout period between doses was observed. Blood samples were collected at regular intervals both before (up to 120 minutes before dosing) and after dosing (at different intervals up to 14 hours) dosing stages. Statistical analyses on pharmacokinetic parameters were performed. Safety and tolerability for both the formulations were evaluated. Results In the first study, bioequivalence was demonstrated for sildenafil citrate ODF administered with water when compared with the Viagra FCT. The ratios of adjusted geometric means (90% confidence interval (CI)) were maximum plasma concentration: 1.02 (94.91–108.78) and area under the plasma concentration-time curve: 1.09 (104.49–113.21) for sildenafil citrate ODF administered with water vs Viagra FCT. These ratios were within the bioequivalence acceptance range of 80% to 125%, indicating that the bioequivalence criteria were met. The pharmacokinetic parameters for the second study also demonstrated bioequivalence for sildenafil citrate ODF when administered without water compared with Viagra FCT. The ratios of adjusted geometric means (90% CI) were maximum plasma concentration: 1.02 (95.47–109.36) and area under the plasma concentration-time curve: 1.06 (103.42–108.40) for sildenafil citrate ODF administered without water vs Viagra FCT. Adverse events in both the studies occurred at similar rates for the 2 formulations and were mild in intensity and were expected from the known safety profile. Conclusions Sildenafil citrate ODF administered with and without water met bioequivalence criteria compared with Viagra FCT administered with water under fasted conditions in healthy adult male volunteers. These results suggest that the new ODF formulation can be used interchangeably with the marketed FCT formulation. Therefore, the new ODF formulation can be used as a suitable alternative to the conventional oral solid dosage form for the treatment of ED. Disclosure Yes, this is sponsored by industry/sponsor: Viatris Inc. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Viatris Inc.

Study of the pharmacokinetic profile of the medicinal product Gidazepam®, tablets, 50 mg in a bioequivalence study

Aim. The primary aim of this study was to evaluate the pharmacokinetic parameters and confirm the bioequivalence of drugs containing gidazepam, namely Gidazepam® (Valenta Pharm, Russia) and Gidazepam VIC (VIVA Pharm, Republic of Kazakhstan), after a single administration of 1 tablet (50 mg) to healthy volunteers under fasting conditions. The secondary aim was a comparative analysis of safety profiles (adverse events) after a single administration of the studied drugs.Materials and methods. An open, randomized, crossover, two-period comparative study of pharmacokinetics and bioequivalence with adaptive design was conducted in healthy volunteers. Blood sampling was performed 15 minutes before and 20 min, 40 min, 1 h, 2 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 8 h, 12 h, 24 h, 48 h, and 72 h after drug administration. High-performance liquid chromatography-tandem mass spectrometry was used for the evaluation of gidazepam and its metabolite (desalkylgidazepam) concentration with the subsequent calculation of pharmacokinetic parameters.Results. From both formulations, gidazepam was quickly absorbed and biotransformed into an active metabolite. Studied drugs had similar pharmacokinetic profiles, as 90% confidence intervals for the ratio of geometric means for Cmax and AUC(0-72) were within the bioequivalence acceptance range of 80.00–125.00 %. No adverse events were recorded as a result of clinical, laboratory or instrument evaluations during the study.Conclusion. Study drugs are considered bioequivalent and show comparable tolerability after a single administration under fasting conditions.

Pharmacokinetic and Pharmacodynamics Study of Multiple Oral Doses of Vildagliptin Sustained Release 100 Mg Tablets under the Fed State in Healthy Volunteers

This study evaluated the pharmacokinetic and pharmacodynamic profile of the vildagliptin 100 mg sustained release (SR) administered once daily compared to vildagliptin 50 mg immediate release (IR) administered twice daily in healthy, adult human subjects under fed conditions.
 This was a randomized, balanced, open-label, two-treatment, two-period, two-sequence, crossover multiple oral dose study in healthy adult subjects under fed conditions. The subjects were randomized to receive either a test product, i.e., vildagliptin SR 100 mg once daily, or a reference product, i.e., vildagliptin 50 mg twice daily. The duration of the study was 25 days. The primary pharmacokinetic parameter evaluated was the area under the concentration-time curve for one dosing interval at steady-state (AUC0-τ, ss). Bioequivalence was determined by assessing whether the 90% confidence intervals (CIs) for the geometric mean ratio of test to reference drug fell within predefined margins of 80% −125% for AUC0-τ, ss. The pharmacodynamics parameters evaluated were percent dipeptidyl-peptidase-4 (DPP-4) inhibition and weighted average percent DPP-4 inhibition. 
 Forty healthy adult males completed the study. There was no significant difference between the pharmacokinetic and pharmacodynamic profiles in reference and test products. The mean ± standard deviation (SD) values of AUC0-τ, ss for test and reference product was 2689.06 ± 835.47 2875.57 ± 703.85 ng. hr/mL, respectively. The 90% CIs of geometric least-square means of test/reference ratio for AUC0-τ, ss with vildagliptin SR 100 mg tablet was 86.32-97.26% within the bioequivalence acceptance range. The test and reference product showed over 90% inhibition of DPP-4 activity with multiple doses. The weighted average percent of DPP-4 inhibition (0-24 hrs) was 92.66% with the test product and 93.26% with the reference product. Both products were well tolerated during the entire study period. No serious or life-threatening adverse events (AEs) were reported during the study.
 The two formulations of vildagliptin, i.e., vildagliptin SR 100 mg once daily and vildagliptin 50 mg twice daily, demonstrated similar pharmacokinetic and pharmacodynamic profiles under fed conditions in healthy adult males. Both formulations were bioequivalent and well tolerated.

Bioequivalence assessment of two Ticagrelor formulations under fasting condition in healthy Pakistani subjects.

To investigate the Bioequivalence of Anplag® 90mg (Ticagrelor) tablet and Brilinta® 90 mg (Ticagrelor) tablet under fasting conditions in healthy Pakistani subjects. This was an open-label, cross-over, randomized, single-dose, two-period, single-center Bioequivalence Study conducted at Center of Bioequivalence Studies and Clinical Research (CBSCR), ICCBS, University of Karachi, Karachi, Pakistan from September 2020 to January 2021. This was an open-label, randomized, single-dose, two-period, cross-over Bioequivalence Study. After randomization, a single dose of Ticagrelor 90mg tablet (test or reference drug) were administered orally in 1:1 ratio to each subject under fasting conditions. Seven days washout period was kept between the two periods in order to avoid carry over. Blood samples were then taken up to 48th hours post-dose. Point estimates and 90% confidence intervals (CI) for the ratio of the log-transformed values were calculated. Bioequivalence assessment of both, the reference and the test drugs were based on the primary Pharmacokinetic PK metrics including peak maximum concentration (Cmax), area under the curve (AUC) from zero to last quantifiable concentration (AUClast), and AUC from zero to infinity (AUCtotal) after log-transformation of data with ANOVA. In this bioequivalence study, the primary pharmacokinetic parameters were assessed for both Ticagrelor and its Active Metabolite (AR-C124910XX). Safety endpoints were evaluated by monitoring adverse events (AEs). The 90% Confidence Intervals (CIs) of the Geometric Mean Ratio for primary PK parameters including Cmax, AUClast, and AUCtotal all were within the accepted bioequivalence range of 80%- 125%. In the current study, no serious adverse events were reported. Our results showed that the two tested formulations of Ticagrelor tablets were bioequivalent and well tolerated.Trial Registration: ClinicalTrials.gov Identifier: NCT04941196.

Bioequivalence study of two formulations of rivaroxaban in healthy adult subjects under fasting conditions

Objectives: Oral anticoagulants exert their antithrombotic effect by disrupting the coagulation cascade. Rivaroxaban is the first oral agent to be developed that inhibits the coagulation process by binding directly to Factor Xa in a competitive manner. The aim of this study was to demonstrate the bioequivalence (BE) and safety of a generic formulation of rivaroxaban by comparing their pharmacokinetic (PK) parameters through statistical data and criteria of validation. Oral tablet formulations of 20 mg of a commercial product rivaroxaban reference (R) were tested against a generic product test (T) in 24 healthy adults under fasting condition. Materials and Methods: The study was an open label, balanced, randomized, two-treatment, two-period, two-sequence, single oral dose, and crossover study. Blood samples were collected pre-dose and at specified intervals up to 48-h post-dose to evaluate PK parameters by quantifying the concentration of rivaroxaban in plasma using a validated Liquid chromatography-mass spectrometry (LC-MS/MS) method of analysis. Statistics and confidence intervals (CIs) were calculated for BE purposes. Results: The geometric means of the T/R ratios and 90% confidence intervals (CIs) were: Cmax 87.80% (82.74 –93.12%), AUC0-t 85.96% (81.88–90.24%), and AUC0-∞ 86.13% (82.2–90.35%). All PK parameters are within BE acceptance range of 80–125% for demonstration of average bioequivalence. Conclusions: The study demonstrates the BE and well tolerance of both formulations of rivaroxaban in healthy subjects under fasting conditions.

Pharmacokinetic and bioequivalence study of two capecitabine tablets in Chinese patients with breast, colorectal or gastric cancer under fed condition: A multicentric, randomized, open-label, single-dose, two-period, two-way crossover clinical trial

ObjectiveThe aim of this study was to examine the pharmacokinetics, bioequivalence, and safety of two tablet formulations of capecitabine 500 mg in Chinese patients with breast, colorectal or gastric cancer under fed condition. MethodsA multicentric, randomized, open-label, single-dose, two-period, two-way crossover trial was conducted by randomizing a single oral dose of test (T) or reference (R, Xeloda®) capecitabine (500 mg) to patients of either sex with colon, colorectal or breast cancer under fed condition (high-fat and high-calorie diet). Pharmacokinetic parameters were calculated using non-compartmental methods. Patients were monitored for safety and tolerability throughout the study. Results74 subjects were randomly enrolled. The T/R geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for Cmax, AUC0-t and AUC0-∞ of capecitabine were 96.60% (85.87–108.67%), 99.07% (95.40–102.89%), 99.17% (95.29–103.21%), respectively. All 90% CIs fell within the bioequivalence acceptance range of 80.00–125.00%. The common adverse events (AEs) included clinically significant laboratory abnormalities and gastrointestinal diseases. There were no serious adverse events (SAEs) or deaths during the study. No subject withdrew from the study due to AEs. ConclusionSingle oral intake of test and the reference capecitabine tablets were bioequivalent under fed condition and had similar favourable safety profiles in Chinese patients with breast, colorectal or gastric cancer. Trial registrationchinadrugtrials.org.cn (CTR20182110).

Bioequivalence Evaluation in Healthy Volunteers: New Generic Formulations of Sitagliptin and Sitagliptin-Metformin Fixed-Dose Combination Compared with the Originator Products.

Three studies compared the bioequivalence (BE) of new generic tablet formulations of sitagliptin (100mg; fasting) and the fixed-dose combination (FDC) of sitagliptin/metformin (50/850mg, 50/1000mg; both fed) in healthy volunteers with the same tablet strengths of the reference products Januvia and Janumet. The study design was open-label, single-dose, randomized with two-way crossover periods. Blood sampling was performed for 72/48h in the sitagliptin/FDC studies, respectively. Primary pharmacokinetic (PK) parameters for sitagliptin and metformin were area under the plasma concentration-time curve from time 0 to last timepoint of measurable concentration (AUC0-t) and maximum plasma concentration (Cmax). Test (T) and reference (R) formulations proved bioequivalent if 90% confidence interval (CI) of geometric least-squares mean ratio for AUC0-t and Cmax were within BE acceptance range of 80.00-125.00%. Safety evaluations included vital signs, clinical laboratory tests, and adverse events (AEs). Treated/evaluable volunteers for BE per study were: 30/28 (sitagliptin 100mg), 26/25 (FDC 50/850mg), and 26/24 (FDC 50/1000mg). The 90% CI of the geometric means of T/R ratios for primary PK parameters were within predefined BE limits: CI for AUC0-t and Cmax were 95.83-100.37% and 91.85-109.56% (sitagliptin 100mg); 100.84-103.69% and 93.44-105.10% (FDC 50/850mg), and 101.26-105.20% and 98.71-112.89% (FDC 50/1000mg); respective values for metformin were 94.23-101.89% and 91.66-99.38% (FDC 50/850mg) and 98.45-104.89% and 96.79-105.62% (FDC 50/1000mg). All AEs were nonserious, transient, and mostly mild. Safety evaluations did not reveal any relevant difference between T and R formulations. The new generic tablet formulations of sitagliptin 100mg and the FDCs sitagliptin/metformin 50/850mg and 50/1000mg demonstrated bioequivalence to originator reference products. Therefore, the new products are expected to provide efficacy and tolerability similar to those of the reference products in the treatment of patients with type 2 diabetes (T2D). EudraCT EU Clinical Trials Registry (2014-005437-31); ClinicalTrials.gov Registry (NCT05549570 and NCT05549583, both retrospectively registered on 20 September 2022).

RF23 | PSAT258 Comparable Bioavailability of a Novel Levothyroxine Solution taken 10 or 30 minutes prior to a High-Fat, High-Calorie Breakfast

Abstract Levothyroxine (LT4) is the recommended treatment for hypothyroidism and the second most prescribed medication in the US. Several formulations are available, however most patients take LT4 tablets. Evidence suggests that absorption of levothyroxine tablets is decreased when taken with food, especially those rich in soy, iodine, and fiber. In order to avoid erratic absorption of LT4, it is recommended that oral formulations are taken on an empty stomach, 30-60 minutes before breakfast. However, compliance with this recommendation is often difficult for patients with busy schedules or on multiple medications, yet important in patients with conditions that are sensitive to changes in TSH levels such as pregnancy and thyroid cancer.There is evidence that oral liquid LT4 formulations that bypass the gastric dissolution phase of absorption may mitigate this food effect. ThyquidityTM (levothyroxine sodium) oral solution has demonstrated bioequivalence to Synthroid® under fasting conditions and allows individualized dosing flexibility. A bioavailability study was conducted to assess the rate and extent of absorption of the oral LT4 solution (100 mcg /5 mL) administered either 10 or 30 minutes before a standardized high-calorie, high-fat breakfast in an open-label, randomized, single-dose, 2-period, 2-sequence, crossover study. A single 600 μg oral dose of LT4 solution (ThyquidityTM, 30 mL) was administered to healthy adults either 10 or 30 minutes before consuming a 950 kcal, high fat (56%) breakfast in each study period and blood was collected for total (bound and free) T4 for 48 hours after drug administration. Treatment periods were separated by a 40-day wash-out period.The ratios of geometric LS means with corresponding 90% confidence intervals were calculated from the exponential of the difference between the LT4 solution administration 10 and 30 minutes prior to the meal for AUC0-48 and Cmax. An absence of food effect (bioequivalence) would be concluded if the baseline corrected 90% confidence intervals of this ratio fell within 80.00% to 125.00% for Ln-transformed AUC0-48 and Cmax.Forty healthy volunteers participated in the trial, 38 were included in the data analysis. There were no serious adverse events or discontinuations due to AEs. The geometric LS mean ratios of AUC0-48 and Cmax for baseline-adjusted LT4 were 88.74% (84.71-92.95%) and 85.07% (81.1-89.33%) respectively. The corresponding 90% CIs were included within the acceptable range for bioequivalence, indicating the absence of a meaningful difference in LT4 absorption when administering at 10 or 30 minutes before a meal.Based on these results, it may be possible to decrease the interval between the administration of Thyquidity (levothyroxine sodium) oral solution to 10 minutes before breakfast, thus offering patients further dosing flexibility. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Sunday, June 12, 2022 12:36 p.m. - 12:41 p.m.

Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union.

Bioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in the European Union is currently established by demonstrating that the 90% confidence interval for the ratio of the population geometric means of the test compared to the reference product’s AUC, and in certain cases Cmax, is included within the tighter acceptance range of 90.00−111.11%. An alternative criterion, consisting of narrowed limits based on the within-subject variability of the reference product, was recently proposed. Its performance for a three-period partial replicate design was tested by simulation in terms of power to show BE, type I error (T1E) and sample size requirements. A new condition, a constraint on the test-to-reference geometric mean ratio (cGMR) to be contained within the range of 90.00−111.11%, was also tested. The probability of showing BE when the products differ more than 10% was increased, but only if the reference product’s within-subject variability was moderate-to-high. The inclusion of the additional cGMR limited this. An increase in the T1E (<7%) was observed. The inclusion of the additional cGMR did not change the highest inflation of the T1E. Finally, a significant sample size reduction was observed and the inclusion of the cGMR usually did not increase the required sample size.

Pharmacokinetics, Bioequivalence, and Safety Studies of a Generic Selective Tyrosine Kinase Inhibitor Nilotinib Capsule Versus a Branded Product in Healthy Chinese Volunteers.

Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved in the United States and Europe as a treatment for patients with newly diagnosed chronic myeloid leukemia (CML)-chronic phase (CP) and patients with CML-CP or chronic myeloid leukemia-accelerated phase (CML-AP) who are resistant or intolerant to imatinib (a first-generation TKI). This study compared the bioequivalence and safety of the test nilotinib capsule and reference nilotinib capsule (Tasigna, Novartis) in healthy Chinese volunteers under fasting conditions for marketing authorization in China. The results of the study are reported for the first time. This was a single-dose, randomized, open-label, two-period, and cross-over study. Thirty healthy volunteers were randomly assigned to receive a single dose of a 200-mg test or reference capsule under fasting conditions in each period with a 10-day washout. Plasma samples were analyzed with liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated with WinNonlin software. The geometric mean ratio and the corresponding 90% confidence intervals of Cmax , AUC0-t , and AUC0-∞ for nilotinib between the two fixed-dose combination formulations were within the bioequivalence acceptance range of 80%-125%, therefore the generic and branded formulations were bioequivalent in healthy Chinese volunteers.

Pharmacokinetics, safety, tolerability, and immunogenicity of FKB238, a new biosimilar of bevacizumab, in healthy participants

To compare the pharmacokinetics (PK), safety, tolerability, and immunogenicity of single intravenous doses of FKB238, a proposed biosimilar of bevacizumab, with European Union (EU)-approved and United States (US)-licensed bevacizumab in healthy participants. In a randomized, double-blind, parallel-group study, 99 healthy men received 5mg of FKB238, EU-bevacizumab, or US-bevacizumab in a 1:1:1 ratio by intravenous infusion. PK, immunogenicity, adverse events, local tolerability, vital signs, electrocardiogram, and safety tests of blood and urine were assessed before and up to 99 days after treatment. The 90% confidence interval for the ratios of the primary (area under the curve ((AUC)0-t and AUC0-inf) and secondary (maximum concentration (Cmax) and elimination half-life (T1/2)) geometric mean PK parameters were entirely within the acceptance range for bioequivalence of 0.80 - 1.25 for all 3 pairwise comparisons by analysis of covariance, with baseline characteristics of age and body weight as covariates. FKB238 was well tolerated in healthy participants, and anti-drug antibody (ADA) incidence was low and similar in all treatment groups. The study demonstrated the PK similarity of FKB238 to both EU-bevacizumab and US-bevacizumab after a single intravenous infusion. FKB238 was well tolerated in healthy participants, and there was no difference in ADA incidence among the 3 products.