Bioequivalence Acceptance Range Research Articles

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

ABSTRACT Objective This study 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.

Bioequivalence Estimation of Two Formulations of Cefixime Tablets among Healthy Chinese Volunteers under Fasting Condition

Objective: To assess the bioequivalence of 200mg Cefixime tablets after oral administration to healthy adults under fasting condition. Method: This study was an open-label, balanced, randomized singledose, two-treatment, two-sequence, two-period, crossover oral bioequivalence study in healthy adult, human subjects under fasting condition. Subjects were fasted overnight for at least 10.00 hours before scheduled time of start of dosing. Investigational Product, one tablet of the test formulation or one tablet of reference formulation (allocated as per the randomization schedule) was administered orally to each subject. The pharmacokinetic parameters maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC0-t), AUC extrapolated to infinity (AUC0-8) was estimated to prove bioequivalence. Acceptance range for bioequivalence was 80.00%-125.00% for 90% confidence intervals of the geometric least square means ratio for Cmax, AUC0-t and AUC0-8. Results: For the test formulation, the Cefixime Mean Cmax was 3891.31ng/ mL (vs. 3676.32ng/mL for reference), AUC0-t was 33299.52ng•h/mL (vs. 32182.07ng•h/mL) and AUC0-8 was 34234.88ng•h/mL (vs. 33162.95ng•h/mL). The 90% confidence intervals for the Geometric Least Squares Means ratios for Cefixime were 105.85% (90% CI: 98.73%-113.48%), 103.47% (90% CI: 96.34%-111.13%) and 103.23% (90% CI: 96.28%-110.69%) for Cmax, AUC0-t and AUC0-8 respectively, which are within the acceptance range of 80.00% to 125.00% for pharmacokinetic parameter Cmax, AUC0-t and AUC0-8 required for concluding bioequivalence between the test and reference formulations. There were no deaths or serious adverse events during the conduct of the study. Conclusion: Test product when compared with the reference product meets the bioequivalence criteria in terms of rate and extent of absorption of cefixime after administration of single dose under fasting condition.

Bioequivalence and Safety of Levetiracetam Granules and Oral Solution: A Randomized, Single-Dose, 2-Period Crossover Study in Healthy Chinese Volunteers Under a Fasting Condition.

The bioequivalence and safety of levetiracetam granules (test formulation) and oral solution (reference formulation) were evaluated in Chinese healthy volunteers under a fasting condition. A total of 24 subjects randomly received the test or reference formulation at the rate of 1:1. The alternative formulation was administered after a 7-day washout period. The blood samples were collected at designated time points. Liquid chromatography-tandem mass spectrometry was applied to determine the plasma concentrations of levetiracetam. Adverse events were monitored and recorded. The 90% CIs for the geometric mean ratios of maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration, and area under the plasma concentration-time curve from time 0 to infinity between test preparation and reference preparation were 95.5% to 110.7%, 100.2% to 105.3%, and 100.3% to 105.7%, respectively, all within an acceptable bioequivalence range of 80.00% 125.00%. Both test and reference preparations were well tolerated. The trial confirmed that a single dose of 500-mg levetiracetam granules was bioequivalent to oral solution under a fasting condition, and may serve as a new dosage form of levetiracetam for clinical practice.

Bioequivalence Study of Palbociclib Capsules in Healthy Chinese Subjects Under Fasting and Fed Conditions.

Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinase 4/6 used for the treatment of advanced breast cancer. This study compared the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of palbociclib capsules in healthy Chinese subjects under fasting and fed conditions and evaluated the bioequivalence of two palbociclib products to obtain sufficient evidence for the marketing approval of the new generic drug. A randomized, open-label, two-period crossover study was conducted in healthy Chinese volunteers under both fasting and fed conditions (30 subjects/condition). Eligible healthy subjects received a single 125-mg dose of the palbociclib test or reference formulation followed by a 14-day washout period. Serial blood samples were collected at scheduled timepoints, and plasma concentrations were determined by a validated high-performance liquid chromatography-tandem mass spectrometry method. A non-compartment method was used to calculate the main pharmacokinetic parameters, including the area under the plasma concentration-time curve(AUC) from time 0 to the time of the last measurable concentration (AUC0-t), the AUC from time 0 to infinity (AUC0-∞), the maximum plasma concentration(Cmax), the time to maximum plasma concentration, and the elimination half-life. The geometric mean ratios and the corresponding 90% confidence intervals of palbociclib were acquired for the bioequivalence analysis. Safety and tolerability were assessed by monitoring adverse events, laboratory assessments, vital signs, physical examinations, and 12-lead electrocardiograms. Under the fasting condition, the pharmacokinetic parameter values of the test formulation were similar to those of the reference formulation. The 90% confidence intervals of geometric mean ratios of the test to reference formulations were 94.35-103.82% for Cmax, 94.79-103.26% for AUC0-t, and 94.82-103.38% for AUC0-∞, which are all within the accepted bioequivalence range of 80.00-125.00%. Meanwhile, under the fed condition, the pharmacokinetic parameter values of the test formulation were also similar to those of the reference formulation. The 90% confidence intervals of geometric mean ratios of the test to reference formulations were 96.65-103.56% for Cmax, 98.06-103.61% for AUC0-t, and 97.88-103.46% for AUC0-∞, which are all within the accepted bioequivalence range of 80.00-125.00%. The test and reference products were well tolerated, and no serious adverse events occurred during the study. Pharmacokinetic bioequivalence of palbociclib in healthy subjects was established between the palbociclib test formulation and the reference formulation under fasting and fed conditions according to predetermined regulatory criteria. The two formulations were safe and well tolerated.

Randomized, double-blind, two-way crossover bioequivalence and adhesion study, in healthy women, of a transdermal contraceptive patch with a newly sourced adhesive component at the end of shelf life vs. the EVRA patch at the beginning of shelf life.

Objective: Evaluate bioequivalence, based on norelgestromin (NGMN) and ethinyl estradiol (EE) plasma concentrations, and adhesion of a transdermal contraceptive patch containing a newly sourced adhesive component (test) at end of shelf life (EOSL) vs. the marketed EVRA patch (reference) at beginning of shelf life (BOSL). Materials and methods: In this randomized, double-blind, two-way crossover study, healthy women received a single, 7-day application of test and reference patches in 4 sequences: two 11-day treatment periods separated by a 21-day washout. Assessments included NGMN and EE pharmacokinetics (PK), adhesion (per European Medicines Agency (EMA) 5-point scale), irritation potential and application-site reactions, and tolerability. Patches were bioequivalent if 90% CIs of geometric mean ratios (GMRs) of test/reference for Cmax, AUC168h, AUC0–tlast, and AUC∞ were 80 – 125%. Patch adhesion was comparable if ratios of geometric mean cumulative adhesion percentages were ≥ 90%. Results: 68 women were randomized, and 62 completed both treatments. 55 and 59 participants in the reference and test group, respectively, had patch adhesion ≥ 80% (EMA score 0 – 1) at end of treatment. Bioequivalence was demonstrated: GMRs for pharmacokinetic (PK) parameters ranged from 102.76 to 105.57% for NGMN and 93.78 – 94.80% for EE, and associated 90% CIs were fully within the bioequivalence acceptance range (80 – 125%) for both. The patches had comparable adhesion properties (GMR, 101.4% (90% CI: 99.2 – 103.6)) and incidences of treatment-emergent adverse events. Conclusion: NGMN-EE transdermal test patch at EOSL was bioequivalent to the marketed patch at BOSL, supporting widening the product’s shelf-life specification. Adhesive properties and safety profiles were comparable between patches.

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

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (Cmax ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%.