Healthy
Conditions
Keywords
phenytoin, chewable tablets, dilantin, epanutin, infatabs, bioequivalence, Partial seizure, Tonic-clonic seizure
Brief summary
In this study, the bioequivalence of Epanutin Infatabs® 50 mg (sourced from Germany) and Dilantin Infatabs® 50 mg (sourced from Australia) will be assessed. This is intended to be a pivotal bioequivalence study.
Interventions
DRUGEpanutin Infatabs (Phenytoin)
Chewable Tablet, 50 mg, Single dose
DRUGDilantin Infatabs (Phenytoin)
Chewable Tablet, 50 mg, Single dose
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male and/or female subjects between the ages of 21 and 55 years, inclusive. * An informed consent document signed and dated by the subject.
Exclusion criteria
* Evidence or history of clinically significant abnormalities. * Any condition possibly affecting drug absorption (e.g. gastrectomy).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours (hrs) post-dose | Area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration (AUClast). |
| Maximum Observed Plasma Concentration (Cmax) | 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞]) | 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose | AUC (0-∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-t) plus AUC (t-∞). |
| Extrapolated Area Under the Curve (AUC Percent [%] Extrap) | 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose | AUC%extrap is the percentage of AUC \[0-∞\] obtained by forward extrapolation. It is calculated as (AUC \[0-∞\] minus AUClast)\*100/ AUC \[0-∞\], where AUC \[0-∞\] = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUClast is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration. |
| Plasma Decay Half Life (t1/2) | 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose | — |
Countries
Singapore
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes participants randomized to receive Epanutin (phenytoin) infatabs 50 mg first and Dilantin (phenytoin) infatabs 50 mg first. | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention Period | Adverse Event | 0 | 1 |
| First Intervention Period | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 31.8 years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 24 | 2 / 26 |
| serious Total, serious adverse events | 0 / 24 | 0 / 26 |
Outcome results
Primary
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
Area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration (AUClast).
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, and 72 hours (hrs) post-dose
Population: Pharmacokinetic (PK) parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanutin Infatabs 50 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 21380.0 ng*hr/mL | Standard Deviation 6043 |
| Dilantin Infatabs 50 mg | Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) | 21370.0 ng*hr/mL | Standard Deviation 5571.2 |
Comparison: Natural log transformed AUClast was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences and 90% confidence intervals (CIs) for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [97.85, 104.94]
Primary
Maximum Observed Plasma Concentration (Cmax)
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanutin Infatabs 50 mg | Maximum Observed Plasma Concentration (Cmax) | 952.10 ng/mL | Standard Deviation 229.25 |
| Dilantin Infatabs 50 mg | Maximum Observed Plasma Concentration (Cmax) | 976.50 ng/mL | Standard Deviation 214.78 |
Comparison: Natural log transformed Cmax was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [97.18, 107.47]
Secondary
Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞])
AUC (0-∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-t) plus AUC (t-∞).
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanutin Infatabs 50 mg | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞]) | 21730.0 ng*hr/mL | Standard Deviation 6345.9 |
| Dilantin Infatabs 50 mg | Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUC [0-∞]) | 21740.0 ng*hr/mL | Standard Deviation 5816.7 |
Comparison: Natural log transformed AUC (0-∞) was analyzed using a mixed effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. The adjusted mean differences and 90% CIs for the differences were exponentiated to provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios.90% CI: [97.56, 105.47]
Secondary
Extrapolated Area Under the Curve (AUC Percent [%] Extrap)
AUC%extrap is the percentage of AUC \[0-∞\] obtained by forward extrapolation. It is calculated as (AUC \[0-∞\] minus AUClast)\*100/ AUC \[0-∞\], where AUC \[0-∞\] = Area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time (0-∞) and AUClast is area under the plasma concentration time-curve from zero (pre-dose) to the last measured concentration.
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Epanutin Infatabs 50 mg | Extrapolated Area Under the Curve (AUC Percent [%] Extrap) | 3.321 Percent AUC | Standard Deviation 4.884 |
| Dilantin Infatabs 50 mg | Extrapolated Area Under the Curve (AUC Percent [%] Extrap) | 3.198 Percent AUC | Standard Deviation 4.805 |
Secondary
Plasma Decay Half Life (t1/2)
Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period. Here, the 'N' (number of participants analyzed) is signifying those participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Epanutin Infatabs 50 mg | Plasma Decay Half Life (t1/2) | 14.380 hr | Standard Deviation 3.247 |
| Dilantin Infatabs 50 mg | Plasma Decay Half Life (t1/2) | 14.970 hr | Standard Deviation 4.777 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time frame: 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48 and 72 hrs post-dose
Population: PK parameter analysis population included all randomized and treated participants who had at least 1 of the PK parameters of primary interest in at least 1 treatment period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Epanutin Infatabs 50 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 3.51 hr |
| Dilantin Infatabs 50 mg | Time to Reach Maximum Observed Plasma Concentration (Tmax) | 4.00 hr |