In a phase 1, open-label, crossover study to evaluate the relative bioavailability of a tablet formulation of ravidasvir (test) versus the capsule formulation of ravidasvir (reference) in 24 healthy adult volunteers (PPI-668-104 study), relatively high intra-subject coefficients of variation were observed for both Cmax and AUC0-t. A two-sequence, four-period replicate design will be used to allow the possibility to scale the acceptance range for Cmax if the observed intra-subject coefficient of variation for the reference formulation is greater than 30%
During the course of development, a new batch of ravidasvir tablets has been prepared by the proposed commercial manufacturer (Doppel Farmaceutici, Italy). Tablets manufactured by Doppel Farmaceutici are intended to be used in subsequent clinical trials and be registered as the commercial product. The purpose of this Phase 1, Open-Label, Four-Period, Two-Sequence, Two-Treatment, Single Dose, Randomized, Crossover Bioequivalence Study is to assess if ravidasvir 200 mg tablets supplied by European Egyptian Pharmaceutical Industries (EEPI) and tablets from Doppel Farmaceutici are bioequivalent. Primary objectives: To compare the rate and extent of absorption for ravidasvir (RDV) when administered as a single 200 mg oral dose of the proposed commercial product ("test") produced by Doppel Farmaceutici with the clinical trial product ("reference") manufactured by EEPI in healthy volunteers, under fasted conditions. Secondary objectives To evaluate the safety and tolerability of single oral doses of RDV in healthy volunteers.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
37
To compare the rate and extent of absorption for RDV when administered as a single 200 mg oral dose of the proposed commercial product ("test") produced by Doppel Farmaceutici with the clinical trial product ("reference") manufactured by EEPI in healthy volunteers, under fasted conditions.
To compare the rate and extent of absorption for RDV when administered as a single 200 mg oral dose of the proposed commercial product ("test") produced by Doppel Farmaceutici with the clinical trial product ("reference") manufactured by EEPI in healthy volunteers, under fasted conditions.
Ampang hospital
Ampang, Selangor, Malaysia
RDV Plasma CMax when administered as a single 200 mg oral dose of the test versus reference product
Plasma RDV Cmax will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose
Time frame: Measurement within 48 hours post-dose
RDV area under the plasma concentration-time curve from time of intake until infinity (AUC0-∞) when administered as a single 200 mg oral dose of the test versus reference product
Area under the plasma concentration-time curve from time of intake until infinity (AUC0-∞) will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Time frame: Measurement within 48 hours post-dose
RDV area under the plasma concentration-time curve from time of intake until the last quantifiable concentration (AUC0-t) when administered as a single 200 mg oral dose of the test versus reference product
Area under the plasma concentration-time curve from time of intake until the last quantifiable concentration (AUC0-t) will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Time frame: Measurement within 48 hours post-dose
RDV maximum plasma concentration (tmax) when administered as a single 200 mg oral dose of the test versus reference product
RDV maximum plasma concentration (tmax) will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Time frame: Measurement within 48 hours post-dose
RDV mean residence time (MRT) when administered as a single 200 mg oral dose of the test versus reference product
RDV mean residence time (MRT) will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Time frame: Measurement within 48 hours post-dose
RDV elimination rate constant (λz) when administered as a single 200 mg oral dose of the test versus reference product
RDV elimination rate constant (λz) will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Time frame: Measurement within 48 hours post-dose
RDV elimination half-life (t1/2, estimated based on λz), when administered as a single 200 mg oral dose of the test versus reference product
RDV elimination half-life (t1/2, estimated based on λz) will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Time frame: Measurement within 48 hours post-dose
RDV apparent volume of distribution when administered as a single 200 mg oral dose of the test versus reference product
RDV apparent volume of distribution will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Time frame: Measurement within 48 hours post-dose
RDV terminal phase (Vz/F) when administered as a single 200 mg oral dose of the test versus reference product
RDV terminal phase (Vz/F) will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Time frame: Measurement within 48 hours post-dose
RDV apparent clearance (CL/F) when administered as a single 200 mg oral dose of the test versus reference product
RDV apparent clearance (CL/F) will be calculated based on plasma RDV concentrations at pre-dose (time 0 hours) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24, 36, and 48 hours post-dose.
Time frame: Measurement within 48 hours post-dose
RDV safety (Incidence of treatment-related adverse events as assessed by CTCAE v4.03) when administered as a single 200 mg oral dose of the test versus reference product
Safety will be assessed by monitoring clinical adverse events (AEs) incidence
Time frame: From 1st patient consent until last patient completes the post-study safety assessment over a total period of 60 days
RDV tolerability (Incidence of treatment-related adverse events as assessed by CTCAE v4.03) when administered as a single 200 mg oral dose of the test versus reference product
Tolerability will be assessed by monitoring clinical adverse events (AEs) incidence
Time frame: From 1st patient consent until last patient completes the post-study safety assessment over a total period of 60 days
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