The purpose of this study is to assess the potential drug-drug interaction of CHF10196 (a dipeptidyl peptidase 1 inhibitor) and its metabolite on the pharmacokinetics of dabigatran (a P-glycoprotein substrate) and Rosuvastatin (a breast cancer resistant protein substrate) in healthy male participants.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Treatment period 1: Single dose administered on Day 1; Treatment period 2: Single dose administered on Day 13
Treatment period 1: Single dose administered on Day 4; Treatment period 2: Single dose administered on Day 16
Treatment period 2: Single dose administered daily from Day 8 to Day 19
Fortrea Clinical Research Unit (CRU) Limited
Leeds, United Kingdom
Pharmacokinetics of Dabigatran : AUC0-t
comparing the ratios of adjusted geometric means between test 1 (dabigatran \[free and total\] with CHF10196) and reference 1 (dabigatran \[free and total\] alone), with 90% two-sided Confidential Intervals(CI), will be calculated for plasma dabigatran (free and total) area under the plasma concentration-time curve, from time 0 to the last measurable concentration (AUC0-t)
Time frame: Up to 72 hours after dosing
Pharmacokinetics of Dabigatran: AUC0-∞
comparing the ratios of adjusted geometric means between test 1 (dabigatran \[free and total\] with CHF10196) and reference 1 (dabigatran \[free and total\] alone), with 90% two-sided CIs, will be calculated for plasma dabigatran (free and total) area under the plasma concentration-time curve, from time 0 to the last measurable concentration (AUC0-∞)
Time frame: Up to 72 hours after dosing
Pharmacokinetics of Dabigatran: Cmax
comparing the ratios of adjusted geometric means between test 1 (dabigatran \[free and total\] with CHF10196) and reference 1 (dabigatran \[free and total\] alone), with 90% two-sided CIs, will be calculated for plasma dabigatran (free and total) maximum observed maximum observed concentration (Cmax)
Time frame: Up to 72 hours after dosing
Pharmacokinetics of Rosuvastatin :AUC0-t
The ratios of adjusted geometric means between test 2 (rosuvastatin with CHF10196) and reference 2 (rosuvastatin alone), with 90% two sided CIs, will be calculated for plasma rosuvastatin AUC0-t
Time frame: Up to 96 hours after dosing
Pharmacokinetics of Rosuvastatin : AUC0-∞
The ratios of adjusted geometric means between test 2 (rosuvastatin with CHF10196) and reference 2 (rosuvastatin alone), with 90% two sided CIs, will be calculated for plasma rosuvastatin (AUC0-∞)
Time frame: Up to 96 hours after dosing
Pharmacokinetics of Rosuvastatin: Cmax
The ratios of adjusted geometric means between test 2 (rosuvastatin with CHF10196) and reference 2 (rosuvastatin alone), with 90% two sided CIs, will be calculated for plasma rosuvastatin Cmax
Time frame: Up to 96 hours after dosing
Safety and Tolerability : Incidence of adverse events (AE)
Number and percentage of study participants by treatment with AEs, adverse events of special interest(AESIs),treatment emergent adverse event(TEAEs), adverse drug reaction(ADRs), non-serious TEAEs, serious TEAEs, serious ADRs, severe TEAEs, TEAEs leading to study discontinuation and to death
Time frame: From Baseline Day -1 until Day 8 of TP1 and from Day 8 to Day 20 of TP2
Safety and Tolerability : change from baseline for laboratory abnormalities
Clinical laboratory abnormalities, based on haematology and blood chemistry test results by treatment period (TP). Number of participants with abnormal blood laboratory test results. Quantitative laboratory parameters (chemistry and haematology) will be summarised by treatment as absolute value and change from baseline using descriptive statistics
Time frame: From Baseline Day -1 until Day 8 for TP1, and from Day 8 to Day 20 of TP 2
Safety and Tolerability: changes from baseline for vital signs - pulse rate
Mean changes from baseline to each post-dose timepoint in vital signs PR (pulse rate) by TP Baselines (the last value before the first administration of dabigatran etexilate of each TP or CHF10196 (TP2 only). In TP2, two separate baselines will be derived relative to dabigatran and CHF10196)
Time frame: From Day 1 to Day 8 for TP1 and from Day 8 to Day 20 for TP2
Safety and Tolerability: changes from baseline for vital signs - respiratory rate
Mean changes from baseline to each post-dose timepoint in vital signs RR (respiratory rate) by TP Baselines (the last value before the first administration of dabigatran etexilate of each TP or CHF10196 (TP2 only). In TP2, two separate baselines will be derived relative to dabigatran and CHF10196)
Time frame: From Day 1 to Day 8 for TP1 and from Day 8 to Day 20 for TP2
Safety and Tolerability: changes from baseline for vital signs - blood pressure
Mean changes from baseline to each post-dose timepoint in vital signs systolic blood pressure (SBP) and diastolic blood pressure (DBP) by TP. Baselines (the last value before the first administration of dabigatran etexilate of each TP or CHF10196 (TP2 only). In TP2, two separate baselines will be derived relative to dabigatran and CHF10196)
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Time frame: From Day 1 to Day 8 for TP1 and from Day 8 to Day 20 for TP2
Safety and Tolerability : change from baseline for ECG intervals
Mean changes from baseline to each post-dose timepoint in 12-lead bedside ECG parameters. Intervals recorded: RR, PR, QT, QTc (Corrected QT interval), and QTcF (Fridericia corrected QT interval), and QRS duration by TP. Baselines (the last value before the first administration of dabigatran etexilate of each TP or CHF10196 (TP2 only). In TP2, two separate baselines will be derived relative to dabigatran and CHF10196)
Time frame: From Day 1 to Day 8 for TP1 and from Day 8 to Day 20 for TP2
Safety and Tolerability : change from baseline for ECG HR
Mean changes from baseline to each post-dose timepoint in 12-lead bedside ECG recording of Heart Rate (HR). Baselines (the last value before the first administration of dabigatran etexilate of each TP or CHF10196 (TP2 only). In TP2, two separate baselines will be derived relative to dabigatran and CHF10196)
Time frame: From Day 1 to Day 8 for TP1 and from Day 8 to Day 20 for TP2
Additional Pharmacokinetic Parameters : CL/F of dabigatran
total body clearance (CL/F) of dabigatran (free and total) will be analysed with descriptive statistics by TP
Time frame: From Day 1 to Day 4 for TP1 and from Day 13 to Day 16 for TP2
Additional Pharmacokinetic Parameters: CL/F of resuvastatin
total body clearance (CL/F) of rosuvastatin will be analysed with descriptive statistics by TP
Time frame: From Day 4 to Day 8 for TP1 and from Day 16 to Day 20 for TP2
Additional Pharmacokinetic Parameters: Vd/F of dabigatran
Apparent volume of distribution (Vd/F) of dabigatran (free and total) will be analysed with descriptive statistics by TP
Time frame: From Day 1 to Day 4 for TP1 and from Day 13 to Day 16 for TP2
Additional Pharmacokinetic Parameters: Vd/F of rosuvastatin
Apparent volume of distribution (Vd/F) of rosuvastatin will be analysed with descriptive statistics by TP
Time frame: From Day 4 to Day 8 for TP1 and from Day 16 to Day 20 forTP2
Additional Pharmacokinetic Parameters: tmax of dabigatran
Difference in median plasma tmax of dabigatran (free and total) between test 1 (dabigatran \[free and total\] with CHF10196) and reference 1 (dabigatran \[free and total\] alone) with 90% two-sided CIs
Time frame: From Day 1 to Day 4 for TP1 and from Day 13 to Day 16 for TP2
Additional Pharmacokinetic Parameters: tmax of rosuvastatin
Difference in median plasma tmax of rosuvastatin between test 2 (rosuvastatin with CHF10196) and reference 2 (rosuvastatin alone) with 90% two-sided CIs
Time frame: From Day 4 to Day 8 for TP1 and from Day 16 to Day 20 for TP2