This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and multiple oral doses of encorafenib in combination with binimetinib on the single oral dose pharmacokinetics (PK) of cytochrome P450 (CYP) enzyme probe substrates using a probe cocktail, on an organic anion-transporting polypeptide/breast cancer resistance protein (OATP/BCRP) substrate using rosuvastatin and on a CYP2B6 substrate using bupropion. The effect of multiple oral doses of the moderate cytochrome P450 (CYP) inhibitor modafinil on encorafenib in combination with binimetinib will also be assessed. The study will have 2 treatment phases, a drug-drug interaction (DDI) phase followed by a post-DDI phase.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
56
taken orally
taken orally
taken orally
taken orally
taken orally
taken orally
taken orally
taken orally
taken orally
taken orally
UC Irvine Health
Orange, California, United States
University of Colorado Hospital - Anschutz Cancer Pavilion (ACP)
Aurora, Colorado, United States
University of Illinois at Chicago
Chicago, Illinois, United States
Hopkins Eye Clinic
Hopkins, Minnesota, United States
Park Nicollet Eye Clinic
Maple Grove, Minnesota, United States
Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Area Under the Concentration-Time Profile From Time 0 to The Time of The Last Quantifiable Concentration (AUClast) of Plasma Midazolam on Day -7, Day 1, and Day 14
AUClast is area under the concentration-time profile (AUC) from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 of E-3174 on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. E-3174 was the metabolite of losartan.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. Dextrorphan was the metabolite of dextromethorphan.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight (MW), which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. 1-OH midazolam was the metabolite of midazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Ratio of AUC From Time Zero Extrapolated to Infinity (AUCinf) Values of the Metabolite Compared to Parent (MRAUCinf) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14
MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUCinf (metabolite) × MW (parent)\] / \[AUCinf (parent) × MW (metabolite)\]. 1-OH midazolam was the metabolite of midazolam. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14
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...and 19 more locations
MRAUCinf is the ratio of AUCinf values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUCinf (metabolite) × MW (parent)\] / \[AUCinf (parent) × MW (metabolite)\]. 5-OH Omeprazole was the metabolite of omeprazole. AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21
MRAUClast is the ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[AUClast (metabolite) × MW (parent)\] / \[AUClast (parent) × MW (metabolite)\]. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. 1-OH midazolam was the metabolite of midazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21
MRCmax is the ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight, which was calculated by \[Cmax (metabolite) × MW (parent)\] / \[Cmax (parent) × MW (metabolite)\]. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Ratio of Ae0-8 Values of the Metabolite Compared to Parent (MRAe0-8) for E-3174/Losartan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. E-3174 was the metabolite of losartan.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14
Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours. MRAe0-8 is the ratio of Ae0-8 values of the metabolite compared to parent, corrected for molecular weight. Dextrorphan was the metabolite of dextromethorphan.
Time frame: 0 to 8 hours after dosing on Days -7, 1 and 14
Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.
Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14
Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14
Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.
T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. The metabolites of midazolam included total 1-OH midazolam, free 1-OH midazolam, and glucuronide conjugated 1-hydroxymidazolam.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14.
T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. Due to dietary caffeine intake may resulted in positive pre-dose concentrations, absolute and/or baseline-adjusted caffeine were analyzed. Baseline adjusted concentration = measured concentration - \[predose concentration\*e\^(-Kel\*t)\], where Kel is terminal elimination rate constant based on actual measured concentration values for each profile and t is the actual sampling time.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. 5-OH Omeprazole was the metabolite of omeprazole.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14
CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14
CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14
Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14
Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14
Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14
Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100.
Time frame: Predose, and 0 to 8 hours postdose on Day -7, Day 1 and Day 14
Fe for E-3174 on Day -7, Day 1 and Day 14
Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. E-3174 was the metabolite of losartan.
Time frame: 0 to 8 hours postdose on Day -7, Day 1 and Day 14
Fe for Dextromethorphan on Day -7, Day 1 and Day 14
Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100.
Time frame: 0 to 8 hours postdose on Day -7, Day 1 and Day 14
Fe for Dextrorphan on Day -7, Day 1 and Day 14
Fe is the percentage of dose recovered in urine from 0 to 8 hours as parent or metabolite, which was calculated as Ae0-8 / dose × 100. Dextrorphan was the metabolite of dextromethorphan.
Time frame: 0 to 8 hours postdose on Day -7, Day 1 and Day 14
Cmax of Encorafenib on Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Cmax of LHY746 on Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Cmax of Binimetinib on Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Cmax of AR00426032 on Day 1 and Day 14
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUClast of Encorafenib on Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
AUClast of LHY746 on Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUClast of Binimetinib on Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUClast of AR00426032 on Day 1 and Day 14
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
Tmax of Encorafenib on Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Tmax of LHY746 on Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours (+/- 15 minutes window for each time-point) postdose on Day 1 and Day 14
Tmax of Binimetinib on Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14.
Tmax of AR00426032 on Day 1 and Day 14
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUCinf of Encorafenib on Day 1
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
AUCinf of Binimetinib on Day 1
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
AUCinf of AR00426032 on Day 1
AUCinf is AUC from time zero to extrapolated infinite time. It is obtained by AUClast + (Clast/kel), where AUClast is the AUC from time zero to the time of last quantifiable concentration (Clast), and kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
T1/2 of Encorafenib on Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
T1/2 of LHY746 on Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
T1/2 of Binimetinib on Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
T1/2 of AR00426032 on Day 1 and Day 14
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14
AUC%Extrap of Encorafenib on Day 1
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
AUC%Extrap of LHY746 on Day 1
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
AUC%Extrap of Binimetinib on Day 1
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
AUC%Extrap of AR00426032 on Day 1
AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Kel of Encorafenib on Day 1
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Kel of LHY746 on Day 1
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Kel of Binimetinib on Day 1
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
Kel of AR00426032 on Day 1
Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1
CL/F of Encorafenib on Day 1
CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
CL/F of Binimetinib on Day 1
CL/F is the apparent total body clearance of drug from the plasma (parent drugs only), which is estimated by Dose / AUCinf (Day -7) or Dose / AUClast (Day 1 and Day 14).
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Vz/F of Encorafenib on Day 1
Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Vz/F of Binimetinib on Day 1
Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1.
Cmax of Binimetinib on Day 14 and Day 21
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Cmax of AR00426032 on Day 14 and Day 21
Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast of Binimetinib on Day 14 and Day 21
AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
AUClast of AR00426032 on Day 14 and Day 21
AUClast is AUC from time 0 (pre-dose) to the time of the last quantifiable concentration. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Tmax of Encorafenib on Day 14 and Day 21
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Tmax of LHY746 on Day 14 and Day 21
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Tmax of Binimetinib on Day 14 and Day 21
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Tmax of AR00426032 on Day 14 and Day 21
Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
T1/2 of Encorafenib on Day 14 and Day 21
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
T1/2 of LHY746 on Day 14 and Day 21
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. LHY746 was the metabolite of encorafenib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
T1/2 of Binimetinib on Day 14 and Day 21
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
T1/2 of AR00426032 on Day 14 and Day 21
T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant. AR00426032 was the metabolite of binimetinib.
Time frame: Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase
An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Laboratory Abnormalities in the DDI Phase
Laboratory parameters:hematology (hemoglobin,hematocrit,red blood cell \[RBC\],platelet,white blood cell count \[WBC\],neutrophils,eosinophils,monocytes, basophils, lymphocytes), chemistry (albumin, alkaline phosphatase, alanine aminotransferase, amylase, aspartate aminotransferase, bicarbonate, total bilirubin, blood urea nitrogen, calcium, chloride, creatine kinase, creatinine, glucose, lactate dehydrogenase, lipase, magnesium, inorganic phosphate, potassium, total protein, sodium, uric acid), urinalysis (appearance, color, specific gravity, pH, ketones, protein, glucose, blood, nitrates, leukocyte esterase, and urine microscopy results including WBC, RBC, bacteria, epithelial cells, and casts), coagulation (activated partial thromboplastin time, prothrombin time/international normalized ratio) and others. Clinically notable: worsening from baseline by at least 2 grades or to greater than or equal to (\>=) Grade 3, by Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase
Vital signs (temperature, pulse rate \[PR\]), systolic blood pressure \[SBP\]), and diastolic blood pressure \[DBP\]) were obtained with participants following at least 5 minutes of supine rest. Categorical criteria were defined as DBP\>=100 millimeters of mercury (mm Hg)/less than or equal to (\<=) 50 mmHg with increase/decrease from baseline of \>=15 mmHg; SBP: \>=160 mmHg/\<=90 mmHg with increase/decrease from baseline of \>=20 mmHg; PR: \>=120 beats per minute (bpm)/\<=50 bpm with increase/decrease from baseline of \>=15 bpm; temperature for Arms 1 and 3: \>=37.5°C/\<=35°C; Arms 2: \>=37.5°C/\<=36°C.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase
Triplicate 12-lead ECG were performed after the participant had rested quietly for at least 10 minutes in a supine position. ECG parameters included RR interval, PR interval, QRS complex, QT interval, corrected QT (QTc) interval, Bazett's correction QT (QTcB) interval, Heart Rate and Fridericia's correction (QTcF) interval. The criterion included: QTcF \>450 - \<=480 mesc, \>480 - \<=500 msec, \>500 msec, increase from baseline \>30 - \<=60 msec and increase from baseline \>60 msec. QT interval \>450 - \<=480 msec, \>480 - \<=500 msec, \>500 msec, increase from baseline \>30 - \<=60 msec and increase from baseline \>60 msec. Heart rate increase from baseline \>25% and value \>100 bpm and decrease from baseline \>25% and value \<60 bpm. PR interval increase from baseline \>25% and value \>200 msec. QRS interval increase from baseline \>25% and value \>110 msec. Any new post-baseline notable ECG findings in the DDI phase was collected and reported in this outcome measure.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase
LVEF abnormalities are defined according to CTCAE grade version 4.03. Participants was considered as having a LVEF abnormality if the worst post-baseline value was Grade 2, 3, or 4 according to the following classification: Grade 0: Non-missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute change from baseline between -10% and \<-20%; Grade 3: LVEF between 20% and 39% or absolute change from baseline lower than or equal to -20%; Grade 4: LVEF lower than 20%.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit in the DDI Phase
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs were those with initial onset or increasing in severity between the first dose of encorafenib/binimetinib and up to 30 days after treatment discontinuation. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. SAEs were adjudicated according to the investigator's assessment. Treatment-related AEs and SAEs were determined by the investigator. Any significant findings in the laboratory test, physical examinations, ophthalmic examinations, vital signs, ECG tests were captured as an AE.
Time frame: After 1st dose of encorafenib/binimetinib on Day 1 up to 30 days after the post-DDI Phase