Pharmacokinetic Drug-drug Interaction Study of Encorafenib and Binimetinib on Probe Drugs in Patients With BRAF V600-mutant Melanoma or Other Advanced Solid Tumors
- Conditions
- Metastatic MelanomaAdvanced Solid Tumors
- Interventions
- Registration Number
- NCT03864042
- Lead Sponsor
- Pfizer
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 56
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm 1 - CYP Probe Cocktail binimetinib Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14: * 25 mg losartan oral tablet * 30 mg dextromethorphan oral capsule * 50 mg caffeine oral liquid * 20 mg omeprazole oral capsule * 2 mg midazolam oral syrup encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 2 - Rosuvastatin and Bupropion bupropion immediate release (IR) Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14: * 10 mg rosuvastatin oral tablet * 75 mg bupropion immediate release (IR) oral tablet encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 1 - CYP Probe Cocktail losartan Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14: * 25 mg losartan oral tablet * 30 mg dextromethorphan oral capsule * 50 mg caffeine oral liquid * 20 mg omeprazole oral capsule * 2 mg midazolam oral syrup encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 1 - CYP Probe Cocktail caffeine Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14: * 25 mg losartan oral tablet * 30 mg dextromethorphan oral capsule * 50 mg caffeine oral liquid * 20 mg omeprazole oral capsule * 2 mg midazolam oral syrup encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 1 - CYP Probe Cocktail dextromethorphan Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14: * 25 mg losartan oral tablet * 30 mg dextromethorphan oral capsule * 50 mg caffeine oral liquid * 20 mg omeprazole oral capsule * 2 mg midazolam oral syrup encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 1 - CYP Probe Cocktail omeprazole Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14: * 25 mg losartan oral tablet * 30 mg dextromethorphan oral capsule * 50 mg caffeine oral liquid * 20 mg omeprazole oral capsule * 2 mg midazolam oral syrup encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 1 - CYP Probe Cocktail midazolam Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14: * 25 mg losartan oral tablet * 30 mg dextromethorphan oral capsule * 50 mg caffeine oral liquid * 20 mg omeprazole oral capsule * 2 mg midazolam oral syrup encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 1 - CYP Probe Cocktail encorafenib Patients will receive a single oral dose of the CYP Probe Cocktail on Day -7, Day 1, and Day 14: * 25 mg losartan oral tablet * 30 mg dextromethorphan oral capsule * 50 mg caffeine oral liquid * 20 mg omeprazole oral capsule * 2 mg midazolam oral syrup encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 2 - Rosuvastatin and Bupropion rosuvastatin Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14: * 10 mg rosuvastatin oral tablet * 75 mg bupropion immediate release (IR) oral tablet encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 2 - Rosuvastatin and Bupropion encorafenib Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14: * 10 mg rosuvastatin oral tablet * 75 mg bupropion immediate release (IR) oral tablet encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 2 - Rosuvastatin and Bupropion binimetinib Patients will receive a single oral dose of rosuvastatin and bupropion once on Day -7, Day 1 and Day 14: * 10 mg rosuvastatin oral tablet * 75 mg bupropion immediate release (IR) oral tablet encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) All drugs will be taken within 10 minutes. Arm 3 - Modafinil encorafenib Patients will begin encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) then receive continuous treatment of modafinil on Day 15 through Day 21: - 400 mg modafinil tablet once daily (QD) Arm 3 - Modafinil binimetinib Patients will begin encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) then receive continuous treatment of modafinil on Day 15 through Day 21: - 400 mg modafinil tablet once daily (QD) Arm 3 - Modafinil modafinil Patients will begin encorafenib/binimetinib continuous daily dosing starting Day 1: * 450 mg (6 x 75 mg) encorafenib oral capsules once daily (QD) * 45 mg (3 x 15 mg) binimetinib oral tablet twice daily (BID) then receive continuous treatment of modafinil on Day 15 through Day 21: - 400 mg modafinil tablet once daily (QD)
- Primary Outcome Measures
Name Time Method Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Cmax of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Cmax of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Cmax of Plasma Paraxanthine on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Cmax of Plasma Omeprazole on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma 5-OH Omeprazole on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Cmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma Bupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day -7, Day 1 and Day 14 Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
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 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Total 1-OH Midazolam on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Free 1-OH Midazolam on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Absolute Caffeine on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Paraxanthine on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Omeprazole on Day -7, Day 1, and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Bupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14 0 to 8 hours after dosing on Days -7, 1 and 14 Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.
Ae0-8 of E-3174 on Day -7, Day 1 and Day 14 0 to 8 hours after dosing on Days -7, 1 and 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.
Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14 0 to 8 hours after dosing on Days -7, 1 and 14 Ae0-8 is the amount excreted into the urine over the collection interval of 0 to 8 hours.
Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14 0 to 8 hours after dosing on Days -7, 1 and 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.
Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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. LHY746 was the metabolite of encorafenib.
- Secondary Outcome Measures
Name Time Method Kel of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Kel of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Kel of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Kel of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Kel of Plasma Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Kel of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Plasma Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Plasma Bupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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).
CL/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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).
Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Vz/F of Plasma Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14 Predose, and 0 to 8 hours postdose 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.
Fe for E-3174 on Day -7, Day 1 and Day 14 0 to 8 hours postdose 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.
Fe for Dextromethorphan on Day -7, Day 1 and Day 14 0 to 8 hours postdose 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.
Fe for Dextrorphan on Day -7, Day 1 and Day 14 0 to 8 hours postdose 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.
Cmax of Encorafenib on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of LHY746 on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Cmax of Binimetinib on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of AR00426032 on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Encorafenib on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of LHY746 on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Binimetinib on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of AR00426032 on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Encorafenib on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Tmax of LHY746 on Day 1 and Day 14 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 is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.
Tmax of Binimetinib on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 and Day 14. Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Tmax of AR00426032 on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Encorafenib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Binimetinib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of AR00426032 on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Encorafenib on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of LHY746 on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Binimetinib on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of AR00426032 on Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUC%Extrap of Encorafenib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
AUC%Extrap of LHY746 on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUC%Extrap of Binimetinib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)\*100/ AUCinf.
AUC%Extrap of AR00426032 on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Kel of Encorafenib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Kel of LHY746 on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Kel of Binimetinib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 1 Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.
Kel of AR00426032 on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
CL/F of Encorafenib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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).
CL/F of Binimetinib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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).
Vz/F of Encorafenib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Vz/F of Binimetinib on Day 1 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Cmax of Binimetinib on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.
Cmax of AR00426032 on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of Binimetinib on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUClast of AR00426032 on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Encorafenib on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Tmax of LHY746 on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Binimetinib on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose on Day 14 and Day 21 Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Tmax of AR00426032 on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Encorafenib on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of LHY746 on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of Binimetinib on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
T1/2 of AR00426032 on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
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 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
MRAUClast for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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 \[AUCinf (metabolite) × MW (parent)\] / \[AUCinf (parent) × MW (metabolite)\]. 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.
MRAUClast for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
MRCmax for Paraxanthine/Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
MRCmax for Hydroxybupropion/Bupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
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 0 to 8 hours after dosing on Days -7, 1 and 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.
MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14 0 to 8 hours after dosing on Days -7, 1 and 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 to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Plasma Paraxanthine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14 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 is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.
Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 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 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.
Tmax of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Plasma Bupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Tmax of Plasma Hydroxybupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Plasma Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Plasma Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Plasma Rosuvastatin on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUCinf of Plasma Bupropion on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUC%Extrap of Plasma Absolute Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUC%Extrap of Plasma Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, Day 1 and Day 14 Predose, and 1, 2, 3, 4, 6 and 8 hours postdose 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.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit 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.
Number of Participants With Laboratory Abnormalities in the DDI Phase After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit 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.
Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit 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.
Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit 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.
Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase After 1st dose of encorafenib/binimetinib on Day 1 and up to Day 28 visit 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%.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase After 1st dose of encorafenib/binimetinib on Day 1 up to 30 days after 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.
Trial Locations
- Locations (29)
Sir Mortimer B Davis Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
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
Regions Cancer Care Center
🇺🇸Saint Paul, Minnesota, United States
HealthPartners Specialty Center-Eye Care
🇺🇸Saint Paul, Minnesota, United States
Gabrail Cancer Center Research
🇺🇸Canton, Ohio, United States
University of TN Medical Center
🇺🇸Knoxville, Tennessee, United States
Mary Crowley Cancer Research - Medical City Hospital
🇺🇸Dallas, Texas, United States
Utah Cancer Specialists
🇺🇸West Valley City, Utah, United States
Universitair Ziekenhuis Antwerpen
🇧🇪Edegem, Belgium
Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Princess Margaret Cancer Centre
🇨🇦Toronto, Ontario, Canada
McGill University Health Center
🇨🇦Montreal, Quebec, Canada
Jewish General Hospital
🇨🇦Montrea, Quebec, Canada
Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis
🇳🇱Amsterdam, Netherlands
Erasmus Medical Center
🇳🇱Rotterdam, Netherlands
Hospital del Mar
🇪🇸Barcelona, Spain
Hospital Clinico Universitario Virgen de la Arrixaca
🇪🇸El Palmar, Spain
Hospital Universitari Arnau de Vilanova
🇪🇸Lleida, Spain
Hospital Beata Maria Ana
🇪🇸Madrid, Spain
Hospital General Universitario Gregorio Marañon
🇪🇸Madrid, Spain
Clinica Rementeria
🇪🇸Madrid, Spain
MD Anderson Cancer Center Madrid
🇪🇸Madrid, Spain
Hospital Universitario HM Sanchinarro - CIOCC
🇪🇸Madrid, Spain
CERCO
🇪🇸Sevilla, Spain
Hospital Universitario Virgen Macarena
🇪🇸Sevilla, Spain