Skip to main content
OpenTrials
Completed

NCT Number: NCT03864042

Pharmacokinetic Drug-drug Interaction Study of Encorafenib and Binimetinib on Probe Drugs in Patients With BRAF V600-mutant Melanoma or Other Advanced Solid Tumors

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.

Completed

Looking for future studies?

Notify Me

Key information

Conditions

Advanced Solid Tumors Melanoma Metastatic Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Universitair Ziekenhuis Antwerpen, Edegem, Belgium

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study:

  • Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors
  • Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test;
  • Evidence of measurable or non-measurable lesions
  • Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry
  • Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
  • Adequate bone marrow, hepatic and renal function as specified in the protocol
  • ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose.

Key Exclusion Criteria - Patients meeting any of the following criteria are not eligible for enrollment in the study:

  • Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT] demonstrating no current evidence of progressive brain metastases at screening);
  • Symptomatic or untreated leptomeningeal disease;
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);
  • Clinically significant cardiac disease
  • Known hyper-coagulability risks other than malignancy (e.g., Factor V Leiden syndrome);
  • Thromboembolic event except catheter-related venous thrombosis ≤ 12 weeks prior to starting study treatment.
  • Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion;
  • ARM 1 ONLY: Positive urine cotinine test at screening
  • ARM 3 ONLY:
  • History of psychosis, depression or mania;
  • History of angioedema;
  • History of mitral valve prolapse;
  • History of left ventricular hypertrophy;

Treatment and study plan

Losartan

Drug

taken orally

dextromethorphan

Drug

taken orally

Caffeine

Drug

taken orally

Omeprazole

Drug

taken orally

midazolam

Drug

taken orally

Rosuvastatin

Drug

taken orally

bupropion immediate release (IR)

Drug

taken orally

Encorafenib

Drug

taken orally

Binimetinib

Drug

taken orally

Modafinil

Drug

taken orally

Primary outcomes

  1. Maximum Concentration (Cmax) of Plasma Midazolam on Day -7, 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

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

  2. Cmax of Plasma Total 1-OH Midazolam on Day -7, 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

    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.

  3. Cmax of Plasma Free 1-OH Midazolam on Day -7, 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

    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.

  4. Cmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, 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

    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.

  5. Cmax of Plasma Absolute Caffeine on Day -7, 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

    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.

  6. Cmax of Plasma Baseline-Adjusted Caffeine on Day -7, 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

    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.

  7. Cmax of Plasma Paraxanthine on Day -7, 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

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.

  8. Cmax of Plasma Omeprazole on Day -7, 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

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

  9. Cmax of Plasma 5-OH Omeprazole on Day -7, 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

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. 5-OH Omeprazole was the metabolite of omeprazole.

  10. Cmax of Plasma Rosuvastatin on Day -7, 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

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

  11. Cmax of Plasma Bupropion on Day -7, 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

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data.

  12. Cmax of Plasma Hydroxybupropion on Day -7, 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

    Cmax is the maximum plasma concentration which was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.

  13. 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

    Time frame: 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.

  14. AUClast of Plasma Total 1-OH Midazolam on Day -7, 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

    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.

  15. AUClast of Plasma Free 1-OH Midazolam on Day -7, 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

    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.

  16. AUClast of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, 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

    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.

  17. AUClast of Plasma Absolute Caffeine on Day -7, 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

    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.

  18. AUClast of Plasma Baseline-Adjusted Caffeine on Day -7, 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

    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.

  19. AUClast of Plasma Paraxanthine on Day -7, 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

    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.

  20. AUClast of Plasma Omeprazole on Day -7, 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

    AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.

  21. AUClast of Plasma 5-OH Omeprazole in Arm 1 on Day -7, 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

    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.

  22. AUClast of Plasma Rosuvastatin on Day -7, 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

    AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.

  23. AUClast of Plasma Bupropion on Day -7, 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

    AUClast is AUC from time 0 to the time of the last quantifiable concentration. It was calculated using the linear trapezoidal/linear interpolation method.

  24. AUClast of Plasma Hydroxybupropion on Day -7, 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

    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.

  25. The Amount Eliminated Via Urine Over an 8-Hour Period (Ae0-8) of Losartan on Day -7, Day 1 and Day 14

    Time frame: 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.

  26. Ae0-8 of E-3174 on Day -7, Day 1 and Day 14

    Time frame: 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.

  27. Ae0-8 of Dextromethorphan on Day -7, Day 1 and Day 14

    Time frame: 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.

  28. Ae0-8 of Dextrorphan on Day -7, Day 1 and Day 14

    Time frame: 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.

  29. Cmax of Plasma Encorafenib on Day 14 and Day 21 in Arm 3

    Time frame: 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.

  30. Cmax of Plasma LHY746 on Day 14 and Day 21 in Arm 3

    Time frame: 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.

  31. AUClast of Plasma Encorafenib on Day 14 and Day 21 in Arm 3

    Time frame: 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.

  32. AUClast of Plasma LHY746 on Day 14 and Day 21 in Arm 3

    Time frame: 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 outcomes

  1. Ratio of AUClast Values of the Metabolite Compared to Parent (MRAUClast) for 1-OH Midazolam/Midazolam on Day -7, 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

    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.

  2. 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

    Time frame: 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.

  3. MRAUClast for Paraxanthine/Caffeine on Day -7, 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

    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.

  4. MRAUClast for 5-OH Omeprazole/Omeprazole on Day -7, 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

    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.

  5. MRAUCinf for 5-OH Omeprazole/Omeprazole on Day -7, 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

    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.

  6. MRAUClast for Hydroxybupropion/Bupropion on Day -7, 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

    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.

  7. MRAUClast for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21

    Time frame: 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.

  8. Ratio of Cmax Values of the Metabolite Compared to Parent (MRCmax) for 1-OH Midazolam/Midazolam on Day -7, 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

    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.

  9. MRCmax for Paraxanthine/Caffeine on Day -7, 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

    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.

  10. MRCmax for 5-OH Omeprazole/Omeprazole on Day -7, 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

    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.

  11. MRCmax for Hydroxybupropion/Bupropion on Day -7, 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

    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.

  12. MRCmax for LHY746/Encorafenib in Arm 3 on Day 14 and Day 21

    Time frame: 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.

  13. 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

    Time frame: 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.

  14. MRAe0-8 for Dextrorphan/Dextromethorphan on Day -7, Day 1 and Day 14

    Time frame: 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.

  15. Time to Reach Cmax (Tmax) of Plasma Midazolam on Day -7, 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

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

  16. Tmax of Plasma Total 1-OH Midazolam on Day -7, 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.

    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.

  17. Tmax of Plasma Free 1-OH Midazolam on Day -7, 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

    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.

  18. Tmax of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, 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

    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.

  19. Tmax of Plasma Absolute Caffeine on Day -7, 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

    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.

  20. Tmax of Plasma Baseline-Adjusted Caffeine on Day -7, 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

    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.

  21. Tmax of Plasma Paraxanthine on Day -7, 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

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Paraxanthine was the metabolite of caffeine.

  22. Tmax of Plasma Omeprazole on Day -7, Day 1 and Day 14

    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 is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

  23. Tmax of Plasma 5-OH Omeprazole on Day -7, Day 1 and Day 14

    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 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.

  24. Tmax of Plasma Rosuvastatin on Day -7, 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

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

  25. Tmax of Plasma Bupropion on Day -7, 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

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data.

  26. Tmax of Plasma Hydroxybupropion on Day -7, 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

    Tmax is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. Hydroxybupropion was the metabolite of bupropion.

  27. AUCinf of Plasma Midazolam on Day -7, 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

    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.

  28. AUCinf of Plasma Total 1-OH Midazolam on Day -7, 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

    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.

  29. AUCinf of Plasma Free 1-OH Midazolam on Day -7, 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

    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.

  30. AUCinf of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, 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

    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.

  31. AUCinf of Plasma Omeprazole on Day -7, 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

    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.

  32. AUCinf of Plasma 5-OH Omeprazole on Day -7, 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

    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.

  33. AUCinf of Plasma Rosuvastatin on Day -7, 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

    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.

  34. AUCinf of Plasma Bupropion on Day -7, 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

    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.

  35. Percent of AUC Extrapolated (AUC%Extrap) of Plasma Midazolam on Day -7, 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

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.

  36. AUC%Extrap of Plasma Total 1-OH Midazolam on Day -7, 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

    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.

  37. AUC%Extrap of Plasma Free 1-OH Midazolam on Day -7, 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

    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.

  38. AUC%Extrap of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, 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

    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.

  39. AUC%Extrap of Plasma Absolute Caffeine on Day -7, 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

    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.

  40. AUC%Extrap of Plasma Baseline-Adjusted Caffeine on Day -7, 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

    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.

  41. AUC%Extrap of Plasma Omeprazole on Day -7, 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

    AUC%extrap is the percentage of AUCinf obtained by forward extrapolation. It is calculated as (AUCinf minus AUClast)*100/ AUCinf.

  42. AUC%Extrap of Plasma 5-OH Omeprazole on Day -7, 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

    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.

  43. Apparent Terminal Elimination Rate Constant (Kel) of Plasma Midazolam on Day -7, 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

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.

  44. Kel of Plasma Total 1-OH Midazolam on Day -7, 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

    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.

  45. Kel of Plasma Free 1-OH Midazolam on Day -7, 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

    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.

  46. Kel of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, 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

    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.

  47. Kel of Plasma Absolute Caffeine on Day -7, 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

    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.

  48. Kel of Plasma Baseline-Adjusted Caffeine on Day -7, 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

    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.

  49. Kel of Plasma Omeprazole on Day -7, 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

    Kel is the apparent terminal elimination rate constant, which is estimated by linear regression of time versus loge concentration.

  50. Kel of Plasma 5-OH Omeprazole on Day -7, 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

    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.

  51. Terminal Elimination Half-Life (T1/2) of Plasma Midazolam on Day -7, 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.

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

  52. T1/2 of Plasma Total 1-OH Midazolam on Day -7, 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

    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.

  53. T1/2 of Plasma Free 1-OH Midazolam on Day -7, 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

    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.

  54. T1/2 of Plasma Glucuronide Conjugated 1-Hydroxymidazolam on Day -7, 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.

    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.

  55. T1/2 of Plasma Absolute Caffeine on Day -7, 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

    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.

  56. T1/2 of Plasma Baseline-Adjusted Caffeine on Day -7, 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

    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.

  57. T1/2 of Plasma Omeprazole on Day -7, 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

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

  58. T1/2 of Plasma 5-OH Omeprazole on Day -7, 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

    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.

  59. T1/2 of Plasma Rosuvastatin on Day -7, 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

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

  60. T1/2 of Plasma Bupropion on Day -7, 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

    T1/2 is the terminal elimination half-life, which is estimated by Loge(2) / kel, where kel is the apparent terminal elimination rate constant.

  61. Apparent Clearance (CL/F) of Plasma Midazolam on Day -7, 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 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).

  62. CL/F of Plasma Omeprazole on Day -7, 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 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).

  63. Apparent Total Volume of Distribution Following Oral Administration (Vz/F) of Plasma Midazolam on Day -7, 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

    Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.

  64. Vz/F of Plasma Omeprazole on Day -7, 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

    Vz/F is the apparent volume of distribution during the terminal phase (parent drugs only), which is calculated by CL/F/kel.

  65. Percentage of Dose Recovered in Urine (Fe) for Losartan on Day -7, Day 1 and Day 14

    Time frame: 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.

  66. Fe for E-3174 on Day -7, Day 1 and Day 14

    Time frame: 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.

  67. Fe for Dextromethorphan on Day -7, Day 1 and Day 14

    Time frame: 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.

  68. Fe for Dextrorphan on Day -7, Day 1 and Day 14

    Time frame: 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.

  69. Cmax of Encorafenib on Day 1 and Day 14

    Time frame: 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.

  70. Cmax of LHY746 on Day 1 and Day 14

    Time frame: 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.

  71. Cmax of Binimetinib on Day 1 and Day 14

    Time frame: 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.

  72. Cmax of AR00426032 on Day 1 and Day 14

    Time frame: 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.

  73. AUClast of Encorafenib on Day 1 and Day 14

    Time frame: 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.

  74. AUClast of LHY746 on Day 1 and Day 14

    Time frame: 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.

  75. AUClast of Binimetinib on Day 1 and Day 14

    Time frame: 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.

  76. AUClast of AR00426032 on Day 1 and Day 14

    Time frame: 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.

  77. Tmax of Encorafenib on Day 1 and Day 14

    Time frame: 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.

  78. Tmax of LHY746 on Day 1 and Day 14

    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 is time to reach maximum observed plasma concentration. It was observed directly from the concentration-time data. LHY746 was the metabolite of encorafenib.

  79. Tmax of Binimetinib on Day 1 and Day 14

    Time frame: 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.

  80. Tmax of AR00426032 on Day 1 and Day 14

    Time frame: 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.

  81. AUCinf of Encorafenib on Day 1

    Time frame: 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.

  82. AUCinf of Binimetinib on Day 1

    Time frame: 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.

  83. AUCinf of AR00426032 on Day 1

    Time frame: 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.

  84. T1/2 of Encorafenib on Day 1 and Day 14

    Time frame: 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.

  85. T1/2 of LHY746 on Day 1 and Day 14

    Time frame: 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.

  86. T1/2 of Binimetinib on Day 1 and Day 14

    Time frame: 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.

  87. T1/2 of AR00426032 on Day 1 and Day 14

    Time frame: 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.

  88. AUC%Extrap of Encorafenib on Day 1

    Time frame: 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.

  89. AUC%Extrap of LHY746 on Day 1

    Time frame: 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.

  90. AUC%Extrap of Binimetinib on Day 1

    Time frame: 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.

  91. AUC%Extrap of AR00426032 on Day 1

    Time frame: 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.

  92. Kel of Encorafenib on Day 1

    Time frame: 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.

  93. Kel of LHY746 on Day 1

    Time frame: 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.

  94. Kel of Binimetinib on Day 1

    Time frame: 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.

  95. Kel of AR00426032 on Day 1

    Time frame: 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.

  96. CL/F of Encorafenib on Day 1

    Time frame: 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).

  97. CL/F of Binimetinib on Day 1

    Time frame: 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).

  98. Vz/F of Encorafenib on Day 1

    Time frame: 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.

  99. Vz/F of Binimetinib on Day 1

    Time frame: 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.

  100. Cmax of Binimetinib on Day 14 and Day 21

    Time frame: 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.

  101. Cmax of AR00426032 on Day 14 and Day 21

    Time frame: 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.

  102. AUClast of Binimetinib on Day 14 and Day 21

    Time frame: 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.

  103. AUClast of AR00426032 on Day 14 and Day 21

    Time frame: 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.

  104. Tmax of Encorafenib on Day 14 and Day 21

    Time frame: 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.

  105. Tmax of LHY746 on Day 14 and Day 21

    Time frame: 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.

  106. Tmax of Binimetinib on Day 14 and Day 21

    Time frame: 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.

  107. Tmax of AR00426032 on Day 14 and Day 21

    Time frame: 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.

  108. T1/2 of Encorafenib on Day 14 and Day 21

    Time frame: 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.

  109. T1/2 of LHY746 on Day 14 and Day 21

    Time frame: 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.

  110. T1/2 of Binimetinib on Day 14 and Day 21

    Time frame: 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.

  111. T1/2 of AR00426032 on Day 14 and Day 21

    Time frame: 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.

  112. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the DDI Phase

    Time frame: 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.

  113. Number of Participants With Laboratory Abnormalities in the DDI Phase

    Time frame: 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.

  114. Number of Participants With Notable Abnormalities in Vital Signs in the DDI Phase

    Time frame: 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.

  115. Number of Participants With Notable Electrocardiogram (ECG) Findings in the DDI Phase

    Time frame: 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.

  116. Number of Participants With Left Ventricular Ejection Fraction (LVEF) Abnormalities in the DDI Phase

    Time frame: 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%.

  117. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) in the Post-DDI Phase

    Time frame: 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.

Sponsors and collaborators

Lead sponsor

Pfizer

Industry

Collaborators

  • Pierre Fabre Laboratories

Registry information

Official study title

An Open-label Phase 1 Study to Evaluate Drug-Drug Interactions of Agents Co-Administered With Encorafenib and Binimetinib in Patients With BRAF V600-mutant Unresectable or Metastatic Melanoma or Other Advanced Solid Tumors

Important dates

Study start
2018
Primary completion
2022
Study completion
2023
First posted
Mar 6, 2019
Registry last updated
Sep 27, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Related clinical trials

Published trials that share one or more normalized conditions with this study.