Outcome
Type |
Measure |
Description |
Time frame |
Safety issue |
Primary |
Midazolam: Area under the plasma concentration-time curve from time zero to infinity (AUC) ratio of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone). |
To assess the effect of savolitinib on the PK of midazolam. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Primary |
Midazolam: Maximum observed plasma concentration (Cmax) ratio of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone). |
To assess the effect of savolitinib on the PK of midazolam. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Secondary |
Midazolam: Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration [AUC(0-t)] ratios of geometric means of test treatment (midazolam + savolitinib), relative to reference treatment (midazolam alone). |
To describe the PK of midazolam in the presence and absence of savolitinib. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Secondary |
Midazolam: Cmax |
To describe the PK of midazolam in the presence and absence of savolitinib. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Secondary |
Midazolam: [AUC(0-t)] |
To describe the PK of midazolam in the presence and absence of savolitinib. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Secondary |
Midazolam: Time to reach maximum observed plasma concentration (tmax) |
To describe the PK of midazolam in the presence and absence of savolitinib. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Secondary |
Midazolam: Half-life associated with terminal slope (?z) of a semi-logarithmic concentration time curve (t½,?z) |
To describe the PK of midazolam in the presence and absence of savolitinib. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Secondary |
Midazolam: Terminal elimination rate constant (?z) |
To describe the PK of midazolam in the presence and absence of savolitinib. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Secondary |
Midazolam and savolitinib: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) |
To describe the PK of midazolam in the presence and absence of savolitinib. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Secondary |
Midazolam and savolitinib: Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) |
To describe the PK of midazolam in the presence and absence of savolitinib. |
Treatment period 1 and 2 (Study Days 1,2, 5 and 6). Midazolam- pre dose, and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, 16 and 24 hours post dose on Study Days 1 and 5. Savolitinib- pre-dose and 1,2, 4, 6, 8, 12 and 24 hours post dose. |
|
Secondary |
Number of subjects with adverse events |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day -1, 1, 2, 3, 4, 5, 6, 19 |
|
Secondary |
Number of subjects with abnormal systolic blood pressure (BP) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day -1, 1, 2, 5, 6, 19. Vital signs on dosing days will be collected at pre dose, 0.5, 1, 2, 3, 4, 8 and 24 hours post dose. |
|
Secondary |
Number of subjects with abnormal diastolic blood pressure (BP) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day -1, 1, 2, 5, 6, 19. Vital signs on dosing days will be collected at pre dose, 0.5, 1, 2, 3, 4, 8 and 24 hours post dose. |
|
Secondary |
Number of subjects with abnormal findings in pulse rate |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day -1, 1, 2, 5, 6, 19. Vital signs on dosing days will be collected at pre dose, 0.5, 1, 2, 3, 4, 8 and 24 hours post dose. |
|
Secondary |
Number of subjects with abnormal findings in physical examination |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day -1, 1, 2, 3, 4, 5, 6 and 19 |
|
Secondary |
Number of subjects with abnormal findings in White blood cell (WBC) count |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Red blood cell (RBC) count |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Hemoglobin (Hb) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Hematocrit (HCT) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Mean corpuscular volume (MCV) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Mean corpuscular hemoglobin (MCH) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Mean corpuscular hemoglobin concentration (MCHC) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Neutrophils absolute count |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Monocytes absolute count |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Eosinophils absolute count |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Basophils absolute count |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Platelets |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Reticulocytes absolute count |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in sodium |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in pottasium |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in urea |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in creatinine |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in albumin |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in calcium |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in phosphate |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in glucose (fasting) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in C-reactive protein (CRP) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in T4 |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening |
|
Secondary |
Number of subjects with abnormal findings in Thyroid-Stimulating Hormone (TSH) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening |
|
Secondary |
Number of subjects with abnormal findings in Alkaline phosphatase (ALP) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Alanine aminotransferase (ALT) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Aspartate aminotransferase (AST) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in Gamma glutamyl transpeptidase (GGT) |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in total bilirubin |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in unconjugated bilirubin |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in urinalysis |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
At screening, Day 1, 4, 5 and 19 |
|
Secondary |
Number of subjects with abnormal findings in pulse oximetry |
To examine the safety and tolerability of midazolam alone and in combination with savolitinib. |
Day 1 and 5 |
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