Effect of Tepotinib on PK of CYP3A Substrate Midazolam

AUC0-t a Pharmacokinetic (PK) parameter was calculated according to the mixed log linear trapezoidal rule.

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Population: PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements.

AUC0-inf was calculated as AUC0-t plus (+) AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastpred/Lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log-linear regression line for Lambda z determination at which the measured plasma concentration is at or above Lower limit of quantification (LLOQ).

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Population: PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements.

Cmax was obtained directly from concentration versus time curve.

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Population: PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements.

AUC0-t a Pharmacokinetic (PK) parameter was calculated according to the mixed log linear trapezoidal rule.

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Population: PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements.

AUC0-inf was calculated as AUC0-t plus (+) AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastpred/Lambda z, where Clastpred is the predicted plasma concentration at the last sampling time point, calculated from the log-linear regression line for Lambda z determination at which the measured plasma concentration is at or above Lower limit of quantification (LLOQ).

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Population: PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements.

Elimination Half Life (t1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half.

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Population: PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements.

Cmax was obtained directly from concentration versus time curve.

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Population: PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements.

Metabolic ratio was calculated as AUC 0-infinity of midazolam divided by AUC 0-infinity of 1-hydroxymidazolam.

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Population: PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements.

Number of participants with clinically significant changes in 12-lead ECG were reported. Clinical significance was decided by the investigator. The 12-lead ECGs were recorded after the participants have rested for at least 5 minute in supine position.

Time frame: Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20)

Population: Safety Analysis Set included all participants who have received atleast 1 dose of planned IMP. Participants was analyzed according to the actual treatment they receive.

Number of participants with clinically significant changes in laboratory values were reported. Clinical significance was decided by the investigator. Laboratory investigation included hematology and urinalysis.

Time frame: From Screening up to the End of Trial visit (Day 20)

Population: Safety Analysis Set included all participants who have received atleast 1 dose of planned IMP. Participants was analyzed according to the actual treatment they receive.

Number of participants with clinically significant changes in vital signs were reported. Clinical significance was decided by Investigator. Vital signs included body temperature, blood pressure and pulse rate.

Time frame: Day 1 (Treatment Period 1) up to the End of Trial visit (Day 20)

Population: Safety Analysis Set included all participants who have received atleast 1 dose of planned IMP. Participants was analyzed according to the actual treatment they receive.

Adverse event (AE) was defined as any untoward medical occurrence in participants which does not necessarily have causal relationship with treatment. AE was any unfavorable and unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. A serious adverse event (SAE) was AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both serious TEAEs and non-serious TEAEs.

Time frame: Baseline (Day 1 of treatment period 1) up to the End of Trial visit (Day 20)

Population: Safety Analysis Set included all participants who have received atleast 1 dose of planned investigational medicinal product (IMP). Participants was analyzed according to the actual treatment they receive.

Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.

Time frame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 43 hours post-dose on Day 1 of period 1 and Day 11 of Period 2

Population: PK Analysis Set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, who have received at least one dose of midazolam and who have at least 3 post-dose concentration measurements.