NCT05203822

Tepotinib Drug-Drug Interaction Study With Itraconazole in Healthy Participants

Completed Phase 1 Results posted Last updated 20 February 2024

What this trial tests

Phase 1 trial testing Tepotinib (HydroChloride hydrate) in Healthy in 18 participants. Completed in 5 July 2022.

Timeline

21 January 2022

Primary endpoint
5 July 2022

5 July 2022

Quick facts

Lead sponsor	Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	na
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	18
Start date	21 January 2022
Primary completion	5 July 2022
Estimated completion	5 July 2022
Sites	1 location across Germany

Drugs / interventions tested

• Tepotinib (HydroChloride hydrate) — full drug profile →
• Itraconazole — full drug profile →

Conditions studied

• Healthy — all drugs for Healthy →

Sponsor

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany — full company profile →

Who can join

Adults 18 to 55, any sex, with Healthy. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib Primary · Predose up to 168 hours post dose

The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda (λ)z determination.

Group	Value	95% CI
Tepotinib	18927	± 28.2
Tepotinib and Itraconazole	23158	± 29.9

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib Primary · Predose up to 168 hours post dose

The AUC from time zero (= dosing time) to time of the last quantifiable concentration (tlast). Calculated using the mixed log-linear trapezoidal rule (linear up, log down).

Group	Value	95% CI
Tepotinib	18300	± 27.9
Tepotinib and Itraconazole	21391	± 30.2

Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite Primary · Predose up to 168 hours post dose

Cmax was obtained directly from the concentration versus time curve.

Group	Value	95% CI
Tepotinib	308	± 24.8
Tepotinib and Itraconazole	313	± 28.2

Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 Secondary · Baseline (Day 1) up to follow up (assessed up to Day 20)

An adverse event (AE) was defined as any untoward medical occurrence in a participant. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. A serious adverse event (SAE) was any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE's were those events with ons

Any TEAE

Group	Value	95% CI
Tepotinib and Itraconazole	14

Any serious TEAE

Group	Value	95% CI
Tepotinib and Itraconazole	0

Any TEAE of Grade ≥ 3 (severe)

Group	Value	95% CI
Tepotinib and Itraconazole	0

Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values Secondary · Baseline (Day 1) up to follow up (assessed up to Day 20)

Laboratory investigation included hematology, biochemistry and urinalysis. Clinically meaningful was decided by the investigator. Number of participants with clinically meaningful change from baseline in laboratory values were reported.

Hematology

Group	Value	95% CI
Tepotinib and Itraconazole	0

Biochemistry

Group	Value	95% CI
Tepotinib and Itraconazole	0

Urinalysis

Group	Value	95% CI
Tepotinib and Itraconazole	0

Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG) Secondary · Baseline (Day 1) up to follow up (assessed up to Day 20)

The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. Clinical Significance was decided by the investigator. Number of participants with clinically meaningful change from baseline in ECG parameters were reported.

Group	Value	95% CI
Tepotinib and Itraconazole	0

Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs Secondary · Baseline (Day 1) up to follow up (assessed up to Day 20)

Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Significance was decided by the investigator. Number of participants with clinically significant change from baseline in vital signs.

Group	Value	95% CI
Tepotinib and Itraconazole	0

Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib Secondary · Predose up to 168 hours post dose

CL/f following oral administration was calculated as Dose/AUC0-inf, where AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastcalc/λz, where Clastcalc was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and λz was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

Group	Value	95% CI
Tepotinib	23.8	± 28.2
Tepotinib and Itraconazole	19.4	± 29.9

Apparent Volume of Distribution (Vz/f) for Tepotinib Secondary · Predose up to 168 hours post dose

Vz/F was defined as the apparent volume of distribution during the terminal phase following extravascular administration.

Group	Value	95% CI
Tepotinib	1102	± 29.4
Tepotinib and Itraconazole	1148	± 34.3

Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib Secondary · Predose up to 168 hours post dose

The time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

Group	Value	95% CI
Tepotinib	8.00	6.00 – 16.00
Tepotinib and Itraconazole	8.00	6.05 – 24.00

Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma Secondary · Predose up to 168 hours post dose

t1/2 was defined as the time taken for the plasma concentration or the amount of drug in the body to be reduced by half.

Group	Value	95% CI
Tepotinib	32.1	± 7.8
Tepotinib and Itraconazole	40.9	± 19.2

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline (Day 1) up to follow up (assessed up to Day 20). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Tepotinib and Itraconazole

Serious: 0/18 (0%)

Deaths: 0/18

Other adverse events (34 terms — click to expand)

Reaction	System	Tepotinib and Itraconazole
Headache	Nervous system disorders	—
Middle insomnia	Psychiatric disorders	—
Abdominal distension	Gastrointestinal disorders	—
Abdominal pain	Gastrointestinal disorders	—
Abdominal pain upper	Gastrointestinal disorders	—
Diarrhoea	Gastrointestinal disorders	—
Chest discomfort	General disorders	—
Fatigue	General disorders	—
Somnolence	Nervous system disorders	—
Abdominal discomfort	Gastrointestinal disorders	—
Dry mouth	Gastrointestinal disorders	—
Dyspepsia	Gastrointestinal disorders	—
Epigastric discomfort	Gastrointestinal disorders	—
Faeces hard	Gastrointestinal disorders	—
Flatulence	Gastrointestinal disorders	—
Gastrointestinal motility disorder	Gastrointestinal disorders	—
Rectal tenesmus	Gastrointestinal disorders	—
Toothache	Gastrointestinal disorders	—
Vomiting	Gastrointestinal disorders	—
Catheter site induration	General disorders	—
Chest pain	General disorders	—
Rhinitis	Infections and infestations	—
Amylase increased	Investigations	—
Lipase increased	Investigations	—
Flank pain	Musculoskeletal and connective tissue disorders	—
Ataxia	Nervous system disorders	—
Clumsiness	Nervous system disorders	—
Dizziness	Nervous system disorders	—
Hypoaesthesia	Nervous system disorders	—
Abnormal dreams	Psychiatric disorders	—
Nocturia	Renal and urinary disorders	—
Cough	Respiratory, thoracic and mediastinal disorders	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—
Hyperhidrosis	Skin and subcutaneous tissue disorders	—

Data from ClinicalTrials.gov NCT05203822 adverse events section.

Sponsor's own description

The purpose of this study was to assess the effect of multiple doses of itraconazole on single dose tepotinib pharmacokinetics in healthy participants. Study details include:

Study Duration: up to 48 days Treatment Duration: single dose of tepotinib on Days 1 and 12, 11 days of treatment with itraconazole (Days 8 to 18) Visit Frequency: residence in the Clinical Research Unit from Days -1 to 4 and Days 11 to 15, ambulatory daily visits from Days 5 to 10 and 16 to 20

Publications & conference data

1 peer-reviewed publication reference this trial (live from Europe PMC):

1. Sensitivity of Tepotinib to Inhibitors or Inducers of CYP3A4 and P-Gp: Drug Interaction Studies and Physiologically-Based Pharmacokinetic Analysis.
   Strotmann R, Lüpfert C, Krebs-Brown A, Ke A, et al · · 2025 · PMID 40679917 · DOI 10.1111/cts.70273