Effect of a Known P-glycoprotein (P-gp) Inhibitor, Itraconazole, on the Pharmacokinetics (PK) of Engasertib

Inclusion criteria

• Age of 18 to 55 years (both inclusive), at the time of signing the informed consent.
• Body weight ≥ 50 and < 120 kg and a body mass index (BMI) within the range 18 to 30 kg/m^2 (both inclusive) at screening.
• Male and female participants are eligible to participate if they are not fertile or if they agree to either be abstinent from intercourse where pregnancy can occur or use contraception/barrier as detailed in the protocol.
• Overtly healthy as determined by medical evaluation including medical history, physical examination, vital signs, electrocardiogram (ECG).
• Clinically acceptable clinical laboratory test results at screening.
• Non-smoker, former smoker or stable non-smoker (= 0 cigarettes, pipes, cigars, or others) for at least 3 months prior to screening. Participants must also have abstained from use of other nicotine containing products (e.g., nicotine patch, chewing gum or e-cigarettes) for at least 3 months before screening.
• Capable of giving signed informed consent.
• Re-admission: overtly healthy as determined by medical evaluation including check of changes in medical history compared to screening, clinical laboratory test results, abbreviated physical examination, vital signs, and ECG.

Exclusion criteria

• Any history or evidence of any clinically relevant cardiovascular, hepatic, renal, gastrointestinal, pancreatic, endocrinologic, hematologic, immunologic, metabolic, and/or other major disease or malignancy as determined by medical evaluation (including physical examination) capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
• Any clinically important illness, medical/surgical procedure, or condition, which, in the opinion of the investigator, is likely to interfere with the study conduct.
• Known or suspected hypersensitivity to engasertib, or itraconazole, or any components of the formulation used.
• History of significant or uncontrolled skin disorders, per the Investigator's judgement.
• Any clinically significant history of allergic conditions (including allergies to more than 3 allergens, drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
• History or presence of disorders of glucose metabolism.
• Known or suspected thyroid disorders as evidenced by assessment of thyroid-stimulating hormone (TSH) levels outside the normal reference range at screening.
• Known or suspected liver disorders (e.g., Morbus Gilbert / Meulengracht) and bile secretion/flow (cholestasis, also history of it).
• Difficulty in swallowing.
• History or evidence of malabsorption or any gastrointestinal surgery except appendectomy and herniotomy.
• History of any chronic disease which might interfere with the absorption, distribution, metabolism or excretion of the study drug.
• Lactose intolerance.
• Contraindications for the use of itraconazole.
• Tendency for vasovagal reactions (e.g., after venipuncture) or history of syncope.
• Febrile illness within 1 week before first dosing.
• Diagnosis or history of immunodeficiency or increased susceptibility to severe infection, or a clinically significant infection within 4 weeks prior to screening.
• Use of any concomitant medication or any drugs / medicines (including dietary supplements, natural and herbal remedies, and hormone replacement therapy) within 2 weeks or 5 times the half-life of the respective drug, whichever is longer, prior to screening. Occasional use of paracetamol (2 grams/day; medicinal products in their original packaging, approved and marketed in Germany) is permitted. Oral, injectable, implantable, and topical contraceptives are permitted.
• Administration of live, attenuated, replication-competent vaccine(s) and vector-based or mRNA COVID-19 vaccine(s) within 1 month prior to screening or plans to receive such vaccines during the study.
• Treatment with biologic agents (such as monoclonal antibodies including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior to screening.
• Use of any investigational drug or participation in any clinical study within 30 days or 5 half-life times of study intervention administered in a previous trial, whichever is longer, prior to the expected date of first administration of study intervention or planning to take other investigational drugs during the study.
• Positive for hepatitis B virus (HBV) panel test (Hepatitis B virus surface antigen [HBsAg], Hepatitis B Core Antibody [HBcAb], Hepatitis B surface antibody [HBsAb]), hepatitis C virus (HCV) (RNA), human immunodeficiency virus (HIV) 1+2 antibodies and HIV-1 p24 antigen combined at screening.
• Positive screen for alcohol, drugs of abuse and cotinine test at screening.
• Supine systolic blood pressure > 140 mmHg or < 90 mmHg; diastolic blood pressure > 90 mmHg or < 50 mmHg and pulse rate < 50 bpm or > 90 bpm (measurements taken after participant has been resting in supine position for 5 min), and tympanic body temperature of < 35.9 and > 37.6°C at screening.
• 12-lead ECG with clinically relevant abnormality.
• Elevations in alanine transaminase (ALT) > 1.1 x ULN, aspartate aminotransferase (AST) > 1.2 x ULN, serum bilirubin > 1.2 x ULN, creatinine ≥ 1.1 x ULN at screening.
• Estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration Creatinine Equation (2009) < 90 mL/min at screening.