Ground Truth
Inclusion criteria:Healthy subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (Blood Pressure (BP), PR), 12-lead Electrocardiogram (ECG), and clinical laboratory testsAge of 18 to 70 years (inclusive)BMI of 18.5 to 29.9 kg/m2 (inclusive)Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislationSubjects genotyped as UGT2B17 extensive metabolizers, i.e., carrying at least one functional allele of the Uridine 5'-diphosphate (UDP) Glucuronosyltransferase family 2 member B17 (UGT2B17) gene (*1/*1 or *1/*2).Male, or female (not of childbearing potential) subjects.
For 'female not of childbearing potential' at least one of the following criteria must be fulfilled:Permanently sterile (permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy)Postmenopausal, defined as at least 1 year of spontaneous amenorrhea without an alternative medical cause (in questionable cases a blood sample with FSH above 40 U/L and estradiol below 30 ng/L is confirmatory)Exclusion criteria:Any finding in the medical examination (including Blood Pressure (BP), PR, or Electrocardiogram (ECG)) deviating from normal and assessed as clinically relevant by the investigator.
In particular a marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) at screeningRepeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 bpmAny laboratory value outside the reference range that the investigator considers to be of clinical relevance; safety laboratory screening evaluation can be repeated a maximum of two timesAny evidence of a concomitant disease assessed as clinically relevant by the investigator or at risk of requiring concomitant drug therapy, e.g., gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or hormonal disorder, diseases of the central nervous system (including, but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disordersHistory of cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)History of relevant orthostatic hypotension, fainting spells, or blackoutsHistory of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients)Subjects with a documented active malignancy, or malignancy for which the subject has undergone resection, radiation therapy, or drug therapy (e.g., cytostatic, protein kinase inhibitor, or immune checkpoint inhibitor therapy), within the last 5 years.Subjects who have been previously randomised in this study.Use of drugs within 30 days of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause QT/QTc interval prolongation)Intake of an investigational drug in another clinical trial within 60 days, or within 5 half-lives of the investigational drug (whichever is longer), of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administeredMajor surgery (major according to the investigator's assessment) performed within 6 weeks prior to randomisation or planned within 3 months after screening, e.g.
hip replacement.Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day), also inability to refrain from smoking during in-house confinementAlcohol abuse (consumption of more than 20 g per day for females and 30 g per day for males) or any other drug abuse or positive drug screeningBlood donation of more than 100 mL within 30 days of planned administration of trial medication or intended blood donation during the trialIntention to perform excessive physical activities within one week prior to the administration of trial medication or during the trialInability to comply with the dietary regimen of the trial siteA history of additional risk factors for Torsade de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome)Subjects with veins unsuited for venipuncture (for instance, veins which are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture) as assessed by the investigator.Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the subject is not considered able to understand and comply with study requirements, or has a condition that would not allow safe participation in the studySubjects carrying the Uridine 5'-diphosphate (UDP) Glucuronosyltransferase family 2 member B17 (UGT2B17) *2/*2 genotype.Male subjects with 'women of childbearing potential' (WOCBP) partner who are unwilling to use male contraception (condom or sexual abstinence) from the first administration of trial medication until 30 days after the last administration of trial medicationKnown relevant immunodeficiency, as judged by the investigatorChronic or relevant acute infectionsHistory and/or presence of tuberculosis; positive result for interferon gamma release assay (IGRA) (i.e., QuantiFERON TB-Gold), or history of pneumococcal infectionPositive results for Hepatitis B antigen, Hepatitis C antibodies, and/or human immunodeficiency virus (HIV) 1 antigen or HIV1/2 antibodies, at screeningAural body temperature of more than 37.7°C on Day -3 to -1, or Day -4 to -2 for subjects receiving Midazolam microdosing.Subjects who have received live or live-attenuated vaccine in the 4 weeks prior to dosingC-reactive protein above upper limit of laboratory reference range at screening and/or on Day -3 to -1, or Day -4 to -2 for subjects receiving Midazolam microdosing.Subjects with signs of current gingivitis/periodontitis.
Inspection of the oral cavity will be performed by the investigator.Current or history of relevant kidney, urinary tract diseases or abnormalities (e.g.
nephrolithiasis, hydronephrosis, acute or chronic nephritis, renal injury, renal failure), according to investigator.Estimated glomerular filtration rate (eGFR) according to CKD-EPI formula < 80 mL/min at screening.Known clinically relevant impairment of liver function or clinically relevant laboratory abnormality at the screening visit (V1) regarding liver aminotransferases, alkaline phosphatase, gamma glutamyl transferase, bilirubin, serum albumin, as judged by the investigator.Subjects with a known coagulopathy or abnormal coagulation laboratory parameters at screening, or subjects who, within 10 days prior to administration of trial medication, used any drug that could reasonably inhibit coagulation.
Prediction
Inclusion criteria:Healthy subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (Blood Pressure (BP), Pulse Rate), 12-lead Electrocardiogram (ECG), and clinical laboratory testsAge of 18 to 70 years (inclusive)BMI of 18.5 to 29.9 kg/m2 (inclusive)Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislationSubjects genotyped as UGT2B17 extensive metabolizers, i.e., carrying at least one functional allele of the Uridine 5'-diphosphate (UDP) Glucuronosyltransferase family 2 member B17 (UGT2B17) gene (*1/*1 or *1/*2).Male, or female (not of childbearing potential) subjects.
For 'female not of childbearing potential' at least one of the following criteria must be fulfilled:Permanently sterile (permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy)Postmenopausal, defined as at least 1 year of spontaneous amenorrhea without an alternative medical cause (in questionable cases a blood sample with FSH above 40 U/L and estradiol below 30 ng/L is confirmatory)Exclusion criteria:Any finding in the medical examination (including Blood Pressure (BP), Pulse Rate, or Electrocardiogram (ECG)) deviating from normal and assessed as clinically relevant by the investigator.
In particular a marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) at screeningRepeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 bpmAny laboratory value outside the reference range that the investigator considers to be of clinical relevance; safety laboratory screening evaluation can be repeated a maximum of two timesAny evidence of a concomitant disease assessed as clinically relevant by the investigator or at risk of requiring concomitant drug therapy, e.g., gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, or hormonal disorders, diseases of the central nervous system (including, but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disordersHistory of cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)History of relevant orthostatic hypotension, fainting spells, or blackoutsHistory of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients)Subjects with a documented active malignancy, or malignancy for which the subject has undergone resection, radiation therapy, or drug therapy (e.g., cytostatic, protein kinase inhibitor, or immune checkpoint inhibitor therapy) within the last 5 yearsSubjects who have previously been randomized in this studyUse of drugs within 30 days of the planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause QT/QTc interval prolongation)Intake of an investigational drug in another clinical trial within 60 days, or within 5 half-lives of the investigational drug (whichever is longer), of the planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which an investigational drug is administeredMajor surgery (major according to the investigator's assessment) performed within 6 weeks prior to randomization or planned within 3 months after screening, e.g., hip replacementSmoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) or inability to refrain from smoking during in-house confinementAlcohol abuse (consumption of more than 20 g per day for females and 30 g per day for males) or any other drug abuse or positive drug screeningBlood donation of more than 100 mL within 30 days of planned administration of trial medication or intended blood donation during the trialIntention to perform excessive physical activity within one week prior to the administration of trial medication or during the trialInability to comply with the dietary regimen of the trial siteA history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome)Subjects with veins unsuitable for venipuncture (for instance, veins which are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture) as assessed by the investigator.Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the subject is not considered able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study.