Healthy Participants
Conditions
Keywords
drug-drug interaction study, DDI study, Healthy participants, Pelabresib, DAK539, Phenytoin, Itraconazole
Brief summary
The purpose of this study is to assess the effect of multiple doses of phenytoin, a strong cytochrome P450 (CYP)3A4 inducer, and itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetic (PK) profile of DAK539 (hereafter referred to as pelabresib) after a single dose in healthy participants. In addition, the safety and tolerability of a single dose of pelabresib with and without the co-administration of itraconazole or phenytoin will be evaluated.
Detailed description
This is a 2-part, open-label, drug-drug interaction (DDI) study to assess the effect of phenytoin (a strong CYP3A4 inducer) and itraconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of pelabresib in healthy participants. The study includes two parts, each with two treatment periods. In Part 1, participants will be administered pelabresib in Treatment Period 1 and pelabresib and phenytoin in Treatment Period 2. In Part 2, participants will be administered pelabresib in Treatment Period 1 and pelabresib and itraconazole in Treatment Period 2.
Interventions
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Participants willing to adhere to the protocol requirements and to provide written informed consent prior to participation in the study. 2. Healthy male and non-childbearing potential female participants between 18 and 55 years of age, inclusive. 3. In good health as determined by no clinically significant findings from medical history, physical examination, vital signs, electrocardiograms (ECG) and laboratory tests. 4. Body Mass Index (BMI) within the range of 18.5 to 29.9 kg/m2, inclusive, with body weight at least 50.0 kg at screening. 5. Vital signs after being supine for 5 minutes in a quiet environment must be within the following ranges: * oral temperature ≤ 37.5°C. * systolic blood pressure between 90 and 139 mmHg. * diastolic blood pressure between 45 and 89 mmHg. * pulse rate between 50 and 100 bpm. 6. Able to read, speak, and understand the local language, to understand and comply with the requirements of the study.
Exclusion criteria
1. History or current diagnosis of ECG or cardiac abnormalities indicating significant risk of safety for participants. 2. History of clinically significant cardiovascular, renal, hepatic, testicular, dermatological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the Investigator. 3. Clinically significant abnormal clinical chemistry, hematology, coagulation, or urinalysis as judged by the Investigator at screening or first baseline (admission). 4. Evidence of renal impairment as indicated by creatinine or blood urea level \> 1.0 × upper limit of normal (ULN) or clinically significant microalbuminuria or hematuria or clinically significant elevated cystatin-C at screening; evidence of urinary obstruction, or difficulty in voiding at screening; evidence of congenital renal abnormalities with known effect on renal function; calculated estimated glomerular filtration rate (eGFR) \< 80 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula for adults at Screening. 5. Any single parameter of amylase or lipase \> 1.2 × ULN, or any history or presence of clinical symptoms suggestive of pancreatitis. 6. History of malignancy in any organ system (excluding localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of evidence of local recurrence or metastases. 7. Participants who have received other investigational drugs within 5 half-lives or within 90 days or until the expected pharmacodynamic effect has returned to baseline prior to first dose of study treatment, whichever is longer. 8. Positive hepatitis B virus surface antigen (HBsAg), hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) 1 and 2 antibody results. 9. Any surgical or medical condition (impaired GI function, inflammatory bowel disease, peptic ulcers, GI bleeding including rectal bleeding, GI surgeries such as gastrectomy, cholecystectomy, gastroenterostomy, or bowel resection) which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, or which may jeopardize the participant in case of participation in the study. 10. History of malignancy in any organ system (excluding localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of evidence of local recurrence or metastases. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and 2: Maximum observed plasma concentration (Cmax) of pelabresib | From pre-dose up to 48 or 72 hours after pelabresib administration | Pharmacokinetic (PK) parameters determined using the actual recorded sampling times and non- compartmental method(s) from the pelabresib plasma concentration-time data. |
| Part 1 and 2: Area under the plasma concentration-time curve from time 0 to the last measurable concentration sampling time (AUClast) of pelabresib | From pre-dose up to 48 or 72 hours after pelabresib administration | PK parameters determined using the actual recorded sampling times and non- compartmental method(s) from the pelabresib plasma concentration-time data. |
| Part 1 and 2: Area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of pelabresib | From pre-dose up to 48 or 72 hours after pelabresib administration | PK parameters determined using the actual recorded sampling times and non- compartmental method(s) from the pelabresib plasma concentration-time data. |
| Part 1 and 2: Time to reach maximum plasma concentration (Tmax) of pelabresib | From pre-dose up to 48 or 72 hours after pelabresib administration | PK parameters determined using the actual recorded sampling times and non- compartmental method(s) from the pelabresib plasma concentration-time data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1 and 2: Apparent plasma clearance (CL/F) of pelabresib | From pre-dose up to 48 or 72 hours after pelabresib administration | Pharmacokinetic (PK) parameters determined using the actual recorded sampling times and non- compartmental method(s) from the pelabresib plasma concentration-time data. |
| Part 1 and 2: Apparent volume of distribution during the terminal elimination phase (Vz/F) of pelabresib | From pre-dose up to 48 or 72 hours after pelabresib administration | Pharmacokinetic (PK) parameters determined using the actual recorded sampling times and non- compartmental method(s) from the pelabresib plasma concentration-time data. |
| Part 1 and 2: Terminal elimination half-life (T1/2) of pelabresib | From pre-dose up to 48 or 72 hours after pelabresib administration | Pharmacokinetic (PK) parameters determined using the actual recorded sampling times and non- compartmental method(s) from the pelabresib plasma concentration-time data. |
| Part 1 and 2: Incidence of adverse events (AEs) and serious adverse events (SAEs) | Up to approximately 30 days after the last dose of study drug (Day 48 in Part 1 and Day 40 in Part 2) | Number of participants with AEs and SAEs, including changes in vital signs, electrocardiograms and laboratory values qualifying and reported as AEs. |
Contacts
CONTACTNovartis Pharmaceuticals
Outcome results
None listed