None listed
Conditions
Brief summary
PRN1008-011 is a single center, four-period, open-label, randomized, complete cross-over study in healthy adult participants.This study will evaluate the relative bioavailability of two novel formulations of PRN1008 (Test Formulations #1 and #2) compared to an existing tablet formulation (Reference Formulation), which has previously been administered in Phase 1 and Phase 2 studies. The information obtained in this study will evaluate the potential of the two novel formulations for use in future PRN1008 patient studies, and determine if any dosage adjustments are needed to obtain similar plasma exposures between the formulations. PRN1008 is a novel, reversible covalent, investigational drug that inhibits Bruton’s agammaglobulinemia tyrosine kinase (BTK). PRN1008 acts as an adenosine triphosphate (ATP) competitive inhibitor that is both potent and selective for BTK. PRN1008 has a slow off-rate for binding to the target site, resulting in prolonged target occupancy relative to its low systemic exposure. This study will also evaluate the PK of PRN1008 when co-administered with a customary dose of famotidine, an H2-receptor antagonist. Co-administration of PRN1008 in the morning after famotidine use, as well as in the evening 2 hours prior to famotidine will be studied. A prior study (PRN1008-006) found that PRN1008, when administered in combination with a proton-pump inhibitor (esomeprazole), demonstrated approximately a 50% reduction in plasma exposure, most likely due to the impact of esomeprazole on gastric pH. Based on these results, proton-pump inhibitors are currently excluded from PRN1008 clinical trials. The objective of this evaluation is to assess the potential impact of co-administering PRN1008 with H2-receptor antagonists, which are less potent reducers of gastric pH compared to proton-pump inhibitors. The results of these evaluations will inform the use of PRN1008 in future clinical studies. Finally, this study will evaluate the potential for PRN1008 to alter the PK of midazolam when co-administered under various scenarios; this information will inform the use of PRN1008 in autoimmune diseases where drugs like midazolam and other CYP 3A substrates may be co-administered.
Interventions
This will be a single center, four-period, open-label, randomized, complete cross-over study in healthy adult participants. Participants will be screened for participation within 29 days before dosing. Participants will be admitted to the study unit on Day -2, the day before the first midazolam dosing (Day -1), and participants will receive PRN1008 on Days 1, 3, 5, and 7. Participants will remain in the study unit to observe safety and protocol compliance until the last PK sample draw on Day 8.
This will be a single center, four-period, open-label, randomized, complete cross-over study in healthy adult participants. Participants will be screened for participation within 29 days before dosing. Participants will be admitted to the study unit on Day -2, the day before the first midazolam dosing (Day -1), and participants will receive PRN1008 on Days 1, 3, 5, and 7. Participants will remain in the study unit to observe safety and protocol compliance until the last PK sample draw on Day 8. All participants will complete all four Periods of the study. All participants will receive a single 2 mg oral dose of midazolam (1 mg/mL solution) on Day -1, followed by intensive blood sampling for 12 hours for midazolam pharmacokinetics (PK). Beginning Day 1, participants will be randomized to order of PRN1008 treatment (Treatment 1, 2, or 3) for the first three Study Periods. All participants will receive Treatment 4 in Period 4. Treatments are as listed below. Subjects will be dosed with PRN1008 once on Days 1, 3, and 5 and twice on Day 7. Doses will be administered approximately 48 hours apart for all PRN1008 Treatments. Treatment 1 Following an overnight fast, participants will receive a single 400 mg oral dose of PRN1008 (Reference Formulation), and simultaneously receive a single 2 mg oral dose of midazolam. Blood samples will be obtained over a period of 12 hours for determination of the PRN1008 and midazolam PK profiles. Treatment 2 Following an overnight fast, participants will receive a single 400 mg oral dose of PRN1008 (Test Formulation #1), and simultaneously receive a single 2 mg oral dose of midazolam. Blood samples will be obtained over a period of 12 hours for determination of the PRN1008 and midazolam PK profiles. Treatment 3 Following an overnight fast, participants will receive a single 400 mg oral dose of PRN1008 (Test Formulation #2), and will receive a single 2 mg oral dose of midazolam 2 hours after PRN1008. Blood samples will be obtained over a period of 14 hours for determination of the PRN1008 and midazolam PK profiles. Treatment 4 Participants will receive 20 mg oral doses of famotidine in the evening of Days 5, 6, and 7. Following an overnight fast on Day 7, participants will receive one 400 mg oral dose of PRN1008 (Reference Formulation) administered in the morning and a second dose in the evening (10-12 hours after the am dose), 2 hours prior to famotidine dosing, and after a four hour period of fasting. Blood samples will be obtained over a period of 12 hours following each PRN1008 dose for determination of PRN1008 PK. Participants will be randomized to complete one of 6 possible treatment sequences: • 1234 • 1324 • 2134 • 2314 • 3124 • 3214 Following discharge from the study unit on the morning of Day 8, subjects will return for a follow-up assessment on Day 15 (+/- 2 days).
Sponsors
Principia Biopharma Inc
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject)
Eligibility
Sex/Gender
All
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy adult male or non-pregnant, non-lactating females, 18 to 75 years of age (inclusive) at the time of screening 2. Body mass index (BMI) greater than or equal 18 and less than or equal to 35 (kg/m2) (inclusive) and a minimum body weight of 45 kg 3. Able to participate and comply with all study procedures and restrictions, and willing to provide written informed consent to participate in the study 4. A female subject of childbearing potential with a negative pregnancy test agrees to abstinence or use of condoms plus one other acceptable form of contraception; i.e. intrauterine device, hormonal contraception, or a female diaphragm, until 4 weeks after dosing with study drug – OR – has only same-sex partners, when this is her preferred and usual lifestyle 5. Male subjects with female partners of childbearing potential must agree to use condoms for the duration of the study and until 12 weeks after dosing with the study drug 6. Negative urine drug and alcohol breath testing at screening and check-in (Day -2). Screening drug/alcohol testing may be repeated once if deemed appropriate by the site Investigator 7. Willing to or has abstain(ed) from consuming grapefruit- or Seville orange-containing products from 14 days prior to first dose of study medication through follow-up
Exclusion criteria
1. Use of any prescription or over-the-counter (OTC) medications, including herbal products and supplements, within the 14 days prior to Day -1 or 5 half-lives, whichever is longer. Use of hormonal contraception and less than or equal to 2g paracetamol per day is allowed prior to and during the study. 2. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV) 3. Use of more than two tobacco/nicotine-containing products per month within 6 months prior to the first study drug administration 4. History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration 5. Regular alcohol consumption >14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit, or a 125 mL glass of wine) 6. History of any significant (as determined by the Investigator) drug-related allergic reactions such as anaphylaxis, Stevens-Johnson syndrome, urticaria, or multiple drug allergies 7. Blood donation or significant blood loss within 30 days prior to screening 8. Plasma donation within 14 days prior to the first study drug administration 9. Participation in another clinical trial of a drug or device whereby the last investigational drug/device administration is within 30 days prior to the first study drug administration or 5 half-lives, whichever is longer 10. Surgery within the past three months prior to the first study drug administration determined by the PI to be clinically relevant 11. Personal or family history of prolonged QT syndrome or family history of sudden death 12. QTcF > 450 msec (males) or > 470 msec (females) or < 300 msec at screening or baseline (Day -2), unless deemed clinically insignificant by the Investigator 13. Evidence of atrial fibrillation, atrial flutter, complete bundle branch or heart block, Wolff-Parkinson-White Syndrome, or cardiac pacemaker at screening or baseline visit 14. Seated or semi-supine resting systolic blood pressure (SBP) greater than 150 or less than 90 mm Hg, or diastolic blood pressure (DBP) greater than 95 or less than 50 mm Hg 15. Resting HR < 40 beats per minute (bpm) or > 90 bpm at screening or baseline (Day -2) (the heart rate recorded from vital sign assessment will be utilized for this exclusion criteria) 16. Hypersensitivity or history of idiosyncratic reaction to any components or excipients of the investigational formulation 17. Active infection 18. Participant is febrile, temperature > 37.5 °C (assessed at Screening and at Baseline [Day -2]) 19. Any acute illness within 30 days prior to Day 1 unless deemed clinically insignificant by the Investigator and discussed with the Sponsor 20. Failure to satisfy the Investigator of fitness to participate for any other reason 21. History or presence of any other medical condition that makes the participant unsuitable for the study in the opinion of the Investigator
Outcome results
None listed