Safety, tolerability and pharmacokinetics of extended release formulations of ATN-249 in healthy volunteers when dosed once a day or over several days

Exclusion Criteria36

• Prior or ongoing medical condition, medical history, physical findings, or laboratory abnormality that, in the Investigator’s (or delegate’s) opinion, could adversely affect the safety of the participant.
• Previous exposure to ATN-249.
• Mentally or legally incapacitated, has significant emotional problems at the time of screening visit or expected during the conduct of the study, or has a history of a clinically significant psychiatric disorder within the last 5 years. Note: Participants who have had situational depression may be enrolled in the study at the discretion of the Investigator or delegate.
• Fever (body temperature greater than 38°C) or symptomatic viral or bacterial infection within 2 weeks prior to screening.
• History of severe allergic or anaphylactic reactions.
• Resting blood pressure greater than 140/90 mm Hg, resting heart rate greater than 90 beats per minute or resting heart rate lower than 50 beats per minute at screening or at Day -1 (repeat measurements are allowed at the discretion of the Investigator. The resting heart rate measurement may be repeated only once if below 50 beats per minute).
• Alkaline phosphatase (ALP), aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) greater than 1.5 x upper limit of normal at screening. Repeat testing at screening is acceptable for out of range values following approval by the Investigator or delegate.
• Serum potassium lower than 3.7 mmol/L or greater than 5.5 mmol/L at Screening or Day -1. Repeat testing at screening is acceptable for out of range values following approval by the Investigator or delegate.
• Positive test for hepatitis C antibody, hepatitis B surface antigen, or human immunodeficiency virus (HIV) antibody at screening.
• Participants with a positive toxicology screening panel (urine test including qualitative identification of barbiturates, Tetrahydrocannabinol (THC), amphetamines, benzodiazepines, opiates and cocaine), cotinine test or alcohol breath test.
• Participants with a history of substance abuse or dependency or history of recreational intravenous (IV) drug use over the last 5 years (by self-declaration).
• Regular alcohol consumption defined as greater than 21 alcohol units per week (where 1 unit equal to 284 mL of beer, 25 mL of 40% spirit or a 125 mL glass of wine). Participant is unwilling to abstain from alcohol beginning 48 hours prior to admission to the CRU until completion of the final follow-up visit.
• Participant has left ventricular hypertrophy defined as the combination of the following ECG criteria (both #a and #b must be met):
• a. Voltage criteria (both criteria must be met):
• a.1 S in V1 plus R in V5 or V6 (whichever is larger) greater or equal than 35 mm; and
• a.2 R in aVL greater or equal than 11 mm
• b. Repolarization abnormalities (at least one criteria needs to be met):
• b.1 At least 1mm ST depression (horizontal or down-sloping); or
• b.2 Abnormal T wave inversions
• Participant has other significant ECG abnormalities that might interfere with ECG analysis including evidence of a previous myocardial infarction (MI), flat T waves (particularly in the inferior leads) or more than minor non- specific ST-T wave changes or:
• a. QRS greater than 110 milliseconds (msec),
• b. QT interval corrected using Fridericia’s formula (QTcF) greater than 440 msec,
• c. PR interval greater than 220 msec
• d. Heart rate lower than 50 beats per minute (BPM) or greater than 90 BPM (the resting heart rate measurement may be repeated only once if below 50 beats per minute)
• e. Complete right bundle branch block or left bundle branch block.
• History of cardiac disease or cerebrovascular disease, including coronary artery disease (including myocardial infarction [MI], angina), cardiac arrhythmias, long QT syndrome (in self or family), valvular disease, heart failure, hypertension or hypotension.
• Family history of hereditary angioedema.
• Use of any prescription medication, over-the-counter medication, herbal products, vitamins or minerals, within 7 days or 5 half-lives (whichever is longer) prior to study drug administration, unless in the opinion of the Principal Investigator and/or Medical Monitor the medication will not compromise participant safety or interfere with study procedures or data validity.
• Use of any potential inducer or inhibitor of cytochrome P450 [CYP] 3A4 or P-glycoprotein [P gp] [eg, St. John’s Wort, rifampin, cyclosporine, or ritonavir]) within 14 days or 5 half lives (whichever is longer) prior to study drug administration, unless in the opinion of the Principal Investigator and/or Medical Monitor the medication will not compromise participant safety or interfere with study procedures or data validity.
• Anticipated use of prescription medication or over-the-counter medication during study participation, with the exception of 1-2 therapeutic doses per week of paracetamol/acetaminophen or non-steroidal anti-inflammatory drugs (e.g: ibuprofen, naproxen).
• Participant is lactose intolerant.
• Participant is unwilling to refrain from strenuous exercise from 7 days prior to admission to the CRU until completion of the final follow-up visit.
• Participant is unwilling to abstain from ingestion of caffeine or xanthine-containing products (e.g., tea, coffee, chocolate, cola,) beginning 96 hours prior to admission to the CRU until the final pharmacokinetic (PK) sample has been collected.
• Participant has consumed grapefruit and/or grapefruit juice within 14 days prior to admission to the CRU and is unwilling to abstain from consuming grapefruit and/or grapefruit juice until completion of the follow-up visit.
• Participant has consumed citrus fruit or citrus fruit juices within 48 hours prior to admission to the CRU and is unwilling to abstain from these items until the final PK sample has been collected.
• Participants who are unlikely to comply with the study protocol or, in the opinion of the Investigator, would not be a suitable candidate for participation in the study.