safety, tolerability and pharmacokinetics of kbp-5074 in healthy subjects and subjects with renal impairment

Conditions: Healthy; Renal Insufficiency

Summary: this multiple ascending dose (mad) study in healthy subjects and subjects with mild to moderate renal impairment will evaluate the safety, tolerability and pharmacokinetics of kbp-5074. safety/tolerability data and pharmacokinetics (pk)/pharmacodynamics (pd) (plasma aldosterone, serum potassium, uacr and blood pressure) relationships will be explored to support the selection of dosing regimens of kbp-5074 that are suitable for the phase ii/iii study.

this study consists of two parts: part 1 is an open-label, multiple ascending dose (mad) study to evaluate the safety, tolerability and pharmacokinetics of kbp-5074 in healthy subjects. the safety and tolerability will be assessed at each dose level before progressing to the next higher dose. part 2 is an open label, randomized, parallel study to assess the safety and tolerability, the effect of renal dysfunction on the pharmacokinetics of kbp-5074, as well as the pk/pd relationship in subjects with mild to moderate renal impairment.

Eligibility criteria:
inclusion criteria for part 1: * healthy male or female subject * are between the ages of 18 and 45 years (inclusive); * body mass index (bmi) of 19 to 30 kg/m2 inclusive and body weight not less than 50 kg. exclusion criteria for part 1: * clinically significant history of gastrointestinal, cardiovascular, musculoskeletal, endocrine, hematologic, psychiatric, renal, hepatic, bronchopulmonary, neurologic, immunologic, lipid metabolism disorders, or drug hypersensitivity; * known or suspected malignancy; * positive blood screen for human immunodeficiency virus (hiv), hepatitis b surface antigen (hbsag), or hepatitis c (hcv) antibody; * positive pregnancy test result. inclusion criteria for part 2: * are between the ages of 18 and 75 years (inclusive); * mild to moderate chronic kidney disease (defined as estimated glomerular filtration rate (egfr) \> 30 and ≤89 ml/min/1.73 m2, using the modification of diet in renal disease (mdrd) formula, for \> 3 months; * proteinuria (defined as urine albumin to creatinine ratio (uacr) ≥100 mg/g and ≤3,000 mg/g in two mid-morning urine specimens within a month interval); * subjects treated with an angiotensin-converting enzyme inhibitor (acei) or angiotensin receptor blocker (arb) * serum potassium≥3.3 mmol/l and ≤4.8 mmol/l; * body mass index (bmi) of 19 to 40 kg/m2 inclusive and body weight not less than 50 kg. exclusion criteria for part 2: * severe uncontrolled hypertension (diastolic \> 115 mmhg or systolic blood pressure \> 180 mmhg) at either the screening visit or the study check-in visit; * type i diabetes mellitus or poorly controlled type 2 diabetes mellitus (hba1c \> 10%) at the screening visit; * prior kidney transplant, or anticipated need for transplant during study participation; * clinical diagnosis of heart failure and persistent symptoms (new york heart association \[nyha\] class ii- iv) at either the screening visit or the study check-in visit; * known or suspected contraindications to study medications, including history of hypersensitivity or allergy to ace inhibitors, arbs, or aldosterone antagonists; * any clinically significant disorder, except for conditions associated with type 2 diabetes mellitus history, which in the investigators opinion could interfere with the results of the trial; * diabetic gastroparesis; * known bilateral clinically relevant renal artery stenosis (\>75% reduction in artery diameter).