Pharmacokinetics and Safety of Omadacycline in Subjects with Impaired Renal Function

Abstract

Many antibiotics require dose adjustments in patients with renal impairment and/or in those undergoing hemodialysis. Omadacycline, the first aminomethylcycline antibiotic in late-stage clinical development, displays activity against a broad spectrum of bacterial pathogens, including drug-resistant strains. Data from completed phase 3 studies of omadacycline for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) showed intravenous (i.v.) to once-daily oral omadacycline to be clinically effective and well tolerated. To determine if the dosing of omadacycline should be adjusted in patients with impaired renal function, a phase 1 study examining the pharmacokinetics (PK) and safety of i.v. omadacycline (100 mg) was conducted in subjects with end-stage renal disease (ESRD) on stable hemodialysis (n = 8) and in matched healthy subjects (n = 8). i.v. administration of omadacycline produced similar plasma concentration-time profiles in subjects with ESRD and healthy subjects. Further, in subjects with ESRD, similar values of the PK parameters were observed when omadacycline was administered i.v. after or before dialysis. The mean area under the concentration-time curve from time zero extrapolated to infinity in plasma was 10.30 μg · h/ml when omadacycline was administered to ESRD subjects after dialysis, 10.20 μg · h/ml when omadacycline was administered to ESRD subjects before dialysis, and 9.76 μg · h/ml when omadacycline was administered to healthy subjects. The mean maximum observed concentration of omadacycline in plasma in ESRD subjects was 1.88 μg/ml when it was administered after dialysis and 2.33 μg/ml when it was administered before dialysis, and in healthy subjects it was 1.92 μg/ml. The 100-mg i.v. dose of omadacycline was generally safe and well tolerated in both ESRD and healthy subjects. This study demonstrates that no dose adjustment is necessary for omadacycline in patients with impaired renal function or on days when patients are receiving hemodialysis.

An Open-Label Study of the Impact of Hepatic Impairment on the Pharmacokinetics and Safety of Single Oral and Intravenous Doses of Omadacycline

“…Systemically available omadacycline undergoes negligible biotransformation and is eliminated largely unchanged in feces and urine ( 15 ). Following oral administration, excretion of unabsorbed drug in feces is the predominant route of elimination of omadacycline, with approximately 14% of the total dose and 40% of the absorbed dose being excreted in urine ( 15 , 16 ). The results of this study suggest that hepatic impairment does not have a clinically relevant impact on the PK of omadacycline following oral or i.v.…”

“…Nonclinical data revealed that omadacycline is cleared hepatically (i.e., by biliary excretion) and renally ( 15 ). Clinical investigations indicate that no adjustment of the omadacycline dose is needed in patients with impaired renal function ( 16 ). The purpose of this study was to determine whether dose adjustment may be necessary for omadacycline in patients with hepatic impairment.…”

Randomized, Double-Blind, Placebo-Controlled Studies of the Safety and Pharmacokinetics of Single and Multiple Ascending Doses of Eravacycline

“…doses ( 16 – 18 ), and for omadacycline it was approximately 2.6 liters/kg after a single 100-mg i.v. dose ( 19 , 20 ). Thus, these newer compounds exhibit a more extensive tissue distribution than older tetracyclines, as exemplified by tetracycline and doxycycline with volumes of distribution of 1.3 liters/kg and 0.7 liter/kg, respectively ( 16 ).…”

Omadacycline Enters the Ring: A New Antimicrobial Contender

“…19 A phase I evaluation of 16 subjects, eight with end-stage renal disease (ESRD) and eight healthy, assessed the pharmacokinetics of omadacycline. 20 The AUC values observed were comparable between ESRD and healthy subjects, irrespective of whether the omadacycline dose was administered before or after dialysis. In addition, volume of distribution and overall clearance were comparable between the two groups, suggesting that dosage adjustments are not required for omadacycline in patients with renal dysfunction.…”

“…A phase I evaluation of 16 subjects, eight with end‐stage renal disease (ESRD) and eight healthy, assessed the pharmacokinetics of omadacycline . The AUC values observed were comparable between ESRD and healthy subjects, irrespective of whether the omadacycline dose was administered before or after dialysis.…”