Abstract
Background
Eravacycline (ERV) is a fluorocycline being developed for the treatment of serious infections, including those caused by multidrug-resistant pathogens. The PK of ERV in subjects with end stage renal disease (ESRD) or hepatic impairment (HI) were investigated.
Methods
Two multi-center studies were completed; one in subjects with ESRD and one in subjects with mild, moderate or severe HI based upon Child-Pugh scoring. Each included a cohort of healthy subjects (HS) matched by gender, age and BMI. A single IV dose of 1.5 mg/kg ERV was administered. PK parameters were calculated using standard non-compartmental methods and within study comparisons of PK for the ESRD and HI subjects were made with HS.
Results
The following comparative AUCinf and Cmax values for ERV were observed:
Conclusion
Following a single IV dose of ERV, the systemic exposures in subjects with ESRD and mild or moderate hepatic impairment were similar to those observed in HS. The 2-fold increase in AUCinf observed in subjects with severe HI did not result in increased adverse events. Therefore, no dose adjustment should be required when ERV is given to subjects with either renal or hepatic impairment.
Funded in whole or in part with Federal funds from the Biomedical Advanced Research and Development Authority, Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, Department of Health and Human Services, under Contract No HHSO100201200002C.
Disclosures
P. Horn, Tetraphase Pharmaceuticals: Employee, Salary; S. Redican, Tetraphase Pharmaceuticals: Employee, Salary; M. Olesky, Tetraphase Pharmaceuticals: Employee, Salary.
| Subjects Status (n) | Ratio of geometric LS, Mean (%) | 90% CI for ratio (%) | Intra- subject CV (%) | ||
|---|---|---|---|---|---|
| ESRD | AUC0-inf (ng*hours/ mL/kg) | ESRD (6) vs. HS (6) | 96 | (82, 112) | 15 |
| Cmax (ng/mL) | ESRD (6) vs. HS (6) | 109 | (82, 145) | 28 | |
| HI | AUC0-inf (ng*hours/ mL/kg) | Mild (4) vs. HS (5) | 123 | (84, 180) | 34 |
| Moderate (5) vs. HS (5) | 138 | (96, 198) | 34 | ||
| Severe (6) vs. HS (5) | 210 | (149, 297) | 34 | ||
| Cmax (ng/mL) | Mild (6) vs. HS (6) | 114 | (89, 145) | 25 | |
| Moderate (6) vs. HS (6) | 116 | (91, 148) | 25 | ||
| Severe (6) vs. HS (6) | 120 | (94, 153) | 25 | ||
For all groups, except severe HI, the 90% CI for the ratio of AUCinf and Cmax compared with HS contains 100%, indicating similar exposures. For subjects with severe HI, Cmax was similar to that in HS while AUCinf was about 2-fold higher. ERV was well tolerated with 2 or fewer subjects in any group reporting drug-related adverse events (1 subject with severe HI).