Pharmacokinetics of Ceftazidime-Avibactam in Combination with Aztreonam (COMBINE) in a Phase 1, Open-Label Study of Healthy Adults.
2022 Dec 20
Journal Article
Authors:
Lodise, T.P.;
O'Donnell, N.;
Balevic, S.;
Liu, X.;
Gu, K.;
George, J.;
Raja, S.;
Guptill, J.T.;
Zaharoff, S.;
Schwager, N.;
Fowler, V.G.;
Wall, A.;
Wiegand, K.;
Chambers, H.F.
Secondary:
Antimicrob Agents Chemother
Volume:
66
Pagination:
e0093622
Issue:
12
PMID:
36394326
URL:
https://pubmed.ncbi.nlm.nih.gov/36394326/
Keywords:
Adult; Anti-Bacterial Agents; Azabicyclo Compounds; Aztreonam; beta-Lactamase Inhibitors; Ceftazidime; Drug Combinations; Humans; Microbial Sensitivity Tests
Abstract:
Scant pharmacokinetic (PK) data are available on ceftazidime-avibactam (CZA) and aztreonam (ATM) in combination, and it is unknown if CZA-ATM exacerbates alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations relative to ATM alone. This phase 1 study sought to describe the PK of CZA-ATM and assess the associations between ATM exposures and ALT/AST elevations. Subjects ( = 48) were assigned to one of six cohorts (intermittent infusion [II] CZA, continuous infusion [CI] CZA, II ATM, CI ATM [8 g/daily], II CZA with II ATM [6 g/daily], and II CZA with II ATM [8 g/daily]), and study product(s) were administered for 7 days. A total of 19 subjects (40%) had ALT/AST elevations, and most (89%) occurred in the ATM/CZA-ATM cohorts. Two subjects in the CI ATM cohort experienced severe ALT/AST elevations, which halted the study. All subjects with ALT/AST elevations were asymptomatic with no other signs of liver injury, and all ALT/AST elevations resolved without sequalae after cessation of dosing. In the population PK (PopPK) analyses, CZA-ATM administration reduced total ATM clearance by 16%, had a negligible effect on total ceftazidime clearance, and was not a covariate in the avibactam PopPK model. In the exposure-response analyses, coadministration of CZA-ATM was not found to augment ALT/AST elevations. Modest associations were observed between ATM exposure (maximum concentration of drug in serum [] and area under the concentration-time curve [AUC]) and ALT/AST elevations in the analysis of subjects in the II ATM/CZA-ATM cohorts. The findings suggest that administration of CZA-ATM reduces ATM clearance but does not exacerbate AST/ALT elevations relative to ATM alone. The results also indicate that CI ATM should be used with caution.
