Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups

Clinical and Translational Science
Jianguo LiShampa Das

Abstract

Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady-state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure-microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime-avibactam dosage regimens (2000-500 mg every 8 hours, adjust...Continue Reading

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Citations

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Methods Mentioned

BETA
urine collection

Clinical Trials Mentioned

NCT01291602
NCT01430910
NCT01920399
NCT01499290
NCT01500239
NCT01726023
NCT01644643
NCT01595438
NCT01599806
NCT01808092

Software Mentioned

NONMEM )
REPROVE
REPRISE
speaks
Perl
RECLAIM
PopPK
NONMEM
RECAPTURE

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