Treating infections with ceftolozane/tazobactam in subjects having impaired renal function
Inventors
Krishna, Gopal • Chandorkar, Gurudatt • Hershberger, Elham • Miller, Benjamin • Xiao, Alan
Assignees
Cubist Pharmaceuticals LLC • Merck Sharp and Dohme LLC • Calixa Therapeutics Inc
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Publication Number
US-10376496-B2
Publication Date
2019-08-13
Expiration Date
Abstract
Disclosed are methods of administering cephalosporin/tazobactam to human patients with end stage renal disease undergoing hemodialysis and suffering from a complicated intra-abdominal infection or a complicated urinary tract infection.
Core Innovation
The disclosed work characterizes ceftolozane/tazobactam population pharmacokinetics in end stage renal disease patients on hemodialysis, using population PK and Monte Carlo probability of target attainment (PTA)/safety analyses. The analysis evaluates the impact of hemodialysis as a covariate on pharmacokinetic parameters and models drug behavior with a two-compartment approach.
Hemodialysis is described as covariately increasing ceftolozane clearance and apparent volume of distribution in the central compartment, with rapid removal and rebound, and similarly increasing tazobactam clearance and apparent volume of distribution in the central compartment. The analysis reports markedly longer ceftolozane terminal half-life in ESRD patients relative to normal renal function.
Based on the model and Monte Carlo simulation, the work simulates ceftolozane/tazobactam loading and maintenance regimens and identifies an intravenous dosing approach involving a single loading dose followed by maintenance doses about every 8 hours. The analysis concludes that the recommended regimen yields high PTA for ceftolozane against MIC up to 8 mg/L while maintaining acceptable tazobactam exposure/AUC within safety limits, with reduced residual accumulation due to hemodialysis removal.
Claims Coverage
The consolidated claim coverage identifies one independent treatment claim with four inventive features, centered on a specific ceftolozane/tazobactam loading and maintenance regimen for a human patient with end stage renal disease on hemodialysis and complicated intra-abdominal infection or complicated urinary tract infection, including specified microorganism limitations.
Complicated infection treatment in ESRD on hemodialysis
A method of treating a complicated intra-abdominal infection or a complicated urinary tract infection in a human patient with end stage renal disease on hemodialysis.
Single loading dose of fixed ceftolozane/tazobactam actives
Administering a single loading dose comprising ceftolozane active and tazobactam active providing 500 mg ceftolozane active and 250 mg tazobactam active.
Maintenance dosing about every 8 hours with fixed actives
Administering maintenance doses providing 100 mg ceftolozane active and 50 mg tazobactam active, delivered intravenously about every 8 hours.
Defined microorganism causative agents for cIAI and cUTI
The complicated intra-abdominal infection or complicated urinary tract infection is caused by one or more microorganisms selected from the specified microorganism sets.
Overall, the claim coverage centers on the specified ceftolozane/tazobactam loading and maintenance regimen for end stage renal disease patients on hemodialysis, delivered intravenously about every 8 hours, and applied to complicated intra-abdominal and/or complicated urinary tract infections caused by the explicitly listed microorganism sets.
Stated Advantages
Provides high probability of target attainment (PTA) for ceftolozane against MIC up to 8 mg/L.
Maintains acceptable tazobactam exposure/AUC within safety limits, while limiting residual accumulation due to hemodialysis removal.
Documented Applications
Treating a complicated intra-abdominal infection in a human patient with end stage renal disease on hemodialysis.
Treating a complicated urinary tract infection in a human patient with end stage renal disease on hemodialysis.
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