Ceftolozane-Tazobactam Population Pharmacokinetics and Dose Selection for Further Clinical Evaluation in Pediatric Patients with Complicated Urinary Tract or Complicated Intra-abdominal Infections

Abstract

Ceftolozane-tazobactam, a combination of the novel antipseudomonal cephalosporin ceftolozane and the well-established extended-spectrum ␤-lactamase inhibitor tazobactam, is approved for treating complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI) in adults. To determine doses likely to be safe and efficacious in phase 2 pediatric trials for the same indications, single-dose ceftolozane-tazobactam plasma pharmacokinetic data from a recently completed phase 1 trial in pediatric patients (birth to Ͻ18 years old) with proven/suspected Gram-negative bacterial infections, along with pharmacokinetic data from 12 adult studies, were integrated into a population pharmacokinetic (popPK) analysis. Two-compartment linear models with first-order elimination described the concentration-time profiles of ceftolozane and tazobactam in pediatric patients well. Renal function and body weight were identified to be significant predictors of ceftolozane-tazobactam pharmacokinetics. Renal function, as measured by the estimated glomerular filtration rate (eGFR), significantly affected the clearance of both ceftolozane and tazobactam. Body weight significantly affected clearance and the distribution volume, also of both ceftolozane and tazobactam. Patients with infections had a 32.3% lower tazobactam clearance than healthy volunteers. Using the final popPK models, simulations of various dosing regimens were conducted to assess each regimen's plasma exposure and the probability of pharmacokinetic/pharmacodynamic target attainment. Based on these simulations, the following doses are recommended for further clinical evaluation in phase 2 pediatric trials for cUTI and cIAI (in patients with an eGFR of Ն50 ml/min/1.73 m 2 only): for children Ն12 years old, 1.5 g ceftolozane-tazobactam (1 g ceftolozane with 0.5 g tazobactam), and for neonates/very young infants, infants, and children Ͻ12 years old, 20/10 mg/kg of body weight ceftolozane-tazobactam, both via a 1-h intravenous infusion every 8 h.

Population Pharmacokinetics of Unbound Ceftolozane and Tazobactam in Critically Ill Patients without Renal Dysfunction

“…In addition, we determined the PTA for a higher exposure of 60% f T >MIC , which is generally considered optimal for cephalosporins (41), and a more aggressive exposure of 100% f T >MIC , which is advocated as a prudent target for severely ill patient populations (10). For tazobactam, we used a 20% f T >1mg/liter (20% of the time above the minimum effective concentration of 1 mg/liter) as a target for assessment of dosing adequacy as previously suggested based on data from preclinical studies (26, 27, 42).…”

Population Pharmacokinetic Analysis for Plasma and Epithelial Lining Fluid Ceftolozane/Tazobactam Concentrations in Patients With Ventilated Nosocomial Pneumonia

“…Similarly, tazobactam was administered alone or in combination with ceftolozane as a single 1‐hour intravenous infusion. Ceftolozane and tazobactam concentrations in plasma and ELF samples were determined using validated liquid chromatography‐mass spectrometry assays 21,25 . Samples with missing concentration data (<0.15%) were excluded from the analysis.…”

Carbapenem-Resistant Gram-Negative Bacterial Infections in Children

“…The doses evaluated yielded exposure levels generally comparable to those previously observed in adults. This dosage was included in two phase II clinical trials in a pediatric population, demonstrating the safety and efficacy of ceftolozane-tazobactam for the treatment of complicated UTIs (cUTIs) and cIAIs (88). Furthermore, a new clinical trial, awaiting the start of recruitment, will evaluate the pharmacokinetics and safety of ceftolozane-tazobactam in neonates and infants (https://clinicaltrials.gov/ct2/show/NCT04126031).…”