Population pharmacokinetics and dosing simulation of the β-lactam temocillin in liver transplanted pediatric patients

Ngougni Pokem, Perrin;Stephenne, Xavier;van der Linden, D;Godet, Marie-Laura;Van Bambeke, Françoise;et.al.
(2023) 33rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) — Location: Copenhagen, Denmark (15.April.2023)

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Populationpharmacokineticsanddosingsimulationofthebeta-lactamtemocillininliver-transplantedpediatricpatients.pdf
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Authors
  • Ngougni Pokem, PerrinUCLouvain
    Author
  • Stephenne, XavierUCLouvain
    Author
  • van der Linden, DUCLouvain
    Author
  • Godet, Marie-LauraUCLouvain
    Author
  • Wijnant, Gert-JanUCLouvain
    Author
  • Chatzis, OlgaUCLouvain
    Author
  • Hoetekie, LaurentUCLouvain
    Author
  • Haenecour, AstridUCLouvain
    Author
  • Wallemacq, PierreUCLouvain
    Author
  • Tulkens, Paul M.orcid-logoUCLouvain
    Author
  • Sokal, Etienneorcid-logoUCLouvain
    Author
  • Van Bambeke, Françoiseorcid-logoUCLouvain
    Author
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Abstract
Background Temocillin, a carbapenem-sparing β-lactam antibiotic, is useful for the empirical treatment or prophylaxis of Gram-negative bacterial infections in liver-transplanted children. Here, we characterize the total and unbound plasma pharmacokinetics (PK) of temocillin in this population, to propose optimized and personalized dosing regimens based on patient characteristics. Methods Patients aged 6-36 months received 25 mg/kg/12h (standard dose) or 25 mg/kg/8h (high dose) temocillin intravenously. Blood samples were collected after the 4th and 8th doses and temocillin concentrations in plasma were measured via a validated LC-MS/MS method. Clinical safety was monitored. Non-compartmental and population PK analyses were performed, together with Monte-Carlo simulations. Probability of target attainment (PTA) calculations were based on a PKPD target of >40% fT>MIC (% time of the dosing interval with unbound drug concentrations above the minimal inhibitory concentration) Results For 25 mg/kg/12h, Cmax and Cmin were 108 ± 22 and 8 ± 4 mg/L (total concentrations), and 38 ± 16 and 2 ± 1 mg/L (unbound concentrations), respectively. For 25 mg/kg/8h, Cmax was similar, but Cmin was increased to 22 ± 8 and 5 ± 3 mg/L for total and unbound concentrations, respectively. Temocillin PK was best described by a two-compartment model with first-order elimination, with body weight and glomerular filtration rate (GFR) as significant covariates. Monte-Carlo simulations suggested that PTA was achieved in 90% of the population for (a) MICs <8 mg/L, GFR ≤120 mL/min or weight ≥11 kg with 25 mg/kg/12h, (b) MICs <16 mg/L, GFR ≤30 mL/min or weight ≥13 kg with 25 mg/kg/8h and (c) for more elevated MICs or GFR, or lower weight, with higher simulated doses. No safety concerns were reported at the tested dose levels. Conclusions The 25 mg/kg temocillin standard dose appears appropriate in specific clinical scenarios, but the dosing interval may need o be reduced from 12 to 8 hours in patients with lower body weight, increased renal function or infections caused by less susceptible bacteria. Simulations showed that higher, off-label doses (> 25 mg/kg/8h) could further improve PK/PD target attainment, yet caution is warranted as their clinical safety remains unknown
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Ngougni Pokem, P., Stephenne, X., van der Linden, D., Godet, M.-L., Wijnant, G.-J., Chatzis, O., Hoetekie, L., Haenecour, A., Wallemacq, P., Tulkens, P. M., Sokal, E., & Van Bambeke, F. (2023). Population pharmacokinetics and dosing simulation of the β-lactam temocillin in liver transplanted pediatric patients. 33rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Copenhagen, Denmark. https://hdl.handle.net/2078.5/101753