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- Title
Temocillin dosing in haemodialysis patients based on population pharmacokinetics of total and unbound concentrations and Monte Carlo simulations.
- Authors
Bastos, Ana C Miranda; Vandecasteele, Stefaan J; Spinewine, Anne; Tulkens, Paul M; Bambeke, Françoise Van; Miranda Bastos, Ana C; Van Bambeke, Françoise
- Abstract
<bold>Objectives: </bold>To develop a population model describing temocillin pharmacokinetics (PK) in patients undergoing haemodialysis and investigate how pharmacokinetic/pharmacodynamic (PD) targets can be met with different dosage regimens.<bold>Patients and methods: </bold>Sixteen patients received the currently licenced dosing of 1, 2 or 3 g of temocillin (total of 61 doses) corresponding to an inter-dialytic period of 20, 44 or 68 h, respectively, and a dialysis period of 4 h. A non-linear mixed-effects model was developed jointly for total and unbound temocillin serum concentrations. The performance of clinically feasible dosing regimens was evaluated using a 5000-subject Monte Carlo (MC) simulation for determining the highest MIC for which the PK/PD target of 40%ƒT>MIC would be reached in 90% of patients [probability of target attainment (PTA)]. This PK study was registered at ClinicalTrials.gov (NCT02285075).<bold>Results: </bold>Temocillin unbound and total serum concentrations (429 samples) were used to fit an open two-compartment model with non-linear albumin binding and first-order elimination. In addition to total body clearance, dialysis clearance was modelled using the Michaels function. The currently licenced dosing achieved a 90% PTA for an MIC up to 8 mg/L. A new temocillin dosage regimen was designed that would achieve a 90% PTA for an MIC of 16 mg/L (MIC90 of target organisms) adjusted to patient weight and inter-dialytic period.<bold>Conclusions: </bold>Currently licensed dosage regimen is suboptimal for MICs >8 mg/L (frequently found in clinical isolates). Model-based simulations allowed suggestion of a new dosage regimen with improved probability of microbiological success, applicability in routine clinical practice and more appropriate for empirical therapy.
- Subjects
HEMODIALYSIS patients; PHARMACOKINETICS; MONTE Carlo method; DRUG resistance; MORTALITY; BACTEREMIA
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2018, Vol 73, Issue 6, p1630
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dky078