1. J Antimicrob Chemother. 2018 Jun 1;73(6):1630-1638. doi: 10.1093/jac/dky078.

Temocillin dosing in haemodialysis patients based on population pharmacokinetics 
of total and unbound concentrations and Monte Carlo simulations.

Miranda Bastos AC(1)(2), Vandecasteele SJ(3), Spinewine A(2), Tulkens PM(1), Van 
Bambeke F(1).

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium.
(2)Clinical Pharmacy Research Group, Louvain Drug Research Institute, Université 
catholique de Louvain, Brussels, Belgium.
(3)Department of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge-Oostende 
AV, Bruges, Belgium.

Objectives: 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
Patients and methods: 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).
Results: 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.
Conclusions: 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.

DOI: 10.1093/jac/dky078 
PMID: 29579214