Miranda Bastos AC (1,2,3) , Vandecasteele SJ (4), Capron A (5), Tulkens PM (1,3), Spinewine A (2,3), Van Bambeke F (1,3)
(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) Center for Clinical Pharmacy, Université catholique de Louvain, Brussels, Belgium (4) Department Nephrology and Infectious Diseases, AZ Sint-Jan Brugge-Oostende AV, Bruges, Belgium (5) Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
Objectives: Temocillin is a narrow-spectrum anti-gram-negative beta-lactam antibiotic. Its pharmacokinetics in hemodialysis patients have not been investigated yet. The purpose of this study was to develop a model describing the pharmacokinetics of total and unbound temocillin serum concentrations in end stage renal disease patients undergoing hemodialysis. In addition, this study aims to evaluate by simulation, the clinical performance of current dosing regimens, considering that β-lactam efficacy is best predicted by the proportion of the dosing interval during which unbound concentrations remain above the MIC (minimal inhibitory concentration) of the offending organism.
Methods: 16 patients were administered a dose of 1, 2, or 3g of temocillin (total of 61 doses) followed by an interdialytic period (off-dialysis) of 20, 44, or 68h, respectively, and dialysis period of 4h. 429 serum samples were collected to measure total and unbound concentrations. A population PK model was constructed and evaluated by a bootstrap analysis (internal evaluation, 1000 runs) and visual predictive check. A 1000-subject Monte Carlo simulation was conducted to determine 95% probability of target attainment (PTA95) versus MIC, based on 40% time above MIC (ƒT > MIC) for measured unbound (free) drug. Data analyses were performed using NONMEM 7.3, Pirana, PsN and R.
Results: Temocillin pharmacokinetics was best described by a two-compartment model, non-linear binding to albumin (Langmuir model) and mixed order elimination. Base PK parameters were allometric weight scaled. Temocillin dialysis unbound clearance was estimated to be 6.16 L/h resulting in marked reduction of temocillin serum concentrations. PTA95 was obtained for a MIC up to 8mg/L, for a typical thrice weekly hemodialysis regimen, with temocillin administered immediately after dialysis.
Conclusions: A joint model has been developed to describe the non-linear PK of total and unbound temocillin concentrations. Once the total temocillin serum concentrations are known, the unbound concentrations, which are pharmacologically active, can be predicted. This model might serve as a useful tool to provide guidance in the optimization of temocillin dosing regimens in hemodialysis patients.
Reference: PAGE 24 () Abstr 3487 [www.page-meeting.org/?abstract=3487]
Poster: Drug/Disease modeling - Infection