Miranda Bastos AC (1,2) , Vandecasteele SJ (3), Capron A (4), Tulkens PM (1), Spinewine A (2), Van Bambeke F (1)
(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 Nephrology and Infectious Diseases, AZ Sint-Jan Brugge-Oostende AV, Bruges, Belgium (4) Department of Clinical Chemistry, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
Objectives: Temocillin is an anti-Gram-negative β-lactam active against many ESBL-producing Enterobacteriaceae but with limited population pharmacokinetics data on patients undergoing haemodialysis. The purpose of this study was to develop a joint PK model of total and unbound temocillin serum concentrations in this patient population. In addition, this model was used to design and evaluate a dosing regimen aiming at a 90% probability of target attainment, i.e. unbound concentrations at least 40% of the dosing interval above the largest minimal inhibitory concentration (40%ƒT > MIC) of the main susceptible organisms (< 16mg/L).
Methods: 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. A nonlinear mixed effects model was fitted, taking both total and unbound temocillin concentrations into account. The model was evaluated by bootstrap analysis and prediction-corrected visual predictive check. 10,000-subject Monte Carlo simulation was conducted to determine the required dose to achieve 90% probability of target attainment over a wide range of patients’ weights (50-100kg). These simulations also investigated the performance of various clinically feasible dosing regimens. Data analyses were performed using NONMEM 7.3, Pirana, PsN and R.
Results: A total of 429 serum samples was collected from 16 end-stage renal disease patients. An open two-compartment model with non-linear binding to albumin (Langmuir model) and mixed order elimination, best characterized the profiles of temocillin concentrations over time. Weight on clearance and volume of distribution parameters using allometric scaling improved the fit. The mean and between-patient variability for central volume of distribution were 22.7L/70kg (38.1%). Vmax for elimination was estimated to be 411mg/h/70kg, whilst the Km was 253mg/L. Model-based simulations suggested a new temocillin dosing regimen, according to patient weight and the interdialytic period, which maintains drug concentrations over a MIC of 16 mg/L for at least 40 % of the dosing interval.
Conclusions: A joint PK model describes the time course of temocillin in patients undergoing haemodialysis. Modeling and simulation of temocillin PK suggest that administration of standard doses are likely to result in underdosing. A new dosing regimen has been developed to more consistently achieve PKPD targets.
Reference: PAGE 25 () Abstr 5895 [www.page-meeting.org/?abstract=5895]
Poster: Drug/Disease modeling - Infection