Temocillin dosing in haemodialysis patients based on population pharmacokinetics of total and unbound concentrations and Monte Carlo simulations. (22nd March 2018)

• Record Type: Journal Article
• Authors: Miranda Bastos, Ana C; Vandecasteele, Stefaan J; Spinewine, Anne; Tulkens, Paul M; Van Bambeke, Françoise
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 73:Number 6(2018)
• Page Start: 1630
• Page End: 1638
• Publication Date: 2018-03-22
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dky078
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: 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 regimens. 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%ƒ T >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.