Target attainment and population pharmacokinetics of flucloxacillin in critically ill patients: a multicenter study.

PURPOSE: Insufficient antimicrobial exposure has been associated with worse clinical outcomes. Reportedly, flucloxacillin target attainment in critically ill patients was heterogeneous considering the study population selection and reported target attainment percentages. Therefore, we assessed flucloxacillin population pharmacokinetics (PK) and target attainment in critically ill patients. METHODS: This prospective, multicenter, observational study was conducted from May 2017 to October 2019 and included adult, critically ill patients administered flucloxacillin intravenously. Patients with renal replacement therapy or liver cirrhosis were excluded. We developed and qualified an integrated PK model for total and unbound serum flucloxacillin concentrations. Monte Carlo dosing simulations were performed to assess target attainment. The unbound target serum concentration was four times the minimum inhibitory concentration (MIC) for ≥ 50% of the dosing interval (ƒT>4xMIC ≥ 50%). RESULTS: We analyzed 163 blood samples from 31 patients. A one-compartment model with linear plasma protein binding was selected as most appropriate. Dosing simulations revealed 26% ƒT>2 mg/L ≥ 50% following continuous infusion of 12 g flucloxacillin and 51% ƒT>2 mg/L ≥ 50% for 24 g. CONCLUSION: Based on our dosing simulations, standard flucloxacillin daily doses of up to 12 g may substantially enhance the risk of underdosing in critically ill patients. Prospective validation of these model predictions is needed.

Population pharmacokinetics of unbound ceftriaxone in a critically ill population.

OBJECTIVE: To develop a reliable 2-compartment population pharmacokinetic (PK) model for unbound ceftriaxone in a critically ill population and determine an optimal dosing regimen. MATERIALS AND METHODS: This was a prospective, single-center, observational study of critically ill patients treated with ceftriaxone. Unbound serum ceftriaxone concentrations were measured using validated ultrafiltration and ultra-performance liquid chromatography-tandem mass spectrometry. PK analysis and dosing simulations were performed using an iterative 2-stage Bayesian fitting procedure and Monte Carlo simulations. The PK/pharmacodynamics (PD) target was attained when unbound serum ceftriaxone concentrations exceeded 4 times the minimum inhibitory concentration (MIC) for ≥ 60% of the dosing interval (ƒT>4xMIC ≥ 60%). RESULTS: 91 patients were enrolled, and 173 unbound ceftriaxone concentrations were acquired. The population PK parameter estimates were hepatic clearance 5.2 ± 0.9 L/h/1.85m2, the unbound renal clearance of ceftriaxone divided by the creatinine clearance 0.61 ± 0.24, lean body mass corrected volume of distribution of the central compartment 0.82 ± 0.21 L/kg, and intercompartmental distribution rate constant from central to peripheral compartment 0.18 ± 0.08 h-1. Dosing simulations predicted ƒT>4 mg/L of 88% (95% CI: 69 - 100%) for 2,000 mg ceftriaxone once daily and ƒT>4 mg/L of 100% (95% CI: 100 - 100%) both for 1,000 mg twice daily and continuous infusion of 2,000 mg daily. CONCLUSION: We developed a reliable population PK model for unbound ceftriaxone in a critically ill population. Dosing simulations revealed ƒT>4 mg/L ≥ 60% for 1,000 mg twice daily and 2,000 mg once daily or by continuous infusion.

Drug switching in the Netherlands: a cohort study of 20 active substances.

BACKGROUND: For a patient, drug switches are not desirable (either between a brand-name drug and a generic drug, or between two generic drugs of the same active substance). Research into the causes of drug switches, and related adverse drug reactions, is hampered by the absence of quantitative data on drug switches. METHODS: We describe the frequency of drug switches in the Netherlands for a selection of active substances. A retrospective cohort study was conducted using the Drug Information System of the National Health Care Institute in the Netherlands. We studied the Dutch patient population from mid-2009 to 2016. The selection of active substances (n = 20) was made based on a report by Lareb, the Netherlands Pharmacovigilance Centre, on adverse drug reactions related to drug switching, and we used qualitative and quantitative descriptive analyses. A drug switch is defined as the replacement of a patient's prescribed drug with a similar drug from a different manufacturer. RESULTS: We identified 23.8 million drug switches on a total of 206 million (11.6%) similar drug dispenses. The frequency of drug switches demonstrated a yearly peak in the period from January to March. In some months, for atorvastatin, losartan, pantoprazole, and irbesartan, more than 60% of similar drug dispenses were drug switches. Most drug switches (80.3%) were between two generic drugs, and 0.12% of these involved a drug from a European parallel import. The proportion of drug switches between two brand-name drugs decreased from 14.5 to 5.53% during our study period, and of these, 86.5% involved a drug from a European parallel import. CONCLUSIONS: Drug switching is common in the Netherlands, and most of the drug switches we studied are between generic drugs. The observed annual peak of drug switches is most likely explained by a specific Dutch reimbursement policy. Not only are the data valuable as is, but they also serve as a first step towards elucidating the reasons for the occurrence of these drug switches. In addition, these data can be used to put into perspective the adverse drug reactions associated with drug switching.

Quantification of Adverse Drug Reactions Related to Drug Switches in The Netherlands.

We performed a retrospective cohort study in the Dutch patient population to identify active substances with a relatively high number of adverse drug reactions (ADRs) potentially related to drug switching. For this, we analyzed drug switches and reported ADRs related to switching between June 1, 2009, and December 31, 2016, for a selection of 20 active substances. We also compared pharmacovigilance analyses based on the absolute, switch-corrected, and user-corrected numbers of ADRs. In total, 1,348 reported ADRs and over 23.8 million drug switches were obtained from the National Health Care Institute in The Netherlands and from Lareb, which is The Netherlands Pharmacovigilance Centre. There was no correlation between the number of ADRs and the number of switches, but, on average, we found 5.7 reported ADRs per 100,000 switches. The number was relatively high for rivastigmine, levothyroxine, methylphenidate, and salbutamol, with 74.9, 50.9, 47.6, and 26.1 ADRs per 100,000 switches, respectively. When comparing analyses using the absolute number and the switch-corrected number of ADRs, we demonstrate that different active substances would be identified as having a relatively high number of ADRs, and different time periods of increased numbers of ADRs would be observed. We also demonstrate similar results when using the user-corrected number of ADRs instead of the switch-corrected number of ADRs, allowing for a more feasible approach in pharmacovigilance practice. This study demonstrates that pharmacovigilance analyses of switch-related ADRs leads to different results when the number of reported ADRs is corrected for the actual number of drug switches.

Antimicrobial resistance (AMR).

The position paper of the European Association of Hospital Pharmacists (EAHP) highlights the importance of the prudent use of antimicrobial drugs through antibiotic stewardship to ensure efficient therapy for patients with life-threatening infections. EAHP calls on national governments and health system managers to utilise the specialised background and knowledge of the hospital pharmacist in multi-professional antibiotic stewardship teams. In addition, the paper recommends the universal application of infection prevention and control measures among healthcare professionals. Due to the lack of funding, EAHP urges increased investment to support the development of innovative proposals and the encouragement of practice-based research projects to investigate new fields of infectious disease control such as immunotherapy and to optimise the cost-effectiveness of systems for surveillance on antibiotic use and resistance. In relation to the 'One Health approach' of the European Commission, EAHP strongly supports regulatory oversight and proper implementation of measures in the veterinary and agriculture sectors at European, national and local level.

Population Pharmacokinetics of Cefuroxime in Critically Ill Patients Receiving Continuous Venovenous Hemofiltration With Regional Citrate Anticoagulation and a Phosphate-Containing Replacement Fluid.

BACKGROUND: Cefuroxime is frequently prescribed as an antimicrobial therapy in critically ill patients. The aim of this study was to develop a new intravenous dosing strategy for cefuroxime in critically ill patients undergoing continuous venovenous hemofiltration with regional citrate anticoagulation (RCA-CVVH) by analyzing its extracorporeal removal and pharmacokinetic (PK) parameters. METHODS: Nine critically ill patients treated with intravenous cefuroxime and RCA-CVVH and a phosphate-containing replacement fluid were investigated. Arterial and effluent samples were obtained from all patients and pre- and postfilter venous blood samples were obtained from a subgroup of 5 patients. Plasma cefuroxime levels were determined by ultraperformance liquid chromatography-mass spectrometry in plasma samples collected before and after intravenous infusion of either 1500 mg cefuroxime every 12 hours or 3000 mg continuously over 24 hours. Population PK analysis and dosing simulations were performed using nonlinear mixed-effects modeling and Monte Carlo simulations. RESULTS: The volume of distribution (VD) of cefuroxime in the central compartment, corrected for lean body mass, was 0.11 ± 0.056 L/kgLBMc, CVVH-mediated clearance was 49.5-50.6 mL/min, the mean elimination half-life (t½) was 90 minutes (77-103), and the mean sieving coefficient was 0.89 ± 0.01. A 2-compartment model with between-subject variability in clearance, VD, and t½ described these data adequately. Simulation of a standard dosing regimen (750 mg/12 hours) predicted failure to achieve the international target plasma cefuroxime concentration (32 mg/L). CONCLUSIONS: Cefuroxime clearance by RCA-CVVH was twice the reported clearance during standard CVVH. Our PK data predicted that a maintenance dose of 3000 mg cefuroxime, infused over 24 hours, would provide an optimal steady-state plasma concentration of 38.5 mg/L. The developed population PK model for cefuroxime has the potential to inform new dosing schedules in patients receiving cefuroxime during RCA-CVVH.

Development of a pharmacokinetic model of mitotane: toward personalized dosing in adrenocortical carcinoma.

BACKGROUND: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy. METHODS: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients. RESULTS: The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 ± 0.37 L/h and a volume of distribution in the steady state at 161 ± 68 L/kg of lean body mass. The mean prediction error was 14% ± 13%. CONCLUSIONS: A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.