Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity.

Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI >30 kg/m2) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC >125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (P < .001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI >60 mL/min/1.73 m2 may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.

Evaluation of the drug-drug interaction between triazole antifungals and cystic fibrosis transmembrane conductance regulator modulators in a real-life cohort.

Limited data on the clinical management of drug-drug interactions between triazoles and Cystic Fibrosis transmembrane conductance regulator (CFTR) modulators are available. We retrospectively evaluated azole target attainment and dose adaptations in patients from two Dutch CF centres concomitantly receiving triazoles and CFTR modulators. In total, 21 patients with 59 triazole trough concentrations were evaluated. Subtherapeutic concentrations were frequently observed, especially for itraconazole and voriconazole. Of the investigated antifungal agents, posaconazole appears the most preferable option. Our results emphasize the importance of adequate management of this interaction and underpin the added value of therapeutic drug monitoring of triazoles in this population.

Fungal infections are serious complications in Cystic Fibrosis (CF) patients. We evaluated patients concomitantly receiving triazoles and CF transmembrane conductance regulator modulators: subtherapeutic triazole exposure was frequently observed. Posaconazole appears the preferable antifungal agent.

Personalized Antifungal Therapy Through Model-Informed Precision Dosing of Posaconazole.

BACKGROUND AND OBJECTIVE: Posaconazole is a pharmacotherapeutic pillar for prophylaxis and treatment of invasive fungal diseases. Dose individualization is of utmost importance as achieving adequate antifungal exposure is associated with improved outcome. This study aimed to select and evaluate a model-informed precision dosing strategy for posaconazole. METHODS: Available population pharmacokinetic models for posaconazole administered as a solid oral tablet were extracted from the literature and evaluated using data from a previously published prospective study combined with data collected during routine clinical practice. External evaluation and selection of the most accurate and precise model was based on graphical goodness-of-fit and predictive performance. Measures for bias and imprecision included mean percentage error (MPE) and normalized relative root mean squared error (NRMSE), respectively. Subsequently, the best-performing model was evaluated for its a posteriori fit-for-purpose and its suitability in a limited sampling strategy. RESULTS: Seven posaconazole models were evaluated using 764 posaconazole plasma concentrations from 143 patients. Multiple models showed adequate predictive performance illustrated by acceptable goodness-of-fit and MPE and NRMSE below ± 10% and ± 25%, respectively. In the fit-for-purpose analysis, the selected model showed adequate a posteriori predictive performance. Bias and imprecision were lowest in the presence of two prior measurements. Additionally, this model showed to be useful in a limited sampling strategy as it adequately predicted total posaconazole exposure from one (non-)trough concentration. CONCLUSION: We validated an MIPD strategy for posaconazole for its fit-for-purpose. Thereby, this study is an important first step towards MIPD-supported posaconazole dosage optimization with the goal to improve antifungal treatment in clinical practice.

Development and validation of an UPLC-MS/MS assay for the simultaneous quantification of seven commonly used antibiotics in human plasma and its application in therapeutic drug monitoring.

OBJECTIVE: To develop and validate an UPLC-MS/MS assay for simultaneous determination of the total concentration of ceftazidime, ciprofloxacin, flucloxacillin, piperacillin, tazobactam, sulfamethoxazole, N-acetyl sulfamethoxazole and trimethoprim, and the protein-unbound concentration of flucloxacillin, in human plasma to be used for research and clinical practice. METHODS: Sample pretreatment included protein precipitation with methanol. For the measurement of protein-unbound flucloxacillin, ultrafiltration was performed at physiological temperature. For all compounds, a stable isotopically labelled internal standard was used. Reliability of the results was assessed by participation in an international quality control programme. RESULTS: The assay was successfully validated according to the EMA guidelines over a concentration range of 0.5-100 mg/L for ceftazidime, 0.05-10 mg/L for ciprofloxacin, 0.4-125 mg/L for flucloxacillin, 0.2-60 mg/L for piperacillin, 0.15-30 mg/L for tazobactam, 1-200 mg/L for sulfamethoxazole and N-acetyl sulfamethoxazole, 0.05-10 mg/L for trimethoprim and 0.10-50 mg/L for unbound flucloxacillin. For measurement of total concentrations, the within- and between-day accuracy ranged from 90.0% to 109%, and 93.4% to 108%, respectively. Within- and between-day precision (variation coefficients, CVs) ranged from 1.70% to 11.2%, and 0.290% to 5.30%, respectively. For unbound flucloxacillin, within-day accuracy ranged from 103% to 106% and between-day accuracy from 102% to 105%. The within- and between-day CVs ranged from 1.92% to 7.11%. Results of the international quality control programme showed that the assay is reliable. CONCLUSIONS: The method provided reliable, precise and accurate measurement of seven commonly prescribed antibiotics, including the unbound concentration of flucloxacillin. This method is now routinely applied in research and clinical practice.

How to Dose Vancomycin in Overweight and Obese Patients with Varying Renal (Dys)function in the Novel Era of AUC 400-600 mg·h/L-Targeted Dosing.

BACKGROUND AND OBJECTIVE: The latest vancomycin guideline recommends area under the curve (AUC)-targeted dosing and monitoring for efficacy and safety. However, guidelines for AUC-targeted starting dosing in patients with obesity and/or renal insufficiency are currently lacking. This study quantifies the pharmacokinetics (PK) of vancomycin in this population and provides AUC-targeted dosing recommendations. METHODS: Vancomycin concentrations (n = 1188) from therapeutic drug monitoring of 210 overweight and obese patients with varying degrees of renal (dys)function from the ward (74.8%) and intensive care unit (ICU, 25.2%) were pooled with published rich concentration-time data (n = 207) from 20 (morbidly) obese subjects undergoing bariatric surgery. A population model was developed using NONMEM 7.4. Stochastic simulations were performed to design dosing guidelines targeting an AUC24 between 400-600 mg·h/L. RESULTS: Vancomycin clearance (CL) was found to increase linearly with total bodyweight and with renal function (CKD-EPI) in a power relation. Additionally, CL proved 15.5% lower in ICU patients. Our model shows that, to reach the target AUC between 400 and 600 mg·h/L in the first 48 h, two loading doses are required for both continuous infusion and intermittent dosing regimens. Maintenance doses were found to require adjustment for total bodyweight, renal function, and ICU admission status. With this guideline, the median AUC24 is well within the target from the start of the treatment onwards. CONCLUSIONS: To achieve safe and effective vancomycin exposure for maintenance doses in overweight and obese patients, renal function, total bodyweight, and ICU admission status should be taken into account. TRIAL REGISTRATION: The AMIGO trial was registered in the Dutch Trial Registry [NTR6058].

Meta-pharmacokinetic analysis of posaconazole following dosing of oral suspension, delayed-release tablet, and intravenous infusion in patients vs. healthy volunteers: Impact of clinical characteristics and race.

OBJECTIVES: To investigate the potential impact of clinical characteristics and the Chinese race on posaconazole pharmacokinetics in patients using an integrated population pharmacokinetic model for posaconazole oral suspension (SUS), delayed-release tablet (DR-tablet), and intravenous (IV) infusion that was developed in healthy volunteers (HV). METHODS: 1046 concentrations from 105 prospectively studied Caucasian patients receiving either of the three posaconazole formulations were pooled with 3898 concentrations from 182 HV. Clinical characteristics were tested for significance. The impact of Chinese race was assessed using 292 opportunistic samples from 80 Chinese patients receiving SUS. RESULTS: Bioavailability of SUS (Fsus) in patients decreased from 38.2% to 24.6% when the dose was increased from 100 mg to 600 mg. Bioavailability of DR-tablet (Ftab) was 59% regardless of dose. Mucositis, diarrhoea, administration through a nasogastric tube, and concomitant use of proton pump inhibitors or metoclopramide reduced Fsus by 61%, 36%, 44%, 48%, and 29%, respectively, putting patients with these characteristics at increased risk of inadequate exposure. Clearance decreased from 7.0 to 5.1 L/h once albumin levels were <30 g/L. Patients showed an 84.4% larger peripheral volume of distribution (Vp) and 67.5% lower intercompartmental clearance (Q) compared with HV. No racial difference could be identified. CONCLUSIONS: Pharmacokinetics of posaconazole in patients differ considerably to those in HV, with altered Fsus that is also impacted by clinical covariates, an Ftab similar to fasted conditions in HV, and altered parameters for clearance, Vp, and Q. There was no evidence to indicate that Chinese patients require a different dose to Caucasian patients.

High Variability in Isavuconazole Unbound Fraction in Clinical Practice: A Call to Reconsider Pharmacokinetic/Pharmacodynamic Targets and Breakpoints.

Isavuconazole exposure-response relationships have been studied with a focus on total rather than unbound exposure, assuming a constant unbound fraction of 1%. We observed a median (range) unbound fraction of 1.59% (0.42-5.30%) in patients. This highly variable protein binding asks for re-evaluation of current pharmacokinetic and pharmacodynamic targets for isavuconazole.

A protocol for an international, multicentre pharmacokinetic study for Screening Antifungal Exposure in Intensive Care Units: The SAFE-ICU study.

Objective: To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate antifungal therapy is a key determinant of survival of critically ill patients with fungal infections. Critical illness can alter an antifungal agents' pharmacokinetics, increasing the risk of inappropriate antifungal exposure that may lead to treatment failure and/or toxicity. Design setting and participants: This international, multicentre, observational pharmacokinetic study will comprise adult critically ill patients prescribed antifungal agents including fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, micafungin, anidulafungin, and amphotericin B for the treatment or prophylaxis of invasive fungal disease. A minimum of 12 patients are targeted for enrolment for each antifungal agent, across 12 countries and 30 intensive care units to perform descriptive pharmacokinetics. Pharmacokinetic sampling will occur during two dosing intervals (occasions): firstly, between days 1 and 3, and secondly, between days 4 and 7 of the antifungal course, collecting three samples per occasion. Patients' demographic and clinical data will be collected. Main outcome measures: The primary endpoint of the study is attainment of pharmacokinetic/pharmacodynamic target exposures that are associated with optimal efficacy. Thirty-day mortality will also be measured. Results and conclusions: This study will describe whether contemporary antifungal drug dosing achieves drug exposures associated with optimal outcomes. Data will also be used for the development of antifungal dosing algorithms for critically ill patients. Optimised drug dosing should be considered a priority for improving clinical outcomes for critically ill patients with fungal infections.

Pharmacokinetic investigations of isavuconazole in paediatric cancer patients show reduced exposure of isavuconazole after opening capsules for administration via a nasogastric tube.

OBJECTIVES: To study the isavuconazole pharmacokinetics in a real-life paediatric cohort and confirm whether the isavuconazole exposures are within the adult exposure range. Furthermore, we are the first to describe unbound isavuconazole pharmacokinetics. METHODS: In this prospective, observational study, the isavuconazole dosing regimen was as follows (IV/oral/nasogastric tube): 5.4 mg/kg isavuconazole (maximum 200 mg/dose) three times daily on Days 1 and 2, followed by 5.4 mg/kg isavuconazole (maximum 200 mg/dose) once daily. At least one pharmacokinetic curve was assessed. Non-linear mixed effects modelling was used for analysis. Monte Carlo simulations were performed with the above mentioned maintenance dose for IV administrations and a weight band dosing regimen for oral/nasogastric tube administrations: I) <18 kg (100 mg daily); II) 18-37 kg (150 mg daily); III)>37 kg (200 mg daily). RESULTS: Seventeen paediatric patients with a median age of 9 years (range 1-17) and median weight of 26.0 kg (range 8.4-78.5) were evaluated. A two-compartment model describing linear pharmacokinetics of the unbound concentrations and saturable protein binding fitted the isavuconazole concentrations best. The absolute bioavailability of isavuconazole was 41.0% (95% CI: 32.4%-50.8%). The median (IQR) simulated exposures (AUC0-24h, SS) of the total isavuconazole concentrations after IV and oral/nasogastric tube administration were 87.7 mg·h/L (70.5-105.1) and 50.3 mg·h/L (39.0-62.4), respectively. The unbound isavuconazole fraction (unbound/total) ranged from 0.5% to 2.3%. CONCLUSIONS: This study revealed low bioavailability after nasogastric tube administration with opened capsules. Isavuconazole exposures were in the expected range following IV administration. Total and unbound isavuconazole pharmacokinetics were reported with a 5-fold range in the unbound fraction.

Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies.

BACKGROUND AND OBJECTIVES: Isavuconazole is a broad-spectrum antifungal agent for the management of invasive fungal disease. Optimised drug exposure is critical for patient outcomes, specifically in the critically ill population. Solid information on isavuconazole pharmacokinetics including protein binding in patients in the intensive care unit is scarce. We aimed to describe the total and unbound isavuconazole pharmacokinetics and subsequently propose a dosage optimisation strategy. METHODS: A prospective multi-centre study in adult intensive care unit patients receiving isavuconazole was performed. Blood samples were collected on eight timepoints over one dosing interval between days 3-7 of treatment and optionally on one timepoint after discontinuation. Total and unbound isavuconazole pharmacokinetics were analysed by means of population pharmacokinetic modelling using NONMEM. The final model was used to perform simulations to assess exposure described by the area under the concentration-time curve and propose an adaptive dosing approach. RESULTS: Population pharmacokinetics of total and unbound isavuconazole were best described by an allometrically scaled two-compartment model with a saturable protein-binding model and interindividual variability on clearance and the maximum binding capacity. The median (range) isavuconazole unbound fraction was 1.65% (0.83-3.25%). After standard dosing, only 35.8% of simulated patients reached a total isavuconazole area under the concentration-time curve > 60 mg·h/L at day 14. The proposed adaptive dosing strategy resulted in an increase to 62.3% of patients at adequate steady-state exposure. CONCLUSIONS: In critically ill patients, total isavuconazole exposure is reduced and protein binding is highly variable. We proposed an adaptive dosing approach to enhance early treatment optimisation in this high-risk population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04777058.

Oral antimicrobial agents in patients with short bowel syndrome: worth a try!

BACKGROUND: The use of oral antimicrobial agents in patients with short bowel syndrome (SBS) is challenging due to the changes in gastrointestinal anatomy that may result in diminished absorption and altered drug bioavailability. Prospective studies evaluating bioavailability of antimicrobial agents after oral administration in SBS patients are lacking. OBJECTIVES: To determine the bioavailability of orally administered antimicrobial agents commonly used for treatment in SBS patients to guide clinical decision making when faced with infections. METHODS: We performed an explorative, clinical study investigating the pharmacokinetics (PK) of clindamycin, ciprofloxacin, flucloxacillin and fluconazole in SBS patients with intestinal failure. Participants received a combination of two antimicrobial agents simultaneously. To determine the oral bioavailability, participants received a single oral and IV dose of both agents on two occasions, after which they underwent intensive PK sampling on six predefined time points up to 12 hours after administration. Primary outcome was the oral bioavailability of these antimicrobial agents. Secondary outcomes were intravenous PK characteristics following non-compartmental analysis. RESULTS: Eighteen SBS patients were included: the mean (SD) age was 59 (17) years and 61% of participants were female. The median observed (IQR) bioavailability of ciprofloxacin, clindamycin, flucloxacillin and fluconazole were 36% (24-50), 93% (56-106), 50% (32-76) and 98% (61-107), respectively. CONCLUSION: The bioavailability of selected antimicrobial agents in certain patients with SBS appeared to be better than expected, providing a feasible treatment option. Due to the large observed differences between patients, therapeutic drug monitoring should be part of the treatment to safeguard adequate exposure in all patients. TRIAL REGISTRATION: Registered in the Dutch Trial Register (NL7796) and EudraCT number 2019-002587-28.

Repurposing antifungals: population pharmacokinetics of itraconazole and hydroxy-itraconazole following administration of a nanocrystal formulation.

OBJECTIVES: To describe itraconazole and hydroxy-itraconazole pharmacokinetics following intravenous (IV) administration of a previously developed nanocrystal formulation (NCF) in haematopoietic cell transplant (HCT) recipients for prophylaxis of invasive fungal disease. METHODS: In a prospective Phase II study, 10 HCT recipients received itraconazole NCF administered in 2-hour infusions of 200 mg twice daily for 2 days, followed by 200 mg once daily until Day 14. Full pharmacokinetic curves were obtained on Days 7 and 14. Additional samples were collected pre- and post-infusion until Day 6, pre-infusion on Days 10 and 12, and during washout on Days 16, 17, 18, 19 and 28. Itraconazole and hydroxy-itraconazole pharmacokinetics were analysed by non-linear mixed-effects population pharmacokinetic modelling. RESULTS: Four-hundred and seventy-one itraconazole and 471 paired hydroxy-itraconazole concentrations from 10 patients were included for analysis. Data were best described by a semi-mechanistic model with central and peripheral itraconazole compartments and a hydroxy-itraconazole compartment with dissolution of itraconazole drug particles from nanocrystals and first-order distribution and elimination. The final model included interindividual variability on itraconazole clearance and hydroxy-itraconazole clearance. CONCLUSIONS: This study provides information on the pharmacokinetic properties of the itraconazole NCF useful for development of this formulation. Our results suggest that itraconazole NCF is a suitable formulation and may warrant renewal in the setting of repurposing. Our findings may be useful for the reformulation of other highly lipophilic compounds as well.

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

BACKGROUND: Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. OBJECTIVE: This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. METHODS: Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. RESULTS: A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥ 0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. CONCLUSIONS: For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial.

OBJECTIVES: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis. METHODS: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. RESULTS: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001). CONCLUSIONS: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT00893555.

Liposomal amphotericin B exposure in critically ill patients: a prospective pharmacokinetic study.

Liposomal amphotericin B (L-AmB) is a broad-spectrum antifungal drug. Little is known about its pharmacokinetics (PK) in critically ill patients. The aim of this study was to document the PK of L-AmB in this population. It was also explored if covariates may be identified that influence its exposure. All adult, critically ill patients (at the intensive care unit or hematology ward) treated with L-AmB between October 2016 and January 2020 were eligible for this study. The administered dose was left at the discretion of the treating clinician. Plasma samples were collected at predose and 1, 2, 4, 8, 12, 16, 20 and 24 h postdose at an early (day 2-3) and/or later (≥ day 6) treatment day. Additionally, daily trough concentrations were collected until day 14. Of 33 included patients, 31 were evaluable; their median [IQR] age and body weight was 59 [54-64] years and 68 [59-77] kg, respectively. L-AmB was administered at doses between 2.7 mg/kg and 12.3 mg/kg, with a median [IQR] trough concentration of 3.1 [2.0-4.7] mg/l. The overall median area under the 24 h concentration-time curve (AUC0-24) and peak plasma concentration (Cmax) were 169.0 [117.0-253.0] mg h/l and 23.2 [16.9-33.7] mg/l, respectively. A considerable intra- and interpatient PK variability for Cmax and AUC0-24 was observed but no explaining variables, except the administered dose, could be identified. The PK of L-AmB in critically ill patients was documented. A considerable variability in exposure was observed between and within patients; however, it was not associated with a multitude of patient-related characteristics.

L-AmB is marketed for decades to treat invasive fungal infections; however, not much is known about its exposure. We documented L-AmB exposure in 31 critically ill patients. Although median exposure was similar compared to noncritically ill patients, a considerable variability was observed.

Total bodyweight and sex both drive pharmacokinetic variability of fluconazole in obese adults.

BACKGROUND: Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the pharmacokinetics and therapeutic efficacy of a drug. In this study, we aim to assess the impact of obesity on fluconazole pharmacokinetics given orally or IV to guide dose adjustments for the obese population. METHODS: We performed a prospective pharmacokinetic study with intensive sampling in obese subjects undergoing bariatric surgery (n = 17, BMI ≥ 35 kg/m2) and non-obese healthy controls (n = 8, 18.5 ≤ BMI < 30.0 kg/m2). Participants received a semi-simultaneous oral dose of 400 mg fluconazole capsules, followed after 2 h by 400 mg IV. Population pharmacokinetic modelling and simulation were performed using NONMEM 7.3. RESULTS: A total of 421 fluconazole concentrations in 25 participants (total bodyweight 61.0-174 kg) until 48 h after dosing were obtained. An estimated bioavailability of 87.5% was found for both obese and non-obese subjects, with a 95% distribution interval of 43.9%-98.4%. With increasing total bodyweight, both higher CL and Vd were found. Sex also significantly impacted Vd, being 27% larger in male compared with female participants. CONCLUSIONS: In our population of obese but otherwise healthy individuals, obesity clearly alters the pharmacokinetics of fluconazole, which puts severely obese adults, particularly if male, at risk of suboptimal exposure, for which adjusted doses are proposed.

Ciprofloxacin Pharmacokinetics After Oral and Intravenous Administration in (Morbidly) Obese and Non-obese Individuals: A Prospective Clinical Study.

BACKGROUND AND OBJECTIVE: Ciprofloxacin is a fluoroquinolone used for empirical and targeted therapy of a wide range of infections. Despite the increase in obesity prevalence, only very limited guidance is available on whether the ciprofloxacin dose needs to be adjusted when administered orally or intravenously in (morbidly) obese individuals. Our aim was to evaluate the influence of (morbid) obesity on ciprofloxacin pharmacokinetics after both oral and intravenous administration, to ultimately guide dosing in this population. METHODS: (Morbidly) obese individuals undergoing bariatric surgery received ciprofloxacin either orally (500 mg; n = 10) or intravenously (400 mg; n = 10), while non-obese participants received semi-simultaneous oral dosing of 500 mg followed by intravenous dosing of 400 mg 3 h later (n = 8). All participants underwent rich sampling (11-17 samples) for 12 h after administration. Non-linear mixed-effects modelling and simulations were performed to evaluate ciprofloxacin exposure in plasma. Prior data from the literature were subsequently included in the model to explore exposure in soft tissue in obese and non-obese patients. RESULTS: Overall, 28 participants with body weights ranging from 57 to 212 kg were recruited. No significant influence of body weight on bioavailability, clearance or volume of distribution was identified (all p > 0.01). Soft tissue concentrations were predicted to be lower in obese individuals despite similar plasma concentrations compared with non-obese individuals. CONCLUSION: Based on plasma pharmacokinetics, we found no evidence of the influence of obesity on ciprofloxacin pharmacokinetic parameters; therefore, ciprofloxacin dosages do not need to be increased routinely in obese individuals. In the treatment of infections in tissue where impaired ciprofloxacin penetration is anticipated, higher dosages may be required. TRIAL REGISTRATION: Registered in the Dutch Trial Registry (NTR6058).

Population pharmacokinetics of intravenous cefotaxime indicates that higher doses are required for critically ill children.

BACKGROUND: Cefotaxime is frequently used in critically ill children, however pharmacokinetic (PK) studies to support adequate dosing in this patient population are limited. OBJECTIVES: To characterize cefotaxime PK in critically ill children and evaluate exposures achieved by current and alternative dosing regimens. METHODS: Children (0-18 years) admitted to the paediatric ICU, receiving intravenous cefotaxime (100-150 mg/kg/day, interval 6-8 h) were included (Clinicaltrials.gov NCT03248349). Total plasma cefotaxime concentrations were measured on multiple study days. Population-PK analysis was performed using nonlinear mixed effects modelling (NONMEM™). Dose evaluations were performed using typical patients across the paediatric age range and target attainment was determined for MICs of 0.5, 2 and 4 mg/L. RESULTS: 479 cefotaxime plasma concentrations from 52 children (median age 1.6, range 0.03-17.7 years) were used to describe cefotaxime PK. We describe a two-compartment structural model with interindividual variability, including bodyweight as covariate for volume of distribution and clearance. Model predicted exposure for 150 mg/kg/day (current dose) showed trough concentrations <0.5 mg/L in patients >4 years of age. The maximum cefotaxime doses (200 mg/kg/day, interval 6 h) proved adequate for MICs ≤0.5 mg/L across the whole age range. Similar daily doses with increased frequency (interval 4 h) covered MICs up to 2 mg/L, while a loading dose followed by continuous infusion regimens are needed to adequately treat MICs of 4 mg/L. CONCLUSIONS: Higher cefotaxime doses are required for adequate exposure for most pathogens in critically ill children. A higher dose frequency or continuous infusion is advisable to improve target attainment for intermediately susceptible pathogens.