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Background: The EASL cystic liver disease guideline states that drug penetration at the site of infection (liver cyst) is essential for successful treatment, but pharmacokinetic (PK) data on cyst penetration are limited., Objectives: This study aims to investigate tissue penetration of four antibiotics in non-infected liver cysts and explores influencing factors., Methods: We performed a prospective, randomized single-dose PK-study. Before percutaneous drainage of a non-infected liver cyst, an intravenous (IV) dose of either ciprofloxacin and piperacillin/tazobactam (group 1); or co-trimoxazole (trimethoprim/sulfamethoxazole) and doxycycline (group 2) was given. Cyst fluid was collected during drainage. Blood samples were obtained before, during and after drainage (within 12 h). Drug concentrations were measured with a validated LC-MS/MS. Primary outcome was liver cyst penetration, defined as the cyst-fluid-to-plasma concentration ratio (%) expressed as median (IQR)., Results: We included 20 patients, and 21 liver cysts were drained (group 1: n = 11, group 2: n = 10). Median drained cyst volume was 700 mL. Median time between infusion and drainage was 139 min (IQR 120-188 min). Median cyst-fluid-to-plasma concentration ratio was 4.2% (IQR 1.6%-8.9%) for ciprofloxacin, 0.3% (IQR 0.0%-1.3%) for piperacillin, 0.2% (IQR 0.0%-1.3%) for tazobactam, 12.2% (IQR 6.3%-16.1%) for trimethoprim, 0.4% (IQR 0.2%-3.8%) for sulfamethoxazole and 1.6% (IQR 0.9%-2.3%) for doxycycline. Time between trimethoprim infusion and cyst drainage was correlated with increased cyst-fluid-to-plasma concentration ratio (P < 0.01)., Conclusions: Trimethoprim and ciprofloxacin have the highest penetration ratios amongst antibiotics tested. We found that liver cyst penetration varies widely between drugs after a single IV dose., Clinical Trial Number: NTR8499The trial was originally registered in the Netherlands Trial Register (ID: NL7290), which was converted to the International Clinical Trials Registry Platform in 2022., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Purpose: We aimed to develop and evaluate a population PK model of mycophenolic acid (MPA) in pediatric kidney transplant patients to aid MPA dose optimization., Methods: Data were collected from pediatric kidney transplant recipients from a Dutch academic hospital (Radboudumc, the Netherlands). Pharmacokinetic model-building and model-validation analyses were performed using NONMEM. Subsequently, we externally evaluated the final model using data from another academic hospital. The final model was used to develop an optimized dosing regimen., Results: Thirty pediatric patients were included of whom 266 measured MPA plasma concentrations, including 20 full pharmacokinetic (PK) curves and 24 limited sampling curves, were available. A two-compartment model with a transition compartment for Erlang-type absorption best described the data. The final population PK parameter estimates were K tr (1.48 h -1 ; 95% CI, 1.15-1.84), CL/F (16.0 L h -1 ; 95% CI, 10.3-20.4), V c /F (24.9 L; 95% CI, 93.0-6.71E25), V p /F (1590 L; 95% CI, 651-2994), and Q/F (36.2 L h -1 ; 95% CI, 9.63-74.7). The performance of the PK model in the external population was adequate. An optimized initial dose scheme based on bodyweight was developed. With the licensed initial dose, 35% of patients were predicted to achieve the target AUC, compared to 42% using the optimized scheme., Conclusion: We have successfully developed a pharmacokinetic model for MPA in pediatric renal transplant patients. The optimized dosing regimen is expected to result in better target attainment early in treatment. It can be used in combination with model-informed follow-up dosing to further individualize the dose when PK samples become available., (© 2024. The Author(s).)

Vancomycin continuous infusion (CI) has suggested benefits over intermittent infusion: reduced nephrotoxicity, higher target attainment, and simpler therapeutic drug monitoring (TDM). Empiric dosing regimens range from 30-60 mg/kg/day and it is unclear which regimen results in optimal exposure. This study evaluates whether a dosing regimen of 45 mg/kg/day after a 20 mg/kg loading dose for patients with estimated glomerular filtration rate (eGFR) ≥ 50 mL/min results in adequate exposure. We retrospectively analyzed plasma concentrations from patients treated with vancomycin CI as routine clinical care between February and October 2021. Patients under 18 years old, with renal replacement therapy, reduced creatinine clearance (Chronic Kidney Disease Epidemiology Collaboration < 50 mL min/1.73 m 2 ) or outpatient antibiotic therapy were excluded. Dose, renal function, and blood draw procedures were assessed for each measured vancomycin sample. Initially, 121 samples were included. Subsequently, 7 samples, 6 of which with concentrations ≥ 40 mg/L, were verified to be incorrectly drawn and excluded. With doses of 40-50 mg/kg/day concentrations ranged from 18.4-61.0 mg/L. Only 25% were within the target window of 17-25 mg/L and 15% were ≥ 40 mg/L. Supratherapeutic concentrations were observed in 89% of samples from patients dosed 40-60 mg/kg/day with eGFR 50-80 mL/min. Concluding, an empiric dosing regimen of 45 mg/kg results in too high vancomycin exposure and thus we recommend lower doses and differentiation according to renal function. Additionally, when measuring concentrations over 40 mg/L incorrect sampling must be excluded before dose adjustment and the large variability in exposure between patients, warrants the need for swift TDM., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: When performing therapeutic drug monitoring (TDM) for flucloxacillin, it is advised to measure the unbound, not the total, flucloxacillin concentration. To be able to accurately quantify unbound flucloxacillin concentrations, a reliable analytical method is indispensable., Objective: To determine the influence of temperature and pH of the sample during ultrafiltration on the measured unbound fraction of flucloxacillin., Materials and Methods: We performed three different experiments. In a single laboratory experiment, we investigated the influence of ultrafiltration temperature (10°C, room temperature and 37°C) on the measured unbound fraction of flucloxacillin for three concentration levels. In a multiple laboratory experiment, the results of eight laboratories participating in an international quality control programme measuring unbound flucloxacillin concentrations were analysed. In the third experiment, patient samples were ultrafiltrated using four different conditions: (i) physiological pH and room temperature; (ii) unadjusted pH (pH 9 after freezing) and room temperature; (iii) physiological pH and 37°C and (iv) unadjusted pH and 37°C., Results: For all experiments, measurement of samples that were ultrafiltrated at room temperature resulted in a substantially lower unbound fraction compared to samples that were ultrafiltrated at 37°C. Adjusting the pH to physiological pH only had a minimal impact on the measured unbound fraction., Conclusions: On the basis of these findings and considering the need for fast, simple and reproducible sample pretreatment for TDM purposes, we conclude that ultrafiltration of flucloxacillin should be performed at physiological temperature (37°C), but adjustment of pH does not seem to be necessary., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: The glycopeptide teicoplanin is considered first-line treatment for severe infections caused by Gram-positive bacteria. Individualized treatment of teicoplanin is gaining interest. As only protein-unbound drug is pharmacologically active, a sensitive assay measuring unbound and total teicoplanin is indispensable for pharmacological research and dose optimization., Objectives: To develop and validate a UPLC-MS/MS method to quantify unbound and total teicoplanin in human serum., Methods: The developed assay was validated according to the ICH guideline M10 on Bioanalytical Method Validation and study sample analysis. Unbound teicoplanin was obtained by ultrafiltration. The assay was cross-validated with a quantitative microsphere (QMS) immunoassay in a side-by-side comparison using 40 patient samples., Results: With the developed and validated method, all main teicoplanin components (A2-1, A2-2/A2-3, A2-4/A2-5 and A3-1) can be quantified. Total run time was 5.5 min. Concentration range was 2.5-150 mg/L for total and 0.1-25 mg/L for unbound teicoplanin. Precision (coefficient of variation) and accuracy (bias) of total teicoplanin were 5.97% and 107%, respectively, and 7.17% and 108%, respectively, for unbound teicoplanin.Bland-Altman analysis showed total concentrations measured with the UPLC-MS/MS method were equivalent to the results of the QMS immunoassay. A total of 188 samples from 30 patients admitted to the ICU and haematology department were measured; total concentrations ranged between 2.92 and 98.5 mg/L, and unbound concentrations ranged between 0.37 and 30.7 mg/L., Conclusions: The developed method provided rapid, precise and accurate measurement of unbound and total teicoplanin. The developed method is now routinely applied in pharmacological research and clinical practice., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Purpose: To provide key pharmacological concepts underlying drug-drug interactions (DDIs), a decision-making framework, and a list of DDIs that should be considered in the context of contemporary acutely ill patients with COVID-19., Summary: DDIs are frequently encountered in the acutely ill. The implications of DDIs include either increased risk of drug toxicity or decreased effectiveness, which may have severe consequences in the acutely ill due to lower physiological and neurocognitive reserves in these patients. In addition, an array of additional therapies and drug classes have been used for COVID-19 that were not typically used in the acute care setting. In this update on DDIs in the acutely ill, we provide key pharmacological concepts underlying DDIs, including a discussion of the gastric environment, the cytochrome P-450 (CYP) isozyme system, transporters, and pharmacodynamics in relation to DDIs. We also provide a decision-making framework that elucidates the identification of DDIs, risk assessment, selection of alternative therapies, and monitoring. Finally, important DDIs pertaining to contemporary acute care clinical practice related to COVID-19 are discussed., Conclusion: Interpreting and managing DDIs should follow a pharmacologically based approach and a systematic decision-making process to optimize patient outcomes., (© American Society of Health-System Pharmacists 2023.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Precision dosing programs are promising tools for optimising antimicrobial dosing. Selecting the ideal program for local application may be challenging due to the large variety of available programs with differing characteristics., Objectives: The objectives of this study were to systematically identify available precision dosing software programs to optimize antimicrobial dosing and describe the characteristics of each program. Details on the ability of programs to provide beta-lactam dosing support was also gathered., Sources: A systematic review search strategy was used to identify candidate software programs described in the literature in Embase and PubMed. A detailed survey was then developed to identify characteristics of programs, including details on the underlying methodology driving dosing software recommendations, interface characteristics, costs and regulatory affairs. Software developers from all identified programs were invited to participate in the survey., Content: The systematic search results identified 18 programs. Fifteen developers responded to the survey (83%) and 11 programs provide dosing support for at least one beta-lactam. Fourteen programs can utilize measured drug concentrations to generate dosing recommendations, with 13 able to generate empiric dosing recommendations. Six programs integrate with local electronic health records and four are registered with at least one regulatory agency. Pharmacokinetic models in combination with Bayesian statistics is the most common methodology used to generate dosing recommendations, with 14 programs utilizing this method., Implications: There was significant variability in the available antimicrobial profiles and characteristics among dosing software programs. As healthcare providers will differ in their requirements within their local settings, clinicians should use these findings to identify potential candidate programs and, if feasible, trial these to ensure they meet their specific requirements., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Although unbound ciprofloxacin is responsible for antibacterial effects, assays measuring the unbound drug plasma concentrations are scarce. This study aimed to develop and validate a rapid, reproducible, and sensitive liquid chromatography-tandem mass spectrometry assay for the determination of total and unbound ciprofloxacin plasma concentrations., Methods: The determination of total ciprofloxacin concentrations required a 10 μL sample, while for unbound ciprofloxacin concentrations, it was 100 μL. Unbound ciprofloxacin was separated from protein-bound ciprofloxacin through ultrafiltration. A deuterated internal standard was used, and the sample preparation involved protein precipitation. The method was fully validated over a concentration range of 0.02-5.0 mg/L, according to the US Food and Drug Administration guidelines. In addition, its clinical application was demonstrated., Results: The total run time was 1.5 minutes. For total ciprofloxacin plasma concentrations, the mean accuracy ranged from 94.5% to 105.0% across the validated range, the intraday imprecision was ≤7.6%, and the interday imprecision was ≤9.8%. For unbound ciprofloxacin plasma concentrations, the mean accuracy ranged from 92.8% to 102.1% across the validated range, the intraday imprecision was ≤7.0%, and the interday imprecision was ≤9.6%. Ciprofloxacin in plasma and ultrafiltrate remained stable for at least 96 hours at room temperature, at least 4 years at -80°C, and at least 3 freeze/thaw cycles (-80°C), with a minimum interval of 24 hours., Conclusions: The presented method is precise and accurate. It has been implemented in clinical care and research projects at a university hospital, permitting rapid determination of total and unbound ciprofloxacin., Competing Interests: S. E. Geerlings has received grants from Nordic Pharma and Vifor Pharma outside of the submitted work; R. A. A. Mathôt has received grants from Baxter/Baxalta/Shire, Bayer Schering Pharma, CSL Behring, Merck Sharp & Dohme, and Zeria outside of the submitted work; R. M. van Hest received grants from Nordic Pharma outside of the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The aim of this study was to develop a mechanistic protein-binding model to predict the unbound flucloxacillin concentrations in different patient populations., Methods: A mechanistic protein-binding model was fitted to the data using non-linear mixed-effects modelling. Data were obtained from four datasets, containing 710 paired total and unbound flucloxacillin concentrations from healthy volunteers, non-critically ill and critically ill patients. A fifth dataset with data from hospitalized patients was used for evaluation of our model. The predictive performance of the mechanistic model was evaluated and compared with the calculation of the unbound concentration with a fixed unbound fraction of 5%. Finally, we performed a fit-for-use evaluation, verifying whether the model-predicted unbound flucloxacillin concentrations would lead to clinically incorrect dose adjustments., Results: The mechanistic protein-binding model predicted the unbound flucloxacillin concentrations more accurately than assuming an unbound fraction of 5%. The mean prediction error varied between -26.2% to 27.8% for the mechanistic model and between -30.8% to 83% for calculation with a fixed factor of 5%. The normalized root mean squared error varied between 36.8% and 69% respectively between 57.1% and 134%. Predicting the unbound concentration with the use of the mechanistic model resulted in 6.1% incorrect dose adjustments versus 19.4% if calculated with a fixed unbound fraction of 5%., Conclusions: Estimating the unbound concentration with a mechanistic protein-binding model outperforms the calculation with the use of a fixed protein binding factor of 5%, but neither demonstrates acceptable performance. When performing dose individualization of flucloxacillin, this should be done based on measured unbound concentrations rather than on estimated unbound concentrations from the measured total concentrations. In the absence of an assay for unbound concentrations, the mechanistic binding model should be preferred over assuming a fixed unbound fraction of 5%., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Limited prospective data on pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ciprofloxacin in patients with adequate and impaired renal function (eGFR <30 mL/min/1.73m 2 ) are available in the literature. We aimed to investigate whether the PK/PD target (AUC/MIC ≥125) is attained in patients with adequate and impaired renal function receiving regular and reduced ciprofloxacin doses. This prospective observational cohort study included adult patients on general wards treated with ciprofloxacin. Three blood samples per patient were obtained for ciprofloxacin concentration measurement. Individual AUCs were calculated using a population PK model developed by non-linear mixed-effects modelling. Forty patients were included, of whom eight had impaired renal function and were treated with a guideline-recommended reduced dose. Using the clinical breakpoint MIC of the most isolated bacteria (Escherichia coli, 0.25 mg/L), AUC 0-24 /MIC ≥125 was attained in 13/32 (41%) patients with adequate renal function receiving regular doses and in 1/8 (13%) patients with impaired renal function receiving reduced doses. Median drug exposure (AUC 0-24 ) for patients with impaired renal function was 19.0 [interquartile range (IQR) 14.2-23.3] mg/L•h, which was statistically significantly lower than that for patients with adequate renal function [29.3 (IQR 25.0-36.0) mg/L•h] (P < 0.01). AUC 0-24 /MIC ≥125 is not attained in the majority of adult patients on general wards for clinically relevant bacteria with MICs at or just below the clinical breakpoint. The risk of not attaining the target appears to be highest in patients with impaired renal function receiving guideline-recommended reduced doses, as drug exposure is significantly lower in these patients., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cisplatin is the first choice treatment in mediastinal germ cell tumors. However, concerns regarding increased toxicity of cisplatin hamper its administration in patients with impaired renal function. We describe a 42-year-old man with chronic kidney disease stage 4 who was diagnosed with a mediastinal germ cell tumor and metastases in lung and brain. Treatment with cisplatin-etoposide was considered essential for a chance of cure. In order to administer the full cisplatin dose, 4-hour hemodialysis sessions were performed after each cisplatin infusion. During treatment cycle 3, 4 and 5, total and unbound plasma platinum concentrations were measured. Trough concentrations and half-life were at the higher end of the range of those observed in patients with adequate renal function who received the same dose of cisplatin. Hemodialysis aided platinum clearance, although our patient was also able to clear some platinum by his own renal function. With this full dose treatment, our patient obtained a favorable tumor response, with a strong decrease of beta-human chorionic gonadotropin and tumor size. The side effects experienced by our patient were serious, although not worse than what could be expected with this type of treatment. His renal function remained stable during the treatment period.

Background: Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets., Objectives: To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients., Methods: First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations., Results: A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h., Conclusions: For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Background: Hereditary folate malabsorption is a multisystem disease owing to biallelic variants in the gene encoding the proton-coupled folate transporter. Hereditary folate malabsorption is treated with folinic acid, aimed to restore blood and cerebrospinal fluid folate levels. Little is known as to whether oral or intramuscular supplementation of folinic acid is most effective., Methods: Here we describe a one-year-old boy with hereditary folate malabsorption presenting with the typical features including failure to thrive, aphthous stomatitis, macrocytic anemia along with severe developmental impairment and epilepsy, as well as a magnetic resonance imaging of the brain showing bilateral occipital, cortical calcifications characteristic of hereditary folate malabsorption. We compared the effect of treatment with oral folinic acid versus intramuscular folinic acid supplementation by measuring plasma and cerebrospinal fluid folate levels., Results: Compared with oral administration, intramuscular treatment resulted in higher folate levels in blood and, most importantly, normalization of folate levels in cerebrospinal fluid. Clinically, nearly all systemic and neurological symptoms resolved., Conclusion: Normal cerebrospinal fluid folate levels can be achieved in individuals with hereditary folate malabsorption with intramuscular (but not with oral) administration of folinic acid., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction : Since the majority of bacterial infections occur at sites outside the bloodstream, antibiotic tissue concentrations are of significant relevance to optimize treatment. The aim of this review is to aid the clinician in choosing optimal regimens for the treatment of extravascular infections. Areas covered : We discuss the principles of antibiotic tissue penetration and assess different approaches to obtain data on this subject. Finally, we present tissue penetration data for several relevant groups of antibiotic agents in a number of extravascular sites. Data were obtained from an extensive literature search in PubMed until February 2019. Expert opinion : There is still a long way to go before reliable information about tissue penetration of antibiotics is sufficiently available to serve as a basis for the design of optimal strategies for drug and dose selection. At this moment, there is a lack of robust data on tissue penetration, where both the sampling and measurement techniques as well as the relationship between tissue concentrations and clinical outcome of antibiotic treatment have to be better defined.

Z-Endoxifen is widely regarded as the most active metabolite of tamoxifen, and has recently demonstrated a 26.3% clinical benefit in a phase I clinical trial to treat metastatic breast cancer after the failure of standard endocrine therapy. Future pharmacological and pre-clinical studies of Z-endoxifen would benefit from reliable and efficient synthetic access to the drug. Here, we describe a short and efficient, stereoselective synthesis of Z-endoxifen capable of delivering multi-gram (37 g) quantities of the drug in >97% purity with a Z/E ratio >99% after trituration., (Copyright © 2018. Published by Elsevier Ltd.)