Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients.

BACKGROUND: Cefiderocol is a siderophore cephalosporin antibiotic active against Gram-negative bacteria, including extended-spectrum beta-lactamase and carbapenemase-producing strains. The pharmacokinetics of cefiderocol has been studied in healthy subjects and particularly in phase II and III studies. This retrospective study investigated intravenous cefiderocol population pharmacokinetics in adult patients treated by cefiderocol. METHODS: We studied 55 consecutive patients hospitalized in an intensive care unit. Cefiderocol plasma samples were obtained on different occasions during treatment. Plasma concentration was assayed using mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2020R1. RESULTS: A total of 205 plasma samples were obtained from 55 patients. Eighty percent of patients received cefiderocol for ventilator-associated pneumonia due to carbapenem-resistant Pseudomonas aeruginosa infection. Cefiderocol concentration time-courses were best fit to a two-compartment open model with first-order elimination. Elimination clearance was positively related to renal function (estimated by the CKD formula). Adding albumin plasma binding in the model significantly improved the model assuming a ~40% unbound drug fraction given a ~40 g/L albuminemia. The final model included CKD plus cefiderocol plasma binding effects. Fat-free mass was better than total body weight to influence, via the allometric rule, clearance and volume terms, but this effect was negligible. The final clearance based on free circulating drug (CLU) for a typical patient, CKD = 90, was 7.38 L/h [relative standard error, RSE, 22%] with a between-subject variability of 0.47 [RSE 10%] (exponential distribution). CONCLUSION: This study showed that albumin binding and CKD effects were significant predictors of unbound and total plasma cefiderocol concentrations. Our results indicate that individual adjustment of cefiderocol can be used to reach high minimum inhibitory concentrations based on an estimation of unbound drug concentration and optimize therapeutic efficacy.

Ciprofloxacin population pharmacokinetics during long-term treatment of osteoarticular infections.

BACKGROUND: Ciprofloxacin is an antibiotic used in osteoarticular infections owing to its very good bone penetration. Very few pharmacokinetic data are available in this population. OBJECTIVES: To investigate oral ciprofloxacin population pharmacokinetics in adult patients treated for osteoarticular infections and propose guidance for more effective dosing. METHODS: A retrospective population-pharmacokinetic analysis was performed on 92 consecutive hospitalized patients in the orthopaedic department. Ciprofloxacin plasma samples were obtained on one or two occasions during treatment. Plasma concentration was measured using ultra-performance liquid chromatography system coupled with tandem mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2019R2. RESULTS: A total of 397 plasma samples were obtained with 11.5% and 41.6% of patients being below the therapeutic target for Gram-negative and staphylococcal infections, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model with a first-order absorption. Ciprofloxacin apparent plasma clearances and volumes of distribution were dependent on patients' fat-free mass according to the allometric rule. Elimination clearance was also positively related to renal function through the modification of diet in renal disease equation (MDRD) and rifampicin co-administration. When patients are co-treated with rifampicin, ciprofloxacin dosage should be increased by 50% to 60%. CONCLUSIONS: This study showed that free-fat mass was a better size predictor than total body weight for ciprofloxacin clearance and volumes terms. Moreover, both MDRD and rifampicin status were significant predictors of individual ciprofloxacin clearance. Our study suggests that individual adjustment of ciprofloxacin dose in osteoarticular infections with less-susceptible bacteria might be indicated to reach required efficacy targets.

Simple and accurate quantitative analysis of cefiderocol and ceftobiprole in human plasma using liquid chromatography-isotope dilution tandem mass spectrometry: interest for their therapeutic drug monitoring and pharmacokinetic studies.

OBJECTIVES: Cefiderocol and ceftobiprole are new generation cephalosporin antibiotics that exhibit high inter-individual plasma concentration variability that potentially impact their efficacy or toxicity. The aim of this study was to develop and validate a selective, simple, and fast UPLC-MS/MS method for simultaneous quantification of cefiderocol and ceftobiprole in human plasma to enable their therapeutic drug monitoring (TDM) and support PK and PK/PD studies, in particular in critically ill patients. METHODS: After a simple and fast single-step protein precipitation, cefiderocol and ceftobiprole were separated on a Waters Acquity UPLC BEH C18 column by linear gradient elution; with subsequent detection by Shimadzu MS 8060 triple quadrupole tandem mass spectrometer in a positive ionization mode. RESULTS: Analysis time was 5 min per run. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect (ME), extraction recovery (ER), limit of quantification, dilution integrity, and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-200 mg/L for cefiderocol and 0.5-100 mg/L for ceftobiprole with a linear regression coefficient above 0.995 for both. CONCLUSIONS: A simple, fast, and selective liquid chroma-tography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of cefiderocol and ceftobiprole. This new method was successfully applied to the measurement of plasma concentration of cefiderocol and ceftobiprole in critically ill patients and showed good performance for their therapeutic monitoring and optimizing antibiotic therapy.

Development and clinical validation of a simple and fast UPLC-ESI-MS/MS method for simultaneous quantification of nine kinase inhibitors and two antiandrogen drugs in human plasma: Interest for their therapeutic drug monitoring.

Kinase inhibitors (KIs) and antiandrogen drugs (AAs) are oral anticancer drugs with narrow therapeutic index that exhibit high inter- and intra-individual variability. We describe here a UPLC-MS/MS method for the simultaneous quantification of nine KIs: cobimetinib, dasatinib, ibrutinib, imatinib, nilotinib, palbociclib, ruxolitinib, sorafenib and vemurafenib; two active metabolites of them: N-desmethyl imatinib, N-oxide sorafenib; and two AAs: abiraterone and enzalutamide; with short pre-treatment and run time in order to be easily used in clinical practice for their therapeutic drug monitoring (TDM) and facilitating pharmacokinetics and pharmacokinetics/pharmacodynamics studies. Plasma samples were prepared by a single-step protein precipitation. Analytes were separated on a Waters Acquity UPLC® T3 HSS C18 column by non-linear gradient elution; with subsequent detection by Xevo® TQD triple quadrupole tandem mass spectrometer in a positive ionization mode. Analysis time was 2.8 min per run, and all analytes eluted within 1.46-1.97 minutes. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect, extraction recovery, limit of quantification, dilution integrity and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-500 ng/mL for abiraterone, dasatinib and ibrutinib; 5-500 ng/mL for cobimetinib and palbociclib; 10-5,000 ng/mL for imatinib, N-desmethyl imatinib, nilotinib, sorafenib, N-oxide sorafenib and ruxolitinib; 100-50,000 ng/mL for enzalutamide and 100-100,000 ng/mL for vemurafenib with coefficient of correlation above 0.995 for all analytes. This novel method was successfully applied to TDM in clinical practice.

Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19.

BACKGROUND: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients. METHODS: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2. RESULTS: HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs). CONCLUSION: The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.

Development and validation of a UPLC-MS/MS method for simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin in human plasma: Application to the therapeutic drug monitoring in osteoarticular infections.

BACKGROUND: Fluoroquinolones and rifampicin are antibiotics frequently used for the treatment of osteoarticular infections, and their therapeutic drug monitoring is recommended. The aim of this study was to develop and validate a rapid and selective method of simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin with short pretreatment and run times in order to be easily used in clinical practice. METHODS: After a simple protein precipitation of plasma samples, the chromatographic separation was performed using an ultra-performance liquid chromatography system coupled with mass tandem spectrometry in a positive ionization mode. The mobile phase consisted of a gradient elution of water-formic acid (100:0.1, v/v)-ammonium acetate 2 mM (A) and methanol-formic acid (100:0.1, v/v)-ammonium acetate 2 mM (B) at a flow rate at 0.3 mL/min. RESULTS: Analysis time was 5 min per run, and all analytes and internal standards eluted within 0.85-1.69 minutes. The calibration curves were linear over the range from 0.5-30 µg/mL for levofloxacin, ciprofloxacin, moxifloxacin and rifampicin with linear regression coefficients above 0.995 for all analytes. The intra-day and inter-day coefficients of variation were below 10 % for lower and higher concentration. This method was successfully applied to drug monitoring in patients with an osteoarticular infection. CONCLUSION: A simple, rapid, and selective liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin in human plasma.

The drugs that mostly frequently induce gynecomastia: A national case - noncase study.

AIMS: Drug-induced gynecomastia accounts for up to 25% of cases of gynecomastia. The objective of the present study was to provide a comprehensive overview of drug-induced gynecomastia on the basis of spontaneously reported adverse drug reactions (ADRs) in the French national pharmacovigilance database (FPVD). METHODS: We performed a case - noncase study of drug-induced gynecomastia. Cases corresponded to reports of gynecomastia recorded in the FPVD between 1 January 2008 and 31 December 2015. The noncases corresponded to all other spontaneously reported ADRs recorded in the FPVD during the same period. Data were expressed as the reporting odds ratio (ROR) and its 95% confidence interval. RESULTS: Of the 255,354 ADRs recorded in the FPVD between 1 January 2008 and 31 December 2015, 327 (0.31%) of relevant cases of gynecomastia and 106,800 noncases were analyzed. The RORs were statistically significant for 54 active compounds mentioned 429 times in cases of gynecomastia. A single drug was involved in 59% of cases. The most frequently implicated drug classes were antiretrovirals (23.5%), diuretics (15.5%), proton pump inhibitors (11.9%), HMG-CoA reductase inhibitors (9.1%), neuroleptics and related drugs (6.5%), calcium channel blockers (6.3%), and 5-alpha reductase inhibitors (4%). CONCLUSIONS: A comprehensive analysis of a national pharmacovigilance database highlighted the main drug classes suspected of inducing gynecomastia. A physiopathological mechanism (a hormone imbalance with elevated estrogen levels) is known or suspected for most of the drugs involved in gynecomastia. However, we noticed a lack of harmonization in the summary of product characteristics for original vs. generic medicines.