Therapeutic Drug Monitoring of Antibiotics in Critically Ill Children: An Observational Study in a Pediatric Intensive Care Unit.

BACKGROUND: Septic critically ill children are at a high risk of inadequate antibiotic exposure, requiring them to undergo therapeutic drug monitoring (TDM). The aim of this study was to describe the use of TDM for antibiotics in critically ill children. METHODS: The authors conducted a single-center observational study between June and December 2019, with all children treated with antibiotics in a pediatric intensive care unit located in a French university hospital. Standard clinical and laboratory data were recorded. Blood samples were collected for routine laboratory tests, and plasma antibiotic levels were assayed using validated analytical methods. RESULTS: A total of 209 children received antibiotics. TDM was performed in 58 patients (27.8%) who had a greater mean organ dysfunction (according to the International Pediatric Sepsis Consensus Conference) (3 versus 1 in the non-TDM group; P < 0.05) and were treated with antibiotics for longer. A total of 208 samples were analyzed. The median [interquartile range] assay turnaround time was 3 (1-5) days, and 48 (46.2%) of the 104 initial antibiotic concentration values were below the pharmacokinetic/pharmacodynamic targets. A total of 34 (46%) of the 74 off-target TDM measurements available before the end of the antibiotic treatment prompted dose adjustment. This dose adjustment increased the proportion of on-target TDM measurements (70% versus 20% without adjustment). Subsequent measurements of the minimum inhibitory concentration showed that the use of the European Committee on Antimicrobial Susceptibility Testing's epidemiological cutoff values led to underestimation of pharmacokinetic/pharmacodynamic target attainment in 10 cases (20%). CONCLUSIONS: TDM seems to be an effective means of optimizing antibiotic exposure in critically ill children. This requires timely plasma antibiotic assays and minimum inhibitory concentration measurements. It is important to define which patients should undergo TDM and how this monitoring should be managed.

Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

Predictive Performance of Population Pharmacokinetic Models of Levetiracetam in Children and Evaluation of Dosing Regimen.

Levetiracetam is a broad-spectrum antiepileptic drug that exhibits high interindividual variability in serum concentrations in children. A population pharmacokinetic approach can be used to explain this variability and optimize dosing schemes. The objectives are to identify the best predictive population pharmacokinetic model for children and to evaluate recommended doses using simulations and Bayesian forecasting. A validation cohort included children treated with levetiracetam who had a serum drug concentration assayed during therapeutic drug monitoring. We assessed the predictive performance of all the population pharmacokinetic models published in the literature using mean prediction errors, root mean squared errors, and visual predictive checks. A population model was finally constructed on the data, and dose simulations were performed to evaluate doses. We included 267 levetiracetam concentrations ranging from 2 to 69 mg/L from 194 children in the validation cohort. Six published models were externally evaluated. Most of the models underestimated the variability of our population. A 1-compartment model with first-order absorption and elimination with allometric scaling was finally fitted on our data. In our cohort, 57% of patients had a trough concentration <12 mg/L and 12% <5 mg/L. To reach a trough concentration >5 mg/L, doses ≥30 mg/kg/d for patients ≤50 kg and ≥2000 mg/d for patients >50 kg are required. In our population, a high percentage of children had low trough concentrations. Our population pharmacokinetic model could be used for therapeutic drug monitoring of levetiracetam in children.

Development of a simple and rapid method to determine the unbound fraction of dolutegravir, raltegravir and darunavir in human plasma using ultrafiltration and LC-MS/MS.

Dolutegravir, raltegravir and darunavir are three antiretroviral drugs widely used in combined antiretroviral therapies. These three drugs are highly bound to plasma proteins. Compared to the total concentration, the concentration of unbound drug which is considered as the only pharmacological active form should be more informative to improve therapeutic drug monitoring in patients to avoid virological failure or toxicity. The aim of the present study was to develop an ultrafiltration protocol and a LC-MS/MS method to simultaneously determine the concentrations of the unbound dolutegravir, raltegravir and darunavir in human plasma. Finally, 150 µL of plasma was ultrafiltrated using Centrifree® ultrafiltration devices with ultracel YM-T membrane (cutoff 30 KDa) during 5 min at 37 °C at 1500 g. Then, 20 µL of the ultrafiltrate were injected into the LC-MS/MS system. The chromatographic separation was carried out on a BEH C18 column using a mobile phase containing deionized water and acetonitrile, both with 0.05 % (v/v) of formic acid, with a gradient elution at a flow rate of 0.5 mL/min. The run time was only 4 min. The calibration curve ranged from 0.5-200 ng/mL for dolutegravir, 1 to 400 ng/mL for raltegravir and 10-4000 ng/mL for darunavir. This method was validated with a good precision (inter- and intra-day CV% lower than 14 %) and a good accuracy (inter- and intra-day bias between -5.6-8.8 %) for all the analytes. This method is simple, reliable and suitable for pharmacokinetic studies.

Plasma Concentrations and Safety of Lopinavir/Ritonavir in COVID-19 Patients.

BACKGROUND: Although the efficacy of lopinavir/ritonavir has not been proven, it has been proposed as an off-label treatment for COVID-19. Previously, it has been reported that the plasma concentrations of lopinavir significantly increase in inflammatory settings. As COVID-19 may be associated with major inflammation, assessing the plasma concentrations and safety of lopinavir in COVID-19 patients is essential. METHODS: Real-world COVID-19 data based on a retrospective study. RESULTS: Among the 31 COVID-19 patients treated with lopinavir/ritonavir between March 18, 2020 and April 1, 2020, higher lopinavir plasma concentrations were observed, which increased by 4.6-fold (interquartile range: 3.6-6.2), compared with the average plasma concentrations in HIV. Lopinavir concentrations in all except one patient were above the upper limit of the concentration range of HIV treatment. Approximately one to 5 patients prematurely stopped treatment mainly because of an ADR related to hepatic or gastrointestinal disorders. CONCLUSIONS: Lopinavir plasma concentrations in patients with moderate-to-severe COVID-19 were higher than expected, and they were associated with the occurrence of hepatic or gastrointestinal adverse drug reactions. However, a high plasma concentration may be required for in vivo antiviral activity against SARS-CoV-2, as suggested by previous studies. Therefore, in the absence of adverse drug reaction, lopinavir dosage should not be reduced. Caution is essential because off-label use can be associated with a new drug safety profile.

HPLC-MS/MS method for the simultaneous quantification of dolutegravir, elvitegravir, rilpivirine, darunavir, ritonavir, raltegravir and raltegravir-ß-d-glucuronide in human plasma.

Therapeutic drug monitoring (TDM) is essential in the optimization of antiretroviral (ARV) treatments. In this work, we describe a new method for the simultaneous quantification of six molecules: the three novel ARV agents dolutegravir (DTG), elvitegravir (ELV) and rilpivirine (RPV), the first integrase inhibitor raltegravir (RAL) and its major metabolite the raltegravir-ß-d-glucuronide (RAL-GLU), an protease inhibitor darunavir (DRV) and its booster ritonavir (RTV) in human plasma. The drugs were extracted from 100 µL of plasma by a simple method of protein precipitation using acetonitrile. The separation was carried out on a Kinetex phehyl-hexyl column using a phase mobile composed of 55 % of water (0.05 % formic acid,v/v) and 45 % of methanol (0.05 % formic acid,v/v). The flow rate was set at 0.5 mL/min. The calibration ranged from 60 to 15000 ng/mL for DRV, from 20 to 5000 ng/mL for DTG and ELV, from 10 to 2500 ng/mL for RAL, RAL-GLU, RTV and RPV. The proposed method was validated with a good precision (inter- and intra-day CV% inferior to 12.3 %) and a good accuracy (inter- and intra-day bias between -9.9 % and 10 %) for all the analytes. The proposed method is simple, reliable and suitable for therapeutic drug monitoring (TDM) and for pharmacokinetics studies.

Association between ABCB1 polymorphisms and response to first-generation antiepileptic drugs in a Tunisian epileptic population.

PURPOSE: We aimed in this study to investigate the association between the ATP-Binding Cassette sub-family B, member1 (ABCB1) polymorphisms: C1236T (rs1128503), G2677T (rs2032582) and C3435T (rs1045642), and the resistance to antiepileptic drugs (AEDs). MATERIALS AND METHODS: The Polymerase Chain Reaction-Restriction Fragment Length Polymorphism genotyping of ABCB1 polymorphisms was conducted on 153 Tunisian epileptic patients treated with AEDs. RESULTS: Two genetic polymorphisms of the ABCB1 gene seemed to influence the response to AEDs. In fact, the G2677T T and the C3435T T alleles appeared to increase the risk of developing AEDs resistance (ORs* = 3.13; 95%CI = [1.16-8.98]; p = 0.024 and ORs* = 3.10; 95%CI = [1.15-8.37]; p = 0.025), respectively. However, the C1236T T allele did not seemed to influence the response to AEDs (ORs* = 1.14; 95%CI = [0.53-3.88]; p = 0.471). Haplotypic analysis indicated high-degree linkage disequilibrium of ABCB1 polymorphisms. Our results showed a synergic effect, in fact patients with the CTT and TTT haplotypes were more likely to be drug resistant than patients with the CGC haplotype, these associations remained significant even after adjustment for confounding parameters (ORs* = 2.68; 95%CI = [1.11-8.25]; p = 0.033 and ORs* = 3.76; 95%CI = [1.69-21.05]; p = 0.006, respectively). CONCLUSION: The G2677T T and C3435T T alleles as well as the TT, CTT and TTT haplotypes seemed to be significantly associated with drug-resistance epilepsy in our population. Genetic predisposition, involved in this resistance, may contribute to the establishment of a personal optimized therapy for newly diagnosed epileptic patients.