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French guidelines recommend reaching an amikacin concentration of ≥8 × MIC 1 h after beginning infusion (C1h), with MIC = 8 mg/L for probabilistic therapy. We aimed to elaborate a nomogram guiding clinicians in choosing the right first amikacin dose for ICU patients in septic shock. A total of 138 patients with 407 observations were prospectively recruited. A population pharmacokinetic model was built using a non-parametric, non-linear mixed-effects approach. The total body weight (TBW) influenced the central compartment volume, and the glomerular filtration rate (according to the CKD–EPI formula) influenced its clearance. A dosing nomogram was produced using Monte Carlo simulations of the amikacin amount needed to achieve a C1h ≥ 8 × MIC. The dosing nomogram recommended amikacin doses from 1700 mg to 4200 mg and from 28 mg/kg to 49 mg/kg depending on the patient's TBW and renal clearance. However, a Cthrough ≤ 2.5 mg/L 24 h and 48 h after an optimal dose of amikacin was obtained with probabilities of 0.20 and 0.81, respectively. Doses ≥ 30 mg/kg are required to achieve a C1h ≥ 8 × MIC with MIC = 8 mg/L. Targeting a MIC = 8 mg/L should depend on local ecology. [ABSTRACT FROM AUTHOR]

Objectives: The metabolic pathways of dolutegravir and nevirapine suggest a potential pharmacokinetic interaction between these drugs. The objective of this study was to investigate the influence of nevirapine administration on the pharmacokinetics of dolutegravir in patients infected with HIV-1.Patients and Methods: This study was an investigator-initiated trial registered at ClinicalTrials.gov under identifier NCT02067767. Dolutegravir (50 mg once daily) was added to the antiretroviral regimen (400 mg of nevirapine once daily + 600/300 mg of abacavir/lamivudine once daily) in 10 adult patients for 5 days. After discontinuation of nevirapine, the combination of dolutegravir + abacavir/lamivudine was continued. Full pharmacokinetic profiles were assessed on the day of nevirapine discontinuation and 2 weeks after discontinuation of nevirapine. The pharmacokinetic parameters of dolutegravir were calculated by non-compartmental analysis. The log-transformed values of these parameters were compared between periods with and without nevirapine co-administration.Results: The co-administration of nevirapine led to a significant decrease (P < 0.05) in the area under the plasma concentration-time curve for dolutegravir from the time the dose was administered until the end of the dosing interval (-19%, P = 0.011), as well as decreases in trough plasma concentration (-34%, P = 0.018) and terminal half-life (-15%, P = 0.039), and a significant increase (P < 0.05) in apparent oral clearance for dolutegravir (+23%, P = 0.011).Conclusions: The decrease in dolutegravir exposure in combination with nevirapine suggests that the metabolism of dolutegravir is induced by nevirapine. According to therapeutic drug monitoring for dolutegravir, some patients may need a higher dose than 50 mg of dolutegravir once daily to maintain the therapeutic plasma concentration throughout the dosing interval. [ABSTRACT FROM AUTHOR]

High-dose baclofen could prove beneficial in patients with unhealthy alcohol use in intensive care units (ICU). However, the pharmacokinetic properties of baclofen are unknown in this population. Our objectives were to investigate the pharmacokinetics of baclofen and the relationship between baclofen exposure and its toxicity in the ICU. As part of a healthcare quality improvement project, we conducted a prospective, single-center study in a surgical intensive care unit at Nantes University Hospital in order to assess our local protocol of sedation in patients with consumption of alcohol above the recommended limits by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Baclofen pharmacokinetics were investigated by a non-compartment analysis and a population approach in 20 patients under mechanical ventilation. After a baclofen loading dose on day 1, daily doses were divided into 3 intakes adapted to glomerular filtration rate (GFR) and blood samples were withdrawn on day 3 for pharmacokinetic analysis. Baclofen was administered until extubation or tracheostomy and agitation-related events as well as the potential side effects of baclofen were noted. In this population, pharmacokinetic parameters [absorption latency time = 0.37 h, absorption constant rate = 2.2 h−1, apparent volume of distribution = 105 L, apparent clearance (l/h) = 13.5 × (GFR/103)0.839] were characterized by modified absorption and the influence of renal function: renal failure significantly increased baclofen exposure (p =.007) and significantly decreased baclofen clearance (p =.007) compared with patients without renal failure. When comparing patients with or without possible signs of baclofen toxicity, no difference was found regarding baclofen exposure (p =.34) and plasma peak concentration (p =.26). The a priori planned algorithm for dose adaptation according to renal clearance appeared to be suitable in our population. Daily administration of 150 mg of baclofen in ICU patients with preserved renal function did not lead to toxic concentrations in the plasma. A dose reduction of approximately 40%, 60% and 70% in patients with mild, moderate and severe renal failure could be suggested. • Alcohol is a leading psychoactive substance responsible for one death every 12 min in France. • Baclofen use in AUD remains controversial and temporary recommendations have recently been updated with lower daily doses • In ICU, 150 mg of baclofen daily did not lead to toxic plasma concentration provided dose adjustment to renal function. [ABSTRACT FROM AUTHOR]

Morbid obesity is known to increase the risk of surgical site infections. Optimal concentrations of prophylactic antibacterial drugs are required. Using Monte Carlo simulations, the aim of this work was to build a population pharmacokinetics model for a morbidly obese population to assess a 4000-mg dose of cefazolin recommended by the guidelines and to propose new administration schemes. One hundred and seventeen morbidly obese patients (mean body mass index, 46.95 kg/m 2 ) received 4000 mg of cefazolin intravenously before sleeve gastrectomy. Using population pharmacokinetics modelling and Monte Carlo simulations, probabilities of target attainment (PTAs) (subcutaneous tissue concentration of cefazolin above the minimum inhibitory concentration (MIC) throughout the surgical procedure was targeted) were determined. For Staphylococcus spp. and S treptococcus spp., which are the most frequent species isolated from post-surgical infections in bariatric surgery (MIC usually ≤2 mg/L), PTA remains greater than 0.9 until 2 h after administration of 4000 mg of cefazolin. For MIC up to 4 mg/L, efficient prophylaxis was checked until 1 h after the initial administration. A 3000-mg regimen followed by a continuous infusion (1000 mg/h) achieves these two targets until 4 h after the loading dose. A 2000-mg and a 3000-mg regimen do not achieve sufficient concentrations. According to the duration of surgery and MIC values, an initial administration of 4000 mg should be sufficient, but for extended surgeries continuous infusion can be considered. [ABSTRACT FROM AUTHOR]