Population pharmacokinetics of the two enantiomers of tramadol and O -demethyl tramadol after surgery in children

International audienceBACKGROUND : Few data are available on the stereoselective pharmacokinetics of tramadol in children. The aim of this study was to develop a population pharmacokinetic model for the (+)- and (-)-enantiomers of tramadol and its O-demethyl tramadol metabolite (M1) in children.METHODS : Twenty-five children (1-8 yr) were included in this study. Tramadol was administered after surgery by continuous infusion (loading dose, 2 mg kg(-1) i.v. over 10 min followed by continuous infusion of 8 mg kg(-1) over 24 h). If pain relief was inadequate, additional 1 mg kg(-1) i.v. bolus doses of tramadol were given over 10 min. A two-compartment structural model was used with NONMEM.RESULTS : For both enantiomers of tramadol, weight was the only patient characteristic parameter showing significant covariate effects on clearance (CL). CL increased by 5.7-6.1 litre h(-1) between 8-12 and 13-16 kg, and by 2.4-3.3 litre h(-1) between 13-16 and 17-33 kg. The rate constants associated with the metabolite elimination [0.144 h(-1), (+)-M1 and 0.18 h(-1), (-)-M1] were smaller than the elimination rate constants of the parent drugs [0.243 h(-1), (+)-tramadol and 0.241 h(-1), (-)-tramadol], suggesting that the metabolite disposition was rate-limited by its elimination. The presence of two subpopulations of patients was suspected on the basis of the observed bimodal distributions of the AUC(M1)/AUC(tramadol) ratios.CONCLUSIONS : The results of this study combine relationships between tramadol CL and patient covariates that may be useful for dose adjustment. Polymorphism is likely to contribute to the interpatient variability observed in the AUC M1/AUC tramadol ratios

New imidazo[1,2-a]quinoxaline derivatives: Synthesis and in vitro activity against human melanoma

International audienceNew imidazo[1,2-a]quinoxaline analogues have been synthesized in good yields via a bimolecular condensation of 2-imidazole carboxylic acid, followed by a coupling with ortho-fluoroaniline and subsequent substitution on the imidazole ring by Suzuki Cross-coupling reaction using microwave assistance. Antitumor activities of these derivatives were evaluated by growth inhibition of A375 cells in vitro. All compounds exhibited high activities compared to imiquimod and fotemustine used as references

Pharmacology of EAPB0203, a novel imidazo[1,2-a]quinoxaline derivative with anti-tumoral activity on melanoma

International audienceIn spite of the development of new anticancer drugs by the pharmaceutical industry, melanoma and T lymphomas are diseases for which medical advances remain limited. Thus, there was an urgent need of new therapeutics with an original mechanism of action. Since several years, our group develops quinox-alinic compounds. In this paper, the first preclinical results concerning one lead compound, EAPB0203, are presented. This compound exhibits in vitro cytotoxic activity on A375 and M4Be human melanoma cell lines superior to that of imiquimod and fotemustine. A liquid chromatography-mass spectrometry method was first validated to simultaneously quantify EAPB0203 and its metabolite, EAPB0202, in rat plasma. Thereafter, the pharmacokinetic profiles of EAPB0203 were studied in rat after intravenous and intraperitoneal administrations. After intraperitoneal administration the absolute bioavailability remains limited (22.7%). In xenografted mouse, after intraperitoneal administration of 5 and 20 mg/kg, EAPB0203 is more potent than fotemustine. The survival time was increased up to 4 and 2 weeks compared to control mice and mice treated by fotemustine, respectively. The results of this study demonstrate the relationship between the dose of EAPB0203 and its effects on tumor growth. Thus, promising efficacy, tolerance and pharmacokinetic data of EAPB0203 encourage the development towards patient benefit

Kinetics of circulating cell-free DNA for biomedical applications: critical appraisal of the literature

International audienceCirculating cell-free DNA is considered as one of the major breakthroughs in the field of innovative diagnosis , used as a liquid biopsy. The kinetic parameters of a biomarker are mandatory to assess its usefulness as a diagnostic tool. Obtaining precise mathematical values for the kinetic parameters (e.g., half-life) is then crucial because it could be used for therapeutic monitoring as a prognostic factor. However, little is known about the intrinsic properties of circulating cell-free DNA, more especially, its kinetic properties within the organism. We summarized the basic principles that may affect the kinetics of circulating cell-free DNA within the organism in the light of biological and clinical evidence. We also meta-analyzed the reported data in the literature and the methodologies that have been used to study the kinetic parameters of human circulating cell-free DNA in vivo. Lay abstract: Circulating cell-free DNA as a biomarker was a major breakthrough in the field of diag-nostics. Understanding the kinetic parameters of a biomarker is mandatory to assess its usefulness as a diagnostic tool, especially for therapeutic monitoring. However, at the present time little is known about its kinetic properties within the organism. This review provides an overview of the basic principles that may impact the kinetics of cell-free DNA within the organism and analyzes the reported data thus far

Population pharmacokinetics of levobupivacaine during a transversus abdominis plane block in children

International audienceBACKGROUND:Levobupivacaine is commonly used during transversus abdominis plane block in pediatric patients. However, the dosing regimen is still empirical, and the pharmacokinetic properties of levobupivacaine are not considered. Here, the pharmacokinetics of levobupivacaine during an ultrasound-guided transversus abdominis plane block were evaluated to optimize dosing regimen, with regard to the between-subject variability and the volume of levobupivacaine injected.METHOD:The clinical trial (prospective, randomized, double-blind study protocol) was conducted in 40 children aged 1 to 5 years, who were scheduled for inguinal surgery. Each patient received 0.4 mg/kg of levobupivacaine with a volume of local anesthesia solution adjusted to 0.2 mL/kg of 0.2% or 0.4 mL/kg of 0.1% levobupivacaine. Blood samples were collected at 5, 15, 20, 25, 30, 45, 60, and 75 min following the block injection. The population pharmacokinetic analysis was performed using the NONMEM software.RESULTS:From the pharmacokinetic parameters obtained, median Cmax, tmax, and area under the concentration versus time curve were 0.315 mg/L, 17 min, and 41 mg/L. min, respectively. Between-subject variability (BSV) of clearance was explained by weight. At the dose regimen of 0.4 mg/kg, none of the infants showed signs of toxicity, but in 13 patients, transversus abdominis plane block failed. After analysis, BSV for absorption rate constant, distribution volume, and clearance were 81%, 47%, and 41%, respectively. Residual unexplained variability was estimated to be 14%.CONCLUSION:For improved efficiency in the pediatric population, the dose of levobupivacaine should be greater than 0.4 mg/kg. Children's weight should be considered to anticipate any risk of toxicity

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Critically Ill Patients: How to Achieve Best Dosage Regimen According to the Clinical Situation

International audienceBackground and Objectives: Meropenem is frequently used for the treatment of severe bacterial infections in critically ill patients. Because critically ill patients are more prone to pharmacokinetic variability than other patients, ensuring an effective blood concentration can be complex. Therefore, describing this variability to ensure a proper use of this antibiotic drug limits the rise and dissemination of antimicrobial resistance, and helps preserve the current antibiotic arsenal. The aims of this study were to describe the pharmacokinetics of meropenem in critically ill patients, to identify and quantify the patients’ characteristics responsible for the observed pharmacokinetic variability, and to perform different dosing simulations in order to determine optimal individually adapted dosing regimens.Methods: A total of 58 patients hospitalized in the medical intensive care unit and receiving meropenem were enrolled, including 26 patients with renal replacement therapy. A population pharmacokinetic model was developed (using NONMEM software) and Monte Carlo simulations were performed with different dosing scenarios (bolus-like, extended, and continuous infusion) exploring the impact of clinical categories of residual diuresis (anuria, oliguria, and preserved diuresis) on the probability of target attainment (MIC: 1–45 mg/L).Results: The population pharmacokinetic model included five covariates with a significant impact on clearance: glomerular filtration rate, dialysis (continuous and semi-continuous), renal function status, and volume of residual diuresis. The clearance for a typical patient in our population is 4.20 L/h and volume of distribution approximately 44 L. Performed dosing regimen simulations suggested that, for equivalent doses, the continuous infusion mode (with loading dose) allowed the obtaining of the pharmacokinetic/pharmacodynamic target for a larger number of patients (100% for MIC ≤ 20 mg/L). Nevertheless, for the treatment of susceptible bacteria (MIC ≤ 2 mg/L), differences in the probability of target attainment between bolus-like, extended, and continuous infusions were negligible.Conclusions: Identified covariates in the model are easily accessible information in patient health records. The model highlighted the importance of considering the patient’s overall condition (renal function and dialysis) and the pathogen’s characteristics (MIC target) during the establishment of a patient’s dosing regimen

Population pharmacokinetics of nalbuphine after surgery in children

International audienceBACKGROUND : Nalbuphine is an opioid analgesic agent widely used for control of mild-to-severe pain. However, limited data are available on the pharmacokinetics of this drug in children. The aim of this study was to characterize the population pharmacokinetics of nalbuphine in patients with ages ranging from 1 to 11 yr and to identify patient characteristics partially explaining inter-individual variability in nalbuphine pharmacokinetic parameters.METHODS : Twenty-two children were included in this study. They received nalbuphine after surgery by continuous infusion (loading dose, 0.2 mg kg(-1) over 10 min followed by continuous infusion of 0.8 mg kg(-1) over 24 h). If pain relief was not adequate, 0.1 mg kg(-1) bolus doses were allowed in 10 min. Eleven blood samples were collected per patient. The data were analysed by non-linear mixed-effect modelling with the use of a two-compartment structural model.RESULTS : Twenty patients completed the study. In the final model, the parameter values were standardized for a body weight of 70 kg using an allometric model. Population parameter estimates were: clearance 130 litre h(-1) 70 kg(-1), inter-compartment clearance 75.6 litre h(-1) 70 kg(-1), central volume of distribution 210 litre 70 kg(-1), and peripheral volume of distribution 151 litre 70 kg(-1). In the children of this study, total clearance expressed in litre h(-1) kg(-1) decreased significantly with increasing age and the elimination half-life significantly increased.CONCLUSIONS : The allometric power model developed in this study best reflected the data and may be useful for dose adjustment

Prior information for population pharmacokinetic and pharmacokinetic/pharmacodynamic analysis: overview and guidance with a focus on the NONMEM PRIOR subroutine

International audiencePopulation pharmacokinetic analysis is used to estimate pharmacokinetic parameters and their variability from concentration data. Due to data sparseness issues, available datasets often do not allow the estimation of all parameters of the suitable model. The PRIOR subroutine in NONMEM supports the estimation of some or all parameters with values from previous models, as an alternative to fixing them or adding data to the dataset. From a literature review, the best practices were compiled to provide a practical guidance for the use of the PRIOR subroutine in NONMEM. Thirty-three articles reported the use of the PRIOR subroutine in NONMEM, mostly in special populations. This approach allowed fast, stable and satisfying modelling. The guidance provides general advice on how to select the most appropriate reference model when there are several previous models available, and to implement and weight the selected parameter values in the PRIOR function. On the model built with PRIOR, the similarity of estimates with the ones of the reference model and the sensitivity of the model to the PRIOR values should be checked. Covariates could be implemented a priori (from the reference model) or a posteriori, only on parameters estimated without prior (search for new covariates)

Target-Mediated Drug Disposition Population Pharmacokinetics Model of Alirocumab in Healthy Volunteers and Patients: Pooled Analysis of Randomized Phase I/II/III Studies

International audienceBackground and Objective Proprotein convertase subtil-isin/kexin type 9 inhibition with monoclonal antibodies such as alirocumab significantly reduces low-density lipoprotein-cholesterol levels ± other lipid-lowering therapies. We aimed to develop and qualify a population pharmacokinetics (PopPK) model for alirocumab in healthy subjects and patients, taking into account the mecha-nistic target-mediated drug disposition (TMDD) process. Methods This TMDD model was developed using a subset of the alirocumab clinical trial database, including nine phase I/II/III studies (n = 527); the model was subsequently expanded to a larger data set of 13 studies (n = 2870). Potential model parameters and covariate relationships were explored, and predictive ability was qualified using a visual predictive check. Results The TMDD model was built using the quasi-steady-state approximation. The final TMDD-quasi-steady-state model included a significant relationship between distribution volume of the central compartment and disease state: distribution volume of the central compartment was 1.56-fold higher in patients vs. healthy subjects. Separately, application of the model to the expanded data set revealed a significant relationship between linear clearance and statin co-administration: linear clearance was 1.27-fold higher with statins. The good predictive performance of the TMDD model was assessed based on graphical and numerical quality criteria, together with the visual predictive check and comparison of the predictions to those from a PopPK model with parallel linear and Michaelis-Menten clearances (i.e., simplification of the TMDD PopPK model). Conclusions This mechanistic TMDD PopPK model integrates the interaction of alirocumab with its target and accurately predicts both alirocumab and total proprotein convertase subtilisin/kexin type 9 concentrations in healthy subjects and patients. Electronic supplementary material The online version of this article