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To date, therapeutic drug monitoring ( TDM) is carried out with antiretrovirals and is usually based on total concentrations ( Ct). However, for some patients, TDM does not reflect efficacy or the avoidance of toxicity as is the case for atazanavir ( ATV), a HIV protease inhibitor. As the unbound concentration ( Cu) is the pharmacological active form, the aim of the study was to evaluate the value of Cu and the unbound fraction ( fu, fu = Cu/ Ct) for the TDM of ATV. The variability of Cu and the corresponding fu of ATV was explored in 43 patients treated with ATV for an average of 13.5 months. Cu was determined by coupling ultrafiltration and liquid chromatography. As ATV is highly bound to alpha-1 acid glycoprotein ( AAG), the correlation between fu and AAG was also evaluated. The viral load was monitored to evaluate the patients' virologic response, while total plasma bilirubin and unconjugated plasma bilirubin were used as biomarkers of ATV toxicity. Median trough Cu and Ct were 37.9 μg/L (Interquartile range ( IQR) 20.6-94.9 μg/L) and 628.6 μg/L ( IQR 362.7-1078.1 μg/L), respectively. fu, Cu and Ct showed high variability, but the fu variability was not correlated with the AAG level. The unbound concentration and fraction were unrelated to the virologic response ( P = 0.21 and P = 0.65 for Cu and fu, respectively) nor to the unconjugated bilirubin (Pearson correlation coefficient (ρ), ρ = 0.22; P = 0.17 for Cu). Neither total nor unbound concentrations of ATV fully explained hyperbilirubinaemia or virologic failure. From this study, we conclude that unbound ATV did not appear to be more relevant than Ct. [ABSTRACT FROM AUTHOR]

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During space flights, the human body is submitted to weightlessness which induces physiological variations that could modify drug disposition during space missions. Since space experiments are infrequent and difficult to perform, in order to evaluate pharmacokinetic modifications, simulation experiments of weightlessness have to be carried out on earth, using animal-models such as the Morey-Holton model. In this model, rats are suspended by the tail with their front paws on the ground. We studied the effects of simulated weightlessness on drug absorption and on gastric emptying, using acetaminophen as a probe. Three periods of suspension (1, 2 and 5 days) were compared with two control groups (free and attached rats). The attached group was used to evaluate a possible ‘stress effect’ caused by the suspension device. Each group was composed of 36 rats (12 sampling times and three rats per time). An oral dose of acetaminophen (100 mg/kg) was administered and blood samples were collected before and up to 12 h after administration. Plasma assays were performed using an high-performance liquid chromatography method with UV detection. The calculated population pharmacokinetic parameters were Ka, Kel (first order absorption and elimination constants) and Vd/F (apparent volume of distribution). The statistical interpretation of the population pharmacokinetic parameters indicated that 2 days of suspension significantly decreased the Vd/F by 83% and the Ka by 125%. The increase in the Ka was probably because of an increased acceleration of the gastric emptying and/or to a decrease in the total peripheral resistance which increased intestinal blood flow. [ABSTRACT FROM AUTHOR]

A letter to the editor about a case report on a 60-year-old male prisoner with Nerium oleander self-poisoning is presented.

The article offers information on the discoverers of ivermectin, a broad-spectrum parasiticide, used in humans and animals. It reports the case of a 13-year-old boy admitted to the pediatric intensive care unit for impaired consciousness. It discusses the cases of neurologic disorders after ivermectin treatment in humans.

Aims: Sertraline is frequently prescribed for mental health conditions in both pregnant and breastfeeding women. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model to describe the pharmacokinetics of sertraline during the perinatal period and explain interindividual variability., Methods: Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort SSRI-Breast Milk study. A popPK model for sertraline maternal plasma and breast milk concentrations was developed and allowed estimating the milk-to-plasma ratio (MPR). An additional fetal compartment allowed cord blood concentrations to be described. Several covariates were tested for significance. Ultimately, model-based simulations allowed infant drug exposure through placenta and breast milk under various conditions to be predicted., Results: Thirty-eight women treated with sertraline were included in the study and provided 89 maternal plasma, 29 cord blood and 107 breast milk samples. Sertraline clearance was reduced by 42% in CYP2C19 poor metabolizers compared to other phenotypes. Doubling milk fat content increased the MPR by 95%. Simulations suggested a median daily infant dosage of 6.9 μg kg -1 after a 50 mg maternal daily dose, representing 0.95% of the weight-adjusted maternal dose. Median cord blood concentrations could range from 3.29 to 33.23 ng mL -1 after maternal daily doses between 25 and 150 mg., Conclusions: Infant exposure to sertraline, influenced by CYP2C19 phenotype and breast milk fat content, remains low, providing reassurance regarding the use of sertraline during pregnancy and breastfeeding., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Data on drug transfer into human breast milk are sparse. This study aimed to quantify concentrations of cetirizine and levocetirizine in breast milk and to estimate drug exposure to infants. Breastfeeding women at least 8 weeks postpartum and using cetirizine or its pure (R)-enantiomer levocetirizine were eligible to participate. Breast milk samples were collected at six predefined times during a dose interval (0, 2, 4, 8, 12 and 24 h after drug intake) at steady state. Infant drug exposure was estimated by calculating the absolute infant dose (AID) and the weight-adjusted relative infant dose (RID). In total, 32 women were eligible for final inclusion, 31 women using cetirizine and one woman using levocetirizine. Means of the individual maximum and average cetirizine milk concentrations were 41.0 and 16.8 μg/L, respectively. Maximum concentrations occurred on average 2.4 h after intake, and the mean half-life in milk was 7.0 h. Estimated AID and RID for cetirizine in a day were 2.5 μg/kg and 1.9%, respectively. The corresponding values for levocetirizine were 1.1 μg/kg and 1.9%. No severe adverse events were reported. Our findings demonstrate that the transfer of cetirizine and levocetirizine into breast milk is low and compatible with breastfeeding., (© 2023 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Medication intake during the postpartum period is common with discontinuation of breastfeeding sometimes unnecessarily recommended for fear of adverse effects in the breastfed infant, while exposure through human milk is generally low. The assessment of risks associated with medication intake during breastfeeding is based, among other things, on the little clinical evidence available in specialized sources of information, and on pharmacokinetic principles. A decision-making support is presented to facilitate communication with mothers, foster medication adherence and prevent unnecessary interruption of breastfeeding., Competing Interests: Les auteur-es n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Introduction: Despite many research efforts, current data on the safety of medicines during breastfeeding are either fragmented or lacking, resulting in restrictive labeling of most medicines. In the absence of pharmacoepidemiologic safety studies, risk estimation for breastfed infants is mainly derived from pharmacokinetic (PK) information on medicine. This manuscript provides a description and a comparison of the different methodological approaches that can yield reliable information on medicine transfer into human milk and the resulting infant exposure., Area Covered: Currently, most information on medicine transfer in human milk relies on case reports or traditional PK studies, which generate data that can hardly be generalized to the population. Some methodological approaches, such as population PK (popPK) and physiologically based PK (PBPK) modeling, can be used to provide a more complete characterization of infant medicine exposure through human milk and simulate the most extreme situations while decreasing the burden of sampling in breastfeeding women., Expert Opinion: PBPK and popPK modeling are promising approaches to fill the gap in knowledge of medicine safety in breastfeeding, as illustrated with our escitalopram example.

Aim: Hypertension is a public health problem managed according to therapeutic strategies published in France by the Hauteautoritéde santé (HAS - French Health Authorities). For patients with resistant hypertension, related or not to a non-adherence, prescribers need to be sure the exposure is high enough to achieve the tensional target. Quantitative analysis of antihypertensive drugs in different biological matrices (blood/urine) is one possible solution. However, this involves determining the concentrations observed at standard doses and knowing how to interpret the measured concentrations. It is also necessary to identify medical laboratories that can assay antihypertensive drugs. This was the aim of our work., Methods: The main antihypertensive drugs recommended by the HAS have been listed. For each of them, we looked for published steady-state plasma/serum concentrations and quantities excreted in the urine at usual dosages. In addition, the elimination half-life and linear pharmacokinetic profile were specified for each antihypertensive agent measured in plasma/serum. Pharmacology-Toxicology laboratories in France likely to carry out assays were identified. The time taken to report the result and the cost of the analysis were also specified., Results: All of the afore-mentioned information has been collected and presented in a table. This can then be used to compare the plasma/serum concentration or the quantity measured in a patient's urine with the values reported in the literature. In cases where the blood sampling times differ between those of the patient and the published data, the patient's measured value is compared to the estimated value based on the published concentrations and pharmacokinetics., Conclusion: Interpretation of the plasma/serum/urinary value measured or estimated for an antihypertensive drug is a particularly interesting approach to determine if drug exposure is enough and a possible non-adherence. However, this activity is mostly carried out in hospital centres., (Copyright © 2019. Published by Elsevier Masson SAS.)

Positron emission tomography-computed tomography is a medical imaging method measuring the activity of a radiotracer chosen to accumulate in cancer cells. A recent trend of medical imaging analysis is to account for the radiotracer's pharmacokinetic properties at a voxel (three-dimensional-pixel) level to separate the different tissues. These analyses are closely linked to population pharmacokinetic-pharmacodynamic modelling. Kineticists possess the cultural background to improve medical imaging analysis. This article stresses the common points with population pharmacokinetics and highlights the methodological locks that need to be lifted.

Quinine monitoring should be based on unbound concentration due to variable unbound fraction in malaria patients., (Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Objective: Several recent studies have established a correlation between NAT2 polymorphism and hepatotoxicity induced by isoniazid. The objective of this work was to assess the place of isoniazid dosage, marker of acetylation phenotype, in clinical practice in the department of Haute-Garonne., Methods: Data from reportable disease of tuberculosis and the results of isoniazid dosage performed at the pharmacokinetics and clinical toxicology laboratory were used during the period 2009-2012., Results: The current practice of dosage is far from being systematical: only 3.9% of patients who developed tuberculosis have benefited from isoniazid dosage. The isoniazid initial posology was adapted to the acetylation capacity for only 33.3% of patients., Conclusion: A decision tree was realized and used to identify populations (low metabolism) liable to benefit from isoniazid dosage., (© 2014 Société Française de Pharmacologie et de Thérapeutique.)

Background: Patients with a simultaneous pancreas-kidney transplant (SPKT), especially those with gastroparesis, often have gastro-intestinal (GI) disorders that can modify immunosuppressant pharmacokinetics. We compared the MPA 12-hours area under the curve (AUC(0-12)) in SKPT patients with severe gastroparesis receiving mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS)., Material/methods: Fifteen SKPT patients having a severe gastroparesis were switched, at 182 (69-1523) days post-transplantation, from MMF to EC-MPS because of GI disorders. MPA AUC(0-12) values were obtained before and after the switch, ie, under MMF (500 mg b.i.d.) at 169 (51-1522) days post-transplantation and EC-MPS (360 mg b.i.d.) at 102 (26-355) days after the switch., Results: Mean MPA AUC(0-12) h did not differ significantly under MMF and EC-MPS, ie, 40.13±14 and 38.24±15.5 mg*h/L, respectively. Trough and maximal MPA concentrations were similar with both MPA formulations. Although all patients had GI disorders under MMF (100%), only 3 had persistent GI disorders under EC-MPS (20%) (p<0.001)., Conclusions: In SKPT patients with severe gastroparesis, exposure to MPA is similar under MMF and EC-MPS. However, the incidence of GI disorders is significantly lower when patients are given EC-MPS.

Diagnostic and interventional radiology of patients is nowadays crucial with increasing requirement for iodinated contrast agents infusion. Besides adverse reactions after administration of the iodinated contrast agents due to their toxicity, immediate hypersensitivity reactions and reactions resembling delayed hypersensitivity appearing from 1 hour to several days later, have been reported. Patients at high risk to develop such adverse events have to be detected on the basis of their risk factors in order to prevent or limit serious outcomes. Previous reactions to contrast media, asthma, atopy and cardiovascular disorders are risk factors for anaphylactic or anaphylactoid reactions. Female gender, age and beta-blockers increase the severity. This article aims to summarize the risk of allergic reactions related to the use of iodinated contrast agents and to suggest a way for diagnosis, treatment and prevention according to each clinical situation.

As the current nutritional zinc intake frequently falls outside the Dietary Reference Intake (DRI) and as zinc is an essential trace mineral involved in the function of many enzymes, zinc supplementation has been recommended to prevent or treat the adverse effects of zinc deficiency. The aim of the present study was to compare the oral bioavailability of zinc bis-glycinate (a new formulation) with zinc gluconate (reference formulation). A randomized, cross-over study was conducted in 12 female volunteers. The two products were administrated orally at the single dose of 15 mg (7.5 mg x 2), with a 7-day wash-out period between the two tests. Serum concentrations of zinc were assayed by a validated inductively coupled plasma optical emission spectrometry (ICP-OES) method and C(max), T(max), and areas-under-the-curve (AUCs) were determined. The comparison between the two treatments was performed by comparing the C(max), AUC(t), and AUC(inf) using an analysis of variance followed by the calculation of the 90% confidence intervals of the ratio test/reference. Bis-glycinate administration was safe and well tolerated and bis-glycinate significantly increased the oral bioavailability of zinc (+43.4%) compared with the gluconate.

The optimisation of the intestinal absorption of drugs represents one of the most important steps in the development of new pharmacologically active products. Several in vitro models are commonly used to study the mechanisms involved in drug absorption and all have advantages and disadvantages, notably they are often very static, and rarely take into account the intestinal motility and blood flow. The aim of this project was to validate a new ex vivo/in vitro model to study drug absorption, the perfused everted intestinal segment of rat, using three absorption markers: antipyrine (CAS 60-80-0) for passive transcellular diffusion, mannitol (CAS 69-65-8) for the paracellular diffusion and digoxin (CAS 20830-75-5) as a P-glycoprotein substrate. The mean apparent permeabilities (P(app)) for the markers were 6.07 (+/- 0.99) x 10(-5), 8.79 (+/- 0.28) x 10(-6) and 3.1 (+/- 0.85) x 10(-5) cm/s, respectively. The model is simple to establish and gives excellent absorption kinetics (r2 > 0.99), providing a valuable tool to study drug absorption during preclinical development, and subsequently the effects of different pharmaceutical formulations on that absorption.