[Risk assessment of drugs during breastfeeding]. / Évaluation des risques liés aux médicaments pendant l'allaitement.

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.

La prise de médicaments pendant la période postnatale est courante et associée à un arrêt de l'allaitement parfois recommandé à tort par crainte d'effets indésirables chez l'enfant allaité, alors que l'exposition à travers le lait maternel est généralement faible. L'évaluation des risques d'utilisation de médicaments pendant l'allaitement repose, entre autres, sur le peu de preuves cliniques disponibles, documentées dans des sources d'information spécialisées, et sur les principes pharmacocinétiques. Un algorithme d'aide à la décision est proposé pour faciliter la communication avec les mères, renforcer l'adhésion thérapeutique et éviter une interruption inutile de l'allaitement.

Efficacy of dihydroartemisinin/piperaquine in patients with non-complicated Plasmodium falciparum malaria in Yaoundé, Cameroon.

BACKGROUND: Dihydroartemisinin/piperaquine is increasingly used for the treatment of uncomplicated Plasmodium falciparum malaria in Africa. The efficacy of this combination in Cameroon is poorly documented, while resistance to dihydroartemisinin/piperaquine readily spreads in Southeast Asia. OBJECTIVES: This study evaluated the clinical efficacy of dihydroartemisinin/piperaquine in Cameroon, as well as the molecular profile and phenotypic susceptibility of collected isolates to dihydroartemisinin and piperaquine. PATIENTS AND METHODS: Dihydroartemisinin/piperaquine efficacy in 42 days was followed-up for 138 patients presenting non-complicated falciparum malaria. Piperaquine concentration was determined at day 7 for 124 patients. kelch13 gene polymorphisms (n = 150) and plasmepsin2 gene amplification (n = 148) were determined as molecular markers of resistance to dihydroartemisinin and piperaquine, respectively. Parasite susceptibility to dihydroartemisinin and piperaquine was determined using validated in vitro survival assays. RESULTS: The efficacy of dihydroartemisinin/piperaquine treatment was 100% after PCR correction. The reinfections were not associated with a variation of piperaquine concentration at day 7. Ninety-six percent (144/150) of the samples presented a WT allele of the kelch13 gene. Two percent (3/150) presented the non-synonymous mutation A578S, which is not associated with resistance to dihydroartemisinin. No duplication of the plasmepsin2 gene was observed (0/148). All the samples tested in vitro by survival assays (n = 87) were susceptible to dihydroartemisinin and piperaquine. CONCLUSIONS: Dihydroartemisinin/piperaquine has demonstrated excellent therapeutic efficacy with no evidence of emerging artemisinin or piperaquine resistance in Yaoundé, Cameroon. This observation suggests that dihydroartemisinin/piperaquine could be a sustainable therapeutic solution for P. falciparum malaria if implemented in areas previously free of artemisinin- and piperaquine-resistant parasites, unlike Southeast Asia.

Determining the therapeutic range for ribavirin in transplant recipients with chronic hepatitis E virus infection.

The aim of this study was to define the therapeutic range for ribavirin (RBV) in transplant recipients with chronic hepatitis E virus (HEV) infection. In this retrospective multicentre cohort study, data of adult transplant recipients with chronic HEV infection, who had been treated with RBV monotherapy between 01-3-2008 and 01-08-2018, were included. ROC curve analyses were performed, and the half-maximal effective RBV concentration was calculated to determine a representative therapeutic range. In 96 patients, RBV monotherapy for a median of three months resulted in a sustained virologic response in 63.5% of the patients, while 88.5% of the patients developed anaemia. RBV plasma concentrations at steady state were significantly higher in clinical responders compared with clinical non-responders: median 1.96 (IQR 1.81-2.70) versus 0.49 (IQR 0.45-0.73) mg/L, P = .0004. RBV caused a dose-dependent haemoglobin reduction with higher RBV plasma concentrations resulting in more haemoglobin reduction. The therapeutic range for RBV for chronic HEV infection in transplant recipients ranges between 1.8 and 2.3 mg/L.

Hydroxychloroquine in Coronavirus Disease 2019 Patients: What Still Needs to Be Known About the Kinetics.

Different dosage regimens of hydroxychloroquine are used to manage coronavirus disease 2019 (COVID-19) patients, without information on the pharmacokinetics in this population. Blood samples (n = 101) were collected from 57 COVID-19 patients for 7 days, and concentrations were compared with simulated kinetic profiles. Hydroxychloroquine exposure is low and cannot be predicted by other populations.

Influence of extracorporeal membrane oxygenation on the pharmacokinetics of ceftolozane/tazobactam: an ex vivo and in vivo study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is increasingly used in intensive care units and can modify drug pharmacokinetics and lead to under-exposure associated with treatment failure. Ceftolozane/tazobactam is an antibiotic combination used for complicated infections in critically ill patients. Launched in 2015, sparse data are available on the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam. The aim of the present study was to determine the influence of ECMO on the pharmacokinetics of ceftolozane-tazobactam. METHODS: An ex vivo model (closed-loop ECMO circuits primed with human whole blood) was used to study adsorption during 8-h inter-dose intervals over a 24-h period (for all three ceftolozane/tazobactam injections) with eight samples per inter-dose interval. Two different dosages of ceftolozane/tazobactam injection were studied and a control (whole blood spiked with ceftolozane/tazobactam in a glass tube) was performed. An in vivo porcine model was developed with a 1-h infusion of ceftolozane-tazobactam and concentration monitoring for 11 h. Pigs undergoing ECMO were compared with a control group. Pharmacokinetic analysis of in vivo data (non-compartmental analysis and non-linear mixed effects modelling) was performed to determine the influence of ECMO. RESULTS: With the ex vivo model, variations in concentration ranged from - 5.73 to 1.26% and from - 12.95 to - 2.89% respectively for ceftolozane (concentrations ranging from 20 to 180 mg/l) and tazobactam (concentrations ranging from 10 to 75 mg/l) after 8 h. In vivo pharmacokinetic exploration showed that ECMO induces a significant decrease of 37% for tazobactam clearance without significant modification in the pharmacokinetics of ceftolozane, probably due to a small cohort size. CONCLUSIONS: Considering that the influence of ECMO on the pharmacokinetics of ceftolozane/tazobactam is not clinically significant, normal ceftolozane and tazobactam dosing in critically ill patients should be effective for patients undergoing ECMO.

Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d'Anesthésie et Réanimation-SFAR).

BACKGROUND: Beta-lactam antibiotics (ßLA) are the most commonly used antibiotics in the intensive care unit (ICU). ICU patients present many pathophysiological features that cause pharmacokinetic (PK) and pharmacodynamic (PD) specificities, leading to the risk of underdosage. The French Society of Pharmacology and Therapeutics (SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (SFAR) have joined forces to provide guidelines on the optimization of beta-lactam treatment in ICU patients. METHODS: A consensus committee of 18 experts from the two societies had the mission of producing these guidelines. The entire process was conducted independently of any industry funding. A list of questions formulated according to the PICO model (Population, Intervention, Comparison, and Outcomes) was drawn-up by the experts. Then, two bibliographic experts analysed the literature published since January 2000 using predefined keywords according to PRISMA recommendations. The quality of the data identified from the literature was assessed using the GRADE® methodology. Due to the lack of powerful studies having used mortality as main judgement criteria, it was decided, before drafting the recommendations, to formulate only "optional" recommendations. RESULTS: After two rounds of rating and one amendment, a strong agreement was reached by the SFPT-SFAR guideline panel for 21 optional recommendations and a recapitulative algorithm for care covering four areas: (i) pharmacokinetic variability, (ii) PK-PD relationship, (iii) administration modalities, and (iv) therapeutic drug monitoring (TDM). The most important recommendations regarding ßLA administration in ICU patients concerned (i) the consideration of the many sources of PK variability in this population; (ii) the definition of free plasma concentration between four and eight times the Minimal Inhibitory Concentration (MIC) of the causative bacteria for 100% of the dosing interval as PK-PD target to maximize bacteriological and clinical responses; (iii) the use of continuous or prolonged administration of ßLA in the most severe patients, in case of high MIC bacteria and in case of lower respiratory tract infection to improve clinical cure; and (iv) the use of TDM to improve PK-PD target achievement. CONCLUSIONS: The experts strongly suggest the use of personalized dosing, continuous or prolonged infusion and therapeutic drug monitoring when administering ßLA in critically ill patients.

Efavirenz and Lopinavir Levels in HIV-Infected Women and Their Nursing Infants, in Mali.

Limited data are currently available on antiretroviral pharmacokinetics in breast milk (BM) and in breastfed infants' blood. To explore these parameters in patients in Mali, we measured plasma antiretroviral levels in human immunodeficiency virus (HIV)-infected mothers and their breastfed infants over 6 months. We specifically analyzed the concentrations of efavirenz (EFV) and lopinavir (LPV) in the plasma of mothers living with HIV and their breastfed infants. Blood samples were collected at delivery and at month 1, 3, and 6 postpartum. EFV and LPV concentrations were measured by liquid chromatography-tandem mass spectrometry. HIV-1 RNA load was measured by Abbott M2000RT RealTime System at delivery and 6 months postpartum for mothers, and at 3 and 6 months postbirth for infants. The median duration of antiretroviral therapy at study inclusion was 57 months [interquartile range (IQR), 0-168 months]. The median EFV ratios of infant plasma/maternal plasma (MP) were 0.057 at month 1, 0.072 at month 3, and 0.048 at month 6. During the study period, the median BM/MP ratio of EFV was 1.16 (IQR, 0.96-20.62), which corresponds to a relative infant dose of 2.46% of the recommended weight-adjusted pediatric EFV dose at month 6. The apparent infant clearance of EFV was 0.146 l/h per kilogram at month 6. The LPV concentrations in the plasma of all infants were undetectable. No drug-related adverse reaction or toxicity was observed in any of the infants. The two women who presented a viral load of >50 copies/ml at month 6 had undetectable plasma drug concentrations at the same period. This study showed that breastfed infants received a low level of EFV but not LPV from their treated mothers.

Quinine unbound concentration is the best marker for therapeutic drug monitoring.

Quinine monitoring should be based on unbound concentration due to variable unbound fraction in malaria patients.

Determination of plasma unbound fraction of voriconazole in patients treated with a prophylactic or a curative treatment.

BACKGROUND: Voriconazole (VOR) is a triazole antifungal used in the curative treatment of invasive fungal infections and the prophylactic treatment of opportunistic fungal infections in immunocompromised patients. It is a drug for which therapeutic drug monitoring (TDM) is highly recommended. METHODS: To determine the best TDM marker, the pharmacologically active form of the drug, represented by the plasma unbound concentration (Cu) and fraction (fu), has been studied using a method based on ultrafiltration and ultra performance liquid chromatography. As albumin (Alb) is a likely factor inducing fluctuations in fu, the correlation between Alb levels and fu was carried out. Similarly, correlations between trough plasma concentrations [total concentration (Ct) and Cu] and both efficacy and safety markers were determined. Efficacy evaluation was based on monitoring fungal antigens and cultures, whereas safety was monitored by measuring bilirubin levels. RESULTS: In vitro, using blank human plasma, the mean fu was determined at 32.3% ± 5.5%, whereas in patients' plasmas treated with VOR, the median (5th-95th percentiles) of the unbound VOR fraction was 22.95% (14.95%-38.42%). A high correlation was found (rho = 0.956, P < 0.001) between Ct and Cu, though there was no correlation between serum Alb levels and fu, except for some patients with severe hypoalbuminemia (<25 g/L). CONCLUSIONS: Based on the efficacy/safety correlations, a therapeutic window has been defined ranging from 4.5 to 6.5 mg/L and 1.5 and 2.0 mg/L for trough Ct and Cu, respectively. For the first time, the relevance of new pharmacokinetic parameters, such as Cu and fu, has been explored and discussed, and our results support the current TDM protocol for VOR.

[Tuberculosis: relevance of isoniazid dosage in prevention of liver side effects]. / Tuberculose: intérêt du dosage de l'isoniazide dans la prévention des effets hépatotoxiques.

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.

Transfer of cetirizine/levocetirizine into human breast milk and estimation of drug exposure to infants through breastfeeding: A human lactation study from the ConcePTION project.

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.

Multivariate Exact Discrepancy: A New Tool for PK/PD Model Evaluation.

BACKGROUND: Pharmacokinetic models are evaluated using three types of metrics: those based on estimating the typical pharmacokinetic parameters, those based on predicting individual pharmacokinetic parameters and those that compare data and model distributions. In the third groups of metrics, the best-known methods are Visual Predictive Check (VPC) and Normalised Prediction Distribution Error (NPDE). Despite their usefulness, these methods have some limitations, especially for the analysis of dependent concentrations, i.e., evaluated in the same patient. OBJECTIVE: In this work, we propose an evaluation method that accounts for the dependency between concentrations. METHODS: Thanks to the study of the distribution of simulated vectors of concentrations, the method provides one probability per individual that its observations (i.e., concentrations) come from the studied model. The higher the probability, the better the model fits the individual. By examining the distribution of these probabilities for a set of individuals, we can evaluate the model as a whole. RESULTS: We demonstrate the effectiveness of our method through two examples. Our approach successfully detects misspecification in the structural model and identifies outlier kinetics in a set of kinetics. CONCLUSION: We propose a straightforward method for evaluating models during their development and selecting a model to perform therapeutic drug monitoring. Based on our preliminary results, the method is very promising but needs to be validated on a larger scale.

Optimization of ICP-MS internal standardization for 26 elements by factorial design experiment.

INTRODUCTION: Internal standardization is a common tool used in inductively coupled plasma - mass spectrometry (ICP-MS) analysis in order to reduce matrix effects, and thus improve the reliability and the robustness of results. However, its efficacy relies on the choice of a proper internal standard (IS) which, ideally, undergoes the same signal variations as the analyte. Thus far, IS selection has mainly relied on the proximity of atomic mass between the analyte and the internal standard. However, while it may be a satisfactory rule of thumb, more recent works suggest that this criterium might not be suitable in several conditions, among which the presence of high amounts of carbon atoms in the sample. This may thus be of particular interest in the case of trace elements determination in biological samples. MATERIALS AND METHODS: In this study, we propose an empirical and global approach to IS selection in ICP-MS through the use of a factorial design of experiments (DoE), with a focus on biological matrices of interest in clinical analysis: human blood and urine. The suitability of 13 potential IS was evaluated for 26 clinically-relevant analytes, including a polyatomic ion obtained through reaction with oxygen, across 324 experimental conditions. RESULTS AND DISCUSSION: The results underline several exceptions to the rule of IS selection based on mass proximity, notably when considering heavy or polyatomic analytes. As a consequence, measurements of said analytes in several extreme experimental conditions using IS selected by mass proximity could yield vastly erroneous results (up to 30 times the theoretical concentrations). By contrast, the use of empirically selected IS yielded much more acceptable results.

Hypoalbuminemia and Pharmacokinetics: When the Misunderstanding of a Fundamental Concept Leads to Repeated Errors over Decades.

Surprisingly, misinterpretation of the influence of hypoalbuminemia on pharmacokinetics and the clinical effects of drugs seems to be a current problem, even though hypoalbuminemia has no impact on the pharmacologically active exposure. Exceptions to this fact are highly protein-bound anaesthetics with high elimination capacity (i.e., <5 drugs on the market). To assess the frequency of misinterpretation of the influence of hypoalbuminemia on pharmacokinetics and the clinical effects of drugs between 1975 and 2021, a PubMed literature review was conducted. Each paragraph on albumin binding was classified as correct, ambiguous or incorrect, creating two acceptable categories: (1) content without any errors, and (2) content containing some incorrect and/or ambiguous statements. The analyses of these articles showed that fewer than 11% of articles contained no interpretation errors. In order to contain this misinterpretation, several measures are proposed: (1) Make the message accessible to a wide audience by offering a simplified and didactic video representation of the lack of impact of albumin binding to drugs. (2) Precise terminology (unbound/free form/concentration) should be used for highly bound drugs. (3) Unbound/free forms should be systematically quantified for highly plasma protein bound drugs for clinical trials as well as for therapeutic drug monitoring.

Safety of medicines during breastfeeding - from case report to modeling: a contribution from the ConcePTION project.

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.

Biased computation of probability of target attainment for antimicrobial drugs.

The medical literature is replete with articles in which there is confusion between "free concentration" and "unbound fraction" (fu ), which is the ratio of free to total plasma concentration. The lack of clarity in distinguishing between these two terms has led to biased computations, erroneous interpretations, and misleading recommendations. The problems are highlighted in this paper, taking the example of calculation of Probability of Target Attainment (PTA). This metric is used to propose pharmacokinetic/pharmacodynamic (PK/PD) breakpoints required for the interpretation of Antimicrobial Susceptibility Testing. Based on Monte Carlo simulations of the PK/PD index, area under the unbound concentration time curve/minimum inhibitory concentration (fAUC/MIC), computation of PTA from total plasma concentrations scaled by fu ineluctably leads to biased estimates. The bias is greater if the variability associated with fu is added, instead of removing it during this scaling. The explanation for the bias is that total plasma drug concentrations are intrinsically more variable than the corresponding free concentrations. This is due to the variability of antimicrobial binding for total, but not for free plasma concentrations. In consequence, the greater variability always leads to underestimation of the PK/PD cutoff (i.e., the critical MIC that is guaranteed for a given percentile of the population). A further consequence is an increase in calculated dosage required to attain the targeted quantile. This erroneous approach, of using free antimicrobial drug fraction, is not limited to the derivation of PK/PD cutoff, but may also have consequences for antimicrobials drug safety in clinical patients.

Exploration of the relationship between cumulative exposure to tobramycin and ototoxicity in patients with cystic fibrosis.

BACKGROUND: Aminoglycosides (AGs), such as tobramycin, are essential antibiotics in the management of pulmonary infections in patients with cystic fibrosis (CF). They induce ototoxicity without the relationship being clearly described in the literature. Our aim is to propose a mathematical and statistical model describing the relationship between the estimated cumulative exposure (Area Under the Curve, AUC) to tobramycin and ototoxicity with audiogram interpretation in young patients with CF. METHODS: Cumulative AUCs were estimated for each course of tobramycin, for the 106 individuals with CF (between 4 and 22 years of age) enrolled in this retrospective study (35 who had received IV tobramycin, 71 controls). Mean hearing loss was calculated for each audiogram and a statistical model was developed to predict hearing loss. RESULTS: The model confirms a significant relationship between cumulative tobramycin exposure and changes in hearing acuity: Meanhearingloss=2.7+(3×10-5)×AUC_tobramycin+individual_susceptibility However, the ototoxic effect is not clinically perceptible (mean hearing loss: 3.8 dB). The impact of AUC on hearing loss is minor in these subjects who received a limited number of courses of tobramycin (median: 5 courses). CONCLUSION: A significant relationship between cumulative exposure to tobramycin and ototoxicity was demonstrated. Individual treatment susceptibility should not be overlooked. As ototoxicity is not clinically perceptible in the study subjects, hearing tests should be continued during adulthood to provide individualized medical guidance and to obtain a lifetime analysis of the relationship between exposure and hearing loss.