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.

[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.

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.

Infant exposure to Fluvoxamine through placenta and human milk: a case series - A contribution from the ConcePTION project.

Introduction: Fluvoxamine is widely used to treat depression during pregnancy and lactation. However, limited data are available on its transfer to the fetus or in human milk. This case series provides additional information on the infant exposure to fluvoxamine during pregnancy and lactation. Case presentation: Two women, aged 38 and 34 years, diagnosed with depression were treated with 50 mg fluvoxamine during pregnancy and lactation. At delivery a paired maternal and cord blood sample was collected for each woman. The first mother exclusively breastfed her child for 4 months and gave one foremilk and one hindmilk sample at 2 days and 4 weeks post-partum, whereas the second mother did not breastfeed. Results: The cord to plasma concentration ratios were 0.62 and 0.48, respectively. At 2 weeks post-partum, relative infant doses (RID) were 0.47 and 0.57% based on fluvoxamine concentrations in foremilk and hindmilk, respectively. At 4 weeks post-partum, the RIDs were 0.35 and 0.90%, respectively. The child from the first mother was born healthy and showed a normal development at the 6th, 18th and 36th month follow-ups. One of the twins from the second woman was hospitalized for hypoglycemia that was attributed to gestational diabetes and low birth weight. The second one was born healthy. Conclusion: These results suggest a minimal exposure to fluvoxamine during lactation which is in accordance with previously published data. Larger clinical and pharmacokinetic studies assessing the long-term safety of this drug during lactation and the variability of its exposure through breastmilk are warranted.

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.

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.

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.

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.

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.

Maternal drugs and breastfeeding: Risk assessment from pharmacokinetics to safety evidence - A contribution from the ConcePTION project.

Human milk is the most appropriate form of nutrition for infants while taking medication during the postpartum period is common. Discontinuation of breastfeeding is sometimes wrongly recommended for fear of adverse effects in the breastfed infant whereas only a few drugs are strictly contraindicated while breastfeeding. Most drugs are transferred from the mother's blood to the milk, but the breastfed infant usually ingests a small drug amount through human milk. As population-based evidence is still scarce on safety of drugs during breastfeeding, risk assessment relies on the little clinical evidence available and on pharmacokinetic principles, as well as on specialized sources of information that are essential for clinical decision-making. Risk assessment should not only be based on the drug's potential risk for the breastfed infant but should always take into account the benefits associated to breastfeeding, the risks of untreated maternal disease and the maternal willingness to breastfeed. Identifying situations with potential for drug accumulation in the breastfed infant is decisive while assessing the risk. Health care providers should always assume that mothers will be concerned and use risk communication as a key to ensure medication adherence and prevent unnecessary interruption of breastfeeding. When a mother still expresses concerns, decision support algorithms may facilitate communication and some strategies can be offered to minimize the drug exposure in the breastfed infant even when clinically not justified.

Method validation and clinical application for the quantification of lopinavir, efavirenz, and ritonavir in breast milk using liquid chromatography tandem mass spectrometry.

A liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been validated for quantification of three antiretroviral drugs (efavirenz [EFV], lopinavir [LPV], and ritonavir [RTV]) from human breast milk. The samples were extracted employing protein precipitation method using methanol as precipitating agent. The supernatant was evaporated and reconstituted before injecting into the chromatograph and separated on a biphenyl column. Calibration curves for the three tested antiretroviral drugs were linear (r ≥ 0.999) over the range examined. The inter- and intra-day coefficients of variation (CV) were ≤15% for efavirenz, lopinavir, and ritonavir. Mean recovery ranged from 96% to 105% and no major matrix effects were observed. This validated LC-MS/MS method was efficiently applied to determine EFV, LPV, and RTV concentrations in breast milk from Human Immunodeficiency Virus (HIV)-positive breastfeeding mothers. This assay requires a simple sample processing method with a short run time, making it well suited for high-throughput routine clinical or research purposes.

Evaluation of 4 quantification methods for monitoring 16 antibiotics and 1 beta-lactamase inhibitor in human serum by high-performance liquid chromatography with tandem mass spectrometry detection.

Antibiotic (ATB) prescription in an intensive care unit (ICU) requires continuous monitoring of serum dosages due to the patient's pathophysiological condition. Dosing adjustment is necessary to achieve effective targeted concentrations. Since ICUs routinely use a large number of ATBs, global monitoring needs to be developed. In the present study, we developed a global analytical method for extracting, separating and quantifying the most widely used ATBs in ICUs: amoxicillin, piperacillin, cefazolin, cefepime, cefotaxime, ceftazidime, ceftolozane, ceftriaxone, ertapenem, meropenem, ciprofloxacin, moxifloxacin, levofloxacin, daptomycin, dalbavancin, linezolid and a beta-lactamase inhibitor: tazobactam. To guarantee the robustness of the quantification, we differentiated the 16 ATBs and the beta lactamase inhibitor into 4 pools (ATB1 to ATB4), taking into account prescription frequency in the ICU, the physicochemical properties and the calibration ranges of the ATBs selected. The whole ATB was then separated with two LC columns in reversed phase: Kinetex Polar-C18 100 Å and Polar-RP-80 synergy, in less than 6.5 min. Detection was carried out by electrospray in positive ion mode, by tandem mass spectrometry (LC-MS/MS. The four quantification methods were validated according to the European guidelines on bioanalytical method validation (EMEA guide), after determining the extraction yields, matrix effects, recovery, precision, accuracy, within-run precision and between-run precision. For all analyses, bias is < 15% and is comparable to the literature and LOQs vary from 0.05 mg.L-1 for ciprofloxacin to 1.00 mg.L-1 for ceftriaxone and dalbavancin. The stability time of cefepime and piperacillin is 3 hrs and for the other ATBs 6 hrs in serum at room temperature. For long-term stability, freezing at - 80 °C guarantees 3 months of stability for ceftriaxone and dalbavancin and more than 6 months for the other ATBs.

"De-Shrinking" EBEs: The Solution for Bayesian Therapeutic Drug Monitoring.

BACKGROUND: Therapeutic drug monitoring (TDM) aims at individualising a dosage regimen and is increasingly being performed by estimating individual pharmacokinetic parameters via empirical Bayes estimates (EBEs). However, EBEs suffer from shrinkage that makes them biased. This bias is a weakness for TDM and probably a barrier to the acceptance of drug dosage adjustments by prescribers. OBJECTIVE: The aim of this article is to propose a methodology that allows a correction of EBE shrinkage and an improvement in their precision. METHODS: As EBEs are defined, they can be seen as a special case of ridge estimators depending on a parameter usually denoted λ. After a bias correction depending on λ, we chose λ so that the individual pharmacokinetic estimations have minimal imprecision. Our estimate is by construction always better than EBE with respect to bias (i.e. shrinkage) and precision. RESULTS: We illustrate the performance of this approach with two different drugs: iohexol and isavuconazole. Depending on the patient's actual pharmacokinetic parameter values, the improvement given by our approach ranged from 0 to 100%. CONCLUSION: This innovative methodology is promising since, to the best of our knowledge, no other individual shrinkage correction has been proposed.

Tacrolimus Intrapatient Variability After Switching From Immediate or Prolonged-Release to Extended-Release Formulation, After an Organ Transplantation.

Background and Purpose: Several formulations of tacrolimus are available, but evidence of the benefit of changing to the most recent formulations is lacking. Tacrolimus intra-patient variability (tacrolimus IPV) is an emerging risk factor associated with poor graft outcomes after solid organ transplantations. Here, we examined the modifications of tacrolimus IPV after switching to a different formulation of tacrolimus. Experimental Approach: We identified 353 solid organ transplant recipients that were switched in our center from immediate-release (IR-tacrolimus) or prolonged-release tacrolimus (PR-tacrolimus) to extended-release, LCP-tacrolimus (LCP-tacrolimus). Among them, 54 patients underwent at least 3 available tacrolimus blood concentrations before and after the switch, allowing us to investigate tacrolimus IPV. Key Results: The switch was considered as a safe procedure since only four of the 353 patients presented a graft rejection after the switch, and no patient was hospitalized for tacrolimus overdose. The tacrolimus IPV estimated by the coefficient of variation (CV-IPV) was stable before and after the switch to LCP-tacrolimus (CV-IPV: 29.0% (IQR 25-75 (15.5; 38.5) before and 24.0% (15.8; 36.5) after the switch, p = 0.65). Conclusion and Implications: Switching from IR- or PR-tacrolimus to LCP-tacrolimus is a safe procedure. However, the CV-tacrolimus IPV was not impacted by the change of formulation.

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.

Neglecting Plasma Protein Binding in COVID-19 Patients Leads to a Wrong Interpretation of Lopinavir Overexposure.

Boffito et al. recalled the critical importance to correctly interpret protein binding. Changes of lopinavir pharmacokinetics in coronavirus disease 2019 (COVID-19) are a perfect illustration. Indeed, several studies described that total lopinavir plasma concentrations were considerably higher in patients with severe COVID-19 than those reported in patients with HIV. These findings have led to a reduction of the dose of lopinavir in some patients, hypothesizing an inhibitory effect of inflammation on lopinavir metabolism. Unfortunately, changes in plasma protein binding were never investigated. We performed a retrospective cohort study. Data were collected from the medical records of patients hospitalized for COVID-19 treated with lopinavir/ritonavir in intensive care units or infectious disease departments of Toulouse University Hospital (France). Total and unbound concentrations of lopinavir, C reactive protein, albumin, and alpha-1-acid glycoprotein (AAG) levels were measured during routine care on the same samples. In patients with COVID-19, increased total lopinavir concentration is the result of an increased AAG-bound lopinavir concentration, whereas the unbound concentration remains constant, and insufficient to reduce the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral load. Although international guidelines have recently recommended against using lopinavir/ritonavir to treat severe COVID-19, the description of lopinavir pharmacokinetics changes in COVID-19 is a textbook case of the high risk of misinterpretation of a total drug exposure when changes in protein binding are not taken into consideration.

A comprehensive review on non-clinical methods to study transfer of medication into breast milk - A contribution from the ConcePTION project.

Breastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBPK modelling to predict transfer of medication into the human milk. However, reliable data as input for PBPK models is often missing. The iterative development of in vitro, animal in vivo and PBPK modelling methods seems to be a promising approach. Human in vitro models will deliver essential data on the transepithelial transport of medication, whereas the combination of animal in vitro and in vivo methods will deliver information to establish accurate in vitro/in vivo extrapolation (IVIVE) algorithms and mechanistic insights. Such a non-clinical platform will be developed and thoroughly evaluated by the Innovative Medicines Initiative ConcePTION.

Safety of Pyrazinamide for the Treatment of Tuberculosis in Older Patients Over 75 Years of Age: A Retrospective Monocentric Cohort Study.

OBJECTIVES: Pyrazinamide (PZA) has a controversial safety profile in older patients. We aimed to assess the frequency and risk factors for adverse drug reactions (ADRs) in patients over 75 years of age treated for tuberculosis with or without PZA. METHODS: We conducted a retrospective monocentric study including patients aged over 75 years treated for active tuberculosis between 2008 and 2018. The frequency, type, seriousness, and causality assessment of ADRs to anti-tuberculosis treatment were compared between patients receiving PZA or not. Risk factors for ADRs were investigated using univariable and multivariable analyses by logistic regression. RESULTS: Among the 110 patients included, 54 (49.1%) received PZA (group 1) and 56 (50.9%) did not (group 2). ADRs to anti-tuberculosis drugs occurred in 31 patients (57.4%) in groups 1 and 15 (26.8%) in group 2 (p = 0.003). PZA-related ADRs occurred in 40.7% of exposed patients. Frequency of renal ADRs was higher in group 1 (9.3% vs 0%; p = 0.026). Rates of hepatic (18.5% vs 12.5%; p = 0.38), digestive (22.2% vs 8.9%; p = 0.054), and allergic (14.8% vs 5.4%; p = 0.12) ADRs were numerically higher in group 1 although the differences were not statistically significant. Serious ADRs occurred more frequently in group 1 (24.1% vs 8.9%; p = 0.03). The use of PZA was the only independent risk factor for ADRs to anti-tuberculosis drugs (odds ratio 3.75, 95% CI 1.5-9.6; p = 0.0056). No risk factors for PZA-related ADRs were identified. CONCLUSION: In older French patients, the use of PZA was associated with more frequent ADRs to anti-tuberculosis drugs.

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.