Optimization of Ganciclovir and Valganciclovir Starting Dose in Children by Machine Learning.

BACKGROUND AND OBJECTIVES: Ganciclovir (GCV) and valganciclovir (VGCV) show large interindividual pharmacokinetic variability, particularly in children. The objectives of this study were (1) to develop machine learning (ML) algorithms trained on simulated pharmacokinetics profiles obtained by Monte Carlo simulations to estimate the best ganciclovir or valganciclovir starting dose in children and (2) to compare its performances on real-world profiles to previously published equation derived from literature population pharmacokinetic (POPPK) models achieving about 20% of profiles within the target. MATERIALS AND METHODS: The pharmacokinetic parameters of four literature POPPK models in addition to the World Health Organization (WHO) growth curve for children were used in the mrgsolve R package to simulate 10,800 pharmacokinetic profiles. ML algorithms were developed and benchmarked to predict the probability to reach the steady-state, area-under-the-curve target (AUC0-24 within 40-60 mg × h/L) based on demographic characteristics only. The best ML algorithm was then used to calculate the starting dose maximizing the target attainment. Performances were evaluated for ML and literature formula in a test set and in an external set of 32 and 31 actual patients (GCV and VGCV, respectively). RESULTS: A combination of Xgboost, neural network, and random forest algorithms yielded the best performances and highest target attainment in the test set (36.8% for GCV and 35.3% for the VGCV). In actual patients, the best GCV ML starting dose yielded the highest target attainment rate (25.8%) and performed equally for VGCV with the Franck model formula (35.3% for both). CONCLUSION: The ML algorithms exhibit good performances in comparison with previously validated models and should be evaluated prospectively.

Area under the curve of tacrolimus using microsampling devices: towards precision medicine in solid organ transplantation?

PURPOSE: Therapeutic drug monitoring of tacrolimus using trough concentration (Cmin) is mandatory to ensure drug efficacy and safety in solid organ transplantation. However, Cmin is just a proxy for the area under the curve of drug concentrations (AUC) which is the best pharmacokinetic parameter for exposure evaluation. Some studies suggest that patients may present discrepancies between these two parameters. AUC is now easily available through mini-invasive microsampling approach. The aim of this study is to evaluate the relationship between AUC and Cmin in patients benefiting from a complete pharmacokinetic profile using a microsampling approach. METHODS: Fifty-one transplant recipients benefited from a complete pharmacokinetic profile using a microsampling approach, and their 24-h AUC were calculated using the trapezoidal method. The correlation with Cmin was then explored. In parallel, we estimated AUC using the sole Cmin and regression equations according to the post-transplantation days and the galenic form. RESULTS: Weak correlations were found between 24-h AUC observed and the corresponding Cmin (R2 = 0.60) and between AUC observed and expected using the sole Cmin (R2 = 0.62). Therapeutic drug monitoring of tacrolimus using Cmin leads to over- or under-estimate drug exposure in 40.3% of patients. CONCLUSION: Tacrolimus Cmin appears to be an imperfect reflection of drug exposure. Evaluating AUC using a microsampling approach offers a mini-invasive strategy to monitor tacrolimus treatment in transplant recipients.

Comparison of different equations for renal function evaluation as proxies for antibiotic drug clearance: The examples of amoxicillin and cloxacillin.

The most appropriate renal function estimation equation to predict drug clearance is a matter of debate. In this study, we compare the Modification of Diet in Renal Disease (MDRD), the Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) and the Cockroft-Gault (CG) equations to predict amoxicillin and cloxacillin clearance among hospitalized patients receiving high doses of these antibiotic treatments. This study aimed to compare different equations used to predict amoxicillin and cloxacillin clearance among hospitalized patients receiving amoxicillin or cloxacillin treatments outside the intensive care unit. Data from 128 patients contributing 268 plasma samples was analyzed, and correlations between the equations and the amoxicillin and cloxacillin antibiotic clearance rates were calculated. We found a correlation between antibiotic clearance and all the renal function estimation equations, CG being the best, with a R2 of 0.35 for amoxicillin and 0.29 for cloxacillin (compared to 0.26 and 0.21 for MDRD and 0.12 and 0.24 for CKD-EPI). CG should be preferentially used as a proxy for amoxicillin and cloxacillin drug clearance, but the use of completely different tools such as therapeutic drug monitoring could help individualize antibiotic dosage.

Quantification of infliximab and adalimumab in human plasma by a liquid chromatography tandem mass spectrometry kit and comparison with two ELISA methods.

Background: This study compared the performance of plasma infliximab and adalimumab quantification using a commercially available kit (mAbXmise kit) and mass spectrometry readout to that of two ELISA methods in patients treated for inflammatory bowel disease. Methods & results: The mAbXmise method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) was linear from 2 to 100 µg/ml. It was validated according to international guidelines. Regarding cross-validation for infliximab (n = 70), the mean bias with LC-MS/MS assay was approximately threefold higher with the commercial ELISA assay compared with the in-house ELISA (-6.1 vs -1.8 µg/ml, respectively). The mean bias between the LC-MS/MS assay and in-house ELISA was -1.2 µg/ml for adalimumab (n = 35). Conclusion: The LC-MS/MS method is a powerful alternative to immunoassays to monitor concentrations of infliximab and adalimumab.

Pharmacokinetics, Pharmacodynamics, and Therapeutic Drug Monitoring of Valganciclovir and Ganciclovir in Transplantation.

Ganciclovir and valganciclovir are first choice drugs for the prevention and treatment of cytomegalovirus infection and disease in solid organ and stem cell transplant recipients. Only a few studies on the pharmacokinetics and exposure/efficacy or exposure/safety relationships of ganciclovir and valganciclovir in transplant recipients have been published so far, and there are still controversies about the exposure parameter to use for therapeutic drug monitoring (TDM). We performed an extensive literature review of the clinical pharmacokinetics data, the exposure/effect relationships in terms of efficacy and safety, and the available tools for valganciclovir and ganciclovir TDM in adults and pediatrics transplant recipients. The pharmacokinetics of ganciclovir and valganciclovir is well described in adults and children, and a high interindividual variability is commonly observed. In contrast, the drug pharmacodynamics has been poorly described in adults and barely in children. The average 24-hour area under the concentration-time curve (AUC0-24h ) seems to be the best predictor of efficacy and toxicity. The benefit of TDM remains controversial in adult patients but should be considered in children due to higher interindividual variability and lower probability of target attainment. Several bayesian estimators based on limited sampling strategies have been developed with this aim and may be used in clinical practice for the AUC-based individual dose adjustment of ganciclovir and valganciclovir.

Thoroughly Validated Bayesian Estimator and Limited Sampling Strategy for Dose Individualization of Ganciclovir and Valganciclovir in Pediatric Transplant Recipients.

BACKGROUND AND OBJECTIVE: Given a high pharmacokinetic inter-individual variability and a low exposure target achievement, ganciclovir (GCV) therapeutic drug monitoring is sometimes used in children. We aimed to develop and validate Bayesian estimators based on limited sampling strategies for the estimation of GCV area under the concentration-time curve from 0 to 24 h in pediatric transplant recipients treated with valganciclovir (VGCV) or GCV. METHODS: Solid organ transplant or stem-cell transplant recipients who received GCV or VGCV and had available GCV concentrations per standard of care were retrospectively included in this study for pharmacokinetic modeling and development of Bayesian estimators using the iterative two-stage Bayesian method. Validation datasets included additional child recipients of a solid organ transplant or stem-cell transplant, and child recipients of a kidney or liver transplant enrolled in a previous study. Various combinations of three or two sampling times, applicable in clinical practice, were assessed based on the relative mean bias, standard deviation, and the root mean square error in a development dataset and three independent validation datasets. RESULTS: In the development dataset, the mean bias/standard deviation/root mean square error for the 1 h/2 h/3 h and 1 h/3 h limited sampling strategies were - 1.4%/9.3%/9.1% and - 3.5%/12.2%/12.3%, respectively for GCV, while for VGCV, the mean bias/standard deviation/root mean square error for the 1 h/2 h/6 h and 1 h/6 h limited sampling strategies were 0.7%/13.5%/13.3% and - 0.1%/12.1%/11.8%, respectively. In the independent validation datasets, seven (13%) and five (14%) children would have had misclassifications of their exposure using these Bayesian estimators and limited sampling strategies for VGCV and GCV, respectively. CONCLUSIONS: Three plasma samples collected at 1 h/2 h/3 h and 1 h/2 h/6 h post-dose for GCV and VGCV respectively, are sufficient to accurately determine GCV area under the concentration-time curve from 0 to 24 h for pharmacokinetic-enhanced therapeutic drug monitoring.

Profile of Antimicrobial Use in the Pediatric Population of a University Hospital Centre, 2015/16 to 2018/19.

BACKGROUND: Antimicrobial stewardship is a standard practice in health facilities to reduce both the misuse of antimicrobials and the risk of resistance. OBJECTIVE: To determine the profile of antimicrobial use in the pediatric population of a university hospital centre from 2015/16 to 2018/19. METHODS: In this retrospective, descriptive, cross-sectional study, the pharmacy information system was used to determine the number of days of therapy (DOTs) and the defined daily dose (DDD) per 1000 patient-days (PDs) for each antimicrobial and for specified care units in each year of the study period. For each measure, the ratio of 2018/19 to 2015/16 values was also calculated (and expressed as a proportion); where the value of this proportion was ≤ 0.8 or ≥ 1.2 (indicating a substantial change over the study period), an explanatory rating was assigned by consensus. RESULTS: Over the study period, 94 antimicrobial agents were available at the study hospital: 70 antibiotics (including antiparasitics and antituberculosis drugs), 14 antivirals, and 10 antifungals. The total number of DOTs per 1000 PDs declined from 904 in 2015/16 to 867 in 2018/19. The 5 most commonly used antimicrobials over the years, expressed as minimum/maximum DOTs per 1000 PDs, were piperacillin-tazobactam (78/105), trimethoprim-sulfamethoxazole (74/84), ampicillin (51/69), vancomycin (53/68), and cefotaxime (55/58). In the same period, the care units with the most antimicrobial use (expressed as minimum/maximum DOTs per 1000 PDs) were hematology-oncology (2529/2723), pediatrics (1006/1408), and pediatric intensive care (1328/1717). CONCLUSIONS: This study showed generally stable consumption of antimicrobials from 2015/16 to 2018/19 in a Canadian mother-and-child university hospital centre. Although consumption was also stable within drug groups (antibiotics, antivirals, and antifungals), there were important changes over time for some individual drugs. Several factors may explain these variations, including disruptions in supply, changes in practice, and changes in the prevalence of infections. Surveillance of antimicrobial use is an essential component of an antimicrobial stewardship program.

CONTEXTE: La gestion des antimicrobiens est une pratique courante dans les centres hospitaliers afin de réduire l'utilisation inappropriée des antimicrobiens et le risque de résistance. OBJECTIF: Décrire l'évolution de l'utilisation des antimicrobiens dans un centre hospitalier universitaire de 2015­16 à 2018­19. MÉTHODES: Dans cette étude rétrospective, descriptive et transversale, les dossiers pharmacologiques ont servi à déterminer le nombre de jours de traitement (NJT) et la dose définie journalière (DDD) par 1000 jours-présence (JP) pour chaque antimicrobien et pour chaque unité de soins par année de l'étude. Pour chaque mesure, on a également comparé le ratio de 2018­19 à celui de 2015­16, qui est exprimé en proportion; lorsque la valeur de cette proportion était ≤ 0,8 ou ≥ 1,2, ce qui indiquait un changement important durant la période de l'étude, une note explicative a été attribuée par consensus. RÉSULTATS: Durant la période à l'étude, 94 antimicrobiens ont été disponibles dans notre centre : 70 antibiotiques (dont les antiparasitaires et les antituberculeux), 14 antiviraux et 10 antifongiques. Le nombre total de NJT par 1000 JP a diminué de 904 en 2015­16 à 867 en 2018­19. Les cinq antimicrobiens utilisés le plus fréquemment et présentés en minimum / maximum de NJT par 1000 JP étaient les suivants : piperacilline-tazobactam (78/105), trimethoprim-sulfamethoxazole (74/84), ampicilline (51/69), vancomycine (53/68) et cefotaxime (55/58). Pendant la même période, les unités de soins qui faisaient la plus grande utilisation d'antimirobiens (exprimée en minimum / maximum de NJT par 1000 JP) étaient hématologie-oncologie (2529/2723), pédiatrie (1006/1408) et soins intensifs pédiatriques (1328/1717). CONCLUSIONS: Cette étude démontre une consommation stable d'antimicrobiens entre 2015­16 et 2018­19 dans un centre hospitalier universitaire mère-enfant canadien. Malgré le fait que la consommation entre les groupes d'antimicrobiens (antibiotiques, antiviraux, antifongiques) était stable, on a constaté d'importantes variations concernant certains médicaments individuels. Plusieurs facteurs peuvent expliquer cette variation, notamment des ruptures d'approvisionnement, des changements de pratique et des changements dans la prévalence d'infections. La surveillance de la consommation des antimicrobiens est une partie essentielle de tout programme d'antibiogouvernance.

Population pharmacokinetics of ganciclovir and valganciclovir in paediatric solid organ and stem cell transplant recipients.

AIMS: Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are first-line agents to prevent and treat cytomegalovirus in transplant recipients. There is high pharmacokinetic (PK) interindividual variability and PK data are scarce, especially in paediatric stem cell transplant (SCT) recipients. We sought to determine the optimal GCV and VGCV dosing in transplanted children. METHODS: We conducted a single-centre retrospective population PK (POPPK) study of IV GCV and enteral VGCV in paediatric solid organ transplant (SOT) and SCT recipients. We included children who were transplanted and had available plasma GCV concentrations, done per standard of care. POPPK analysis was performed using a nonlinear mixed effects modelling approach with NONMEM. Optimal dosing was determined based on the achievement of the surrogate efficacy target: GCV 24 h area under the concentration-time curve (AUC0-24h ) of 40-60 mg.h.L-1 . RESULTS: Fifty children with a median [range] age of 7.5 years [0.5-17.4] contributed 580 PK samples. A two-compartment model with first-order absorption with a lag time and first-order elimination fit the data well. Creatinine clearance and body weight (WT) were significant covariates for GCV clearance (CL); and WT for the volumes of distribution. IV GCV 15-20 mg.kg-1 .day-1 divided every 12 hours achieved the highest probability of target achievement (PTA) (33.0-33.8%). Enteral VGCV 30 and 40 mg.kg-1 .day-1 divided every 12 hours in children 0-<6 years, and 6-18 years, respectively, achieved the highest PTA (29.1-33.0%). CONCLUSION: This is the first POPPK model developed in children with either SOT or SCT. Concentration target achievement was low, suggesting a potential benefit for therapeutic drug monitoring to ensure optimal exposure.

Population pharmacokinetics of gentamicin in haemodialysis patients: modelling, simulations and recommendations.

PURPOSE: The usual recommended dose for gentamicin is 3 to 7 mg/kg/day for patients with a normal renal function while 1.7 mg/kg/day is recommended for patients undergoing chronic haemodialysis. The objectives of this study were to develop a population pharmacokinetics model (POPPK) for gentamicin, designed for patients undergoing dialysis, and to investigate the best dosing scheme for different MIC clinical breakpoints using Monte Carlo simulations. METHODS: In this monocentric prospective interventional open clinical study, 23 patients (141 gentamicin samples) were included. The covariates investigated were weight, creatinine, dialysis (yes/no), dialysis flow and dialysis duration. The POPPK model was developed in Pmetrics and 1000 time-concentration profiles were simulated for 9 doses between 2 and 10 mg/kg/day, with an inter-dose period of 24, 48 or 96 h to predict the probability of having both a serum peak > 8*MIC and a trough < 1 mg/L for MIC values between 0.25 and 4 mg/L. RESULTS: A two-compartment model including the dialysis on the elimination constant and bodyweight on the volume of distribution best described the data. A 30-min gentamicin infusion of 2 mg/kg/day (for MIC = 1 mg/L) or 8 mg/kg/day (for MIC = 4 mg/L) just before dialysis eliminated by two dialysis sessions before the next administration (dose interval of at least 96 h) led to a peak > 8*MIC for > 90% of the simulations and a trough concentration < 1 mg/L at 96 h for 92% and 34% respectively. CONCLUSION: The gentamicin dose generally used to treat infections in dialysis patients is insufficient and might be increased to 3-8 mg/kg/day just before dialysis, taking into account the type of infection.

Self-poisoning with 60 tablets of Apixaban, a pharmacokinetics case report.

A 67-year-old man was admitted to the emergency department about 5 h after deliberate self-poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 µg l-1 of Apixaban. The Cmax was observed 17 h after the intake (3654 µg l-1 ), about four times the classical Tmax value (median [range]: 4 h [2-4]). The Apixaban was then eliminated following a first order elimination with a calculated half-life of 10.8 h. The anti-Xa activity seems to be linearly related to concentration up to 4000 µg l-1 . This report suggests that the use of activated charcoal should be effective up to 17 h after a massive intake.