Model-Based Comparative Analysis of Rifampicin and Rifabutin Drug-Drug Interaction Profile.

Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) are a major issue. We used a model-based approach to predict the magnitude of DDI with RIF and rifabutin (RBT) for 217 cytochrome P450 (CYP) substrates. On average, DDI caused by low-dose RIF were twice as potent as those caused by RBT. Contrary to RIF, RBT appears unlikely to cause severe DDI, even with sensitive CYP substrates.

Pharmacokinetic/Pharmacodynamic Dosage Individualization of Cefepime in Critically Ill Patients: A Case Study.

OBJECTIVE: The authors report on a case of a 59-year-old man hospitalized in the intensive care unit because of severe SARS-COV-2 infection (COVID-19). BACKGROUND: The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 hours. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of >60 mg/L. METHODS: Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software. RESULTS: The patient had unexpected pharmacokinetic parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration was also considered in the dosing decisions. After dose reduction to 0.5 g/8 hours, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure. CONCLUSION: This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in intensive care unit patients.

Goal-Oriented Monitoring of Cyclosporine Is Effective for Graft-versus-Host Disease Prevention after Hematopoietic Stem Cell Transplantation in Sickle Cell Disease and Thalassemia Major.

Graft-versus-host disease (GVHD) is an important challenge and a major cause of morbidity and mortality in children after hematopoietic stem cell transplant (HSCT). Herein we report our institution's experience of goal-oriented Bayesian monitoring for cyclosporine (CsA) used alone as GVHD prophylaxis during the post-transplant period in pediatric patients with thalassemia major (TM) or sickle cell anemia (SCA) undergoing HLA-matched HSCT. We also studied evolution of chimerism. Twenty-six consecutive patients (SCA, 14; TM, 12) underwent matched sibling donor (MSD) HSCT from 2004 to 2014. All patients received a myeloablative conditioning regimen. GVHD prophylaxis consisted of 20 mg/kg antithymocyte globulin in the conditioning regimens and then CsA alone in the post-transplant period. Target CsA trough blood concentration (TBC) was 150 ± 20 ng/mL. At last follow-up, all patients were alive and free of disease, even in cases of mixed chimerism. Engraftment occurred in all patients. No patient developed grades II to IV acute GVHD, 4 patients developed acute grade I skin GVHD, and only 1 presented with chronic pulmonary GVHD. A better control of GVHD and immunosuppression by a strict monitoring of CsA TBC as described herein is promising and could play a crucial role. Further investigations are required, but this study opens new perspectives to improve survival and safety of HSCT from alternative donors in TM and SCA to levels compatible with that obtained with MSDs.

A decision support tool to find the best cyclosporine dose when switching from intravenous to oral route in pediatric stem cell transplant patients.

PURPOSE: Managing the pharmacokinetic variability of immunosuppressive drugs after pediatric hematopoietic stem cell transplantation (HSCT) is a clinical challenge. Thus, the aim of our study was to design and validate a decision support tool predicting the best first cyclosporine oral dose to give when switching from intravenous route. METHODS: We used 10-years pediatric HSCT patients' dataset from 2008 to 2018. A tree-augmented naïve Bayesian network model (method belonging to artificial intelligence) was built with data from the first eight-years, and validated with data from the last two. RESULTS: The Bayesian network model obtained showed good prediction performances, both after a 10-fold cross-validation and external validation, with respectively an AUC-ROC of 0.89 and 0.86, a percentage of misclassified patients of 28.7% and 35.2%, a true positive rate of 0.71 and 0.65, and a false positive rate of 0.12 and 0.14 respectively. CONCLUSION: The final model allows the prediction of the most likely cyclosporine oral dose to reach the therapeutic target specified by the clinician. The clinical impact of using this model needs to be prospectively warranted. Respecting the decision support tool terms of use is necessary as well as remaining critical about the prediction by confronting it with the clinical context.

Sickle cell disease perceptions of caregivers, adolescent, and adult patients: Barriers and facilitators to medical care adherence.

AIMS: To provide an understanding of medical care adherence factors as reported by caregivers, adolescent, and adult patients with sickle cell disease and to analyse those concerns to identify barriers and facilitators about medical care adherence. Three topics influenced medical care adherence: the disease itself, therapeutics, and the healthcare system. This study will focus on the first topic. DESIGN: Qualitative explorative study, using semi-structured and life-experience interviews and manual inductive content analysis. METHODS: From December 2016 - March 2017, one semi-structured interview was conducted by a researcher with each of the 15 adolescent patients, 10 adult patients, and 19 caregivers in a French public hospital. Interviews were audio-taped and transcribed before a content analysis. Perceptions were classified into barriers and facilitators of medical care adherence. RESULTS: This article presents disease perceptions of caregivers and patients (adolescents and adults): daily management and social representations. These perceptions differ among parents, adolescent patients, and adult patients. However, all report important disease-related "limitations" in their lives. The objective for adults (parents and patients) is to "live with the disease" and to achieve this, they find coping resources. Two major resources expressed by adults emerged: social resources (support from friends, patients' association, and social visibility) and disease knowledge (theoretical and derived from experience). This is not the case of adolescents for whom social normality was the main concern. CONCLUSION: Care management adherence is partly based on coping with the disease. Given the lower number of facilitators expressed by adolescents, it is essential to propose interventions in this population. It will help them cope with the disease and, consequently, optimize care management adherence. IMPACT: Showing differences among caregivers, adult, and adolescent patient perceptions, this study impact future care practices. It revealed needs of intervention for adolescents.

Increased Risk of Thrombosis Associated with Peripherally Inserted Central Catheters Compared with Conventional Central Venous Catheters in Children with Leukemia.

OBJECTIVE: To study the risk of catheter-associated thrombosis (CAT) between peripherally inserted central catheters (PICCs) and tunneled central venous catheters in children with leukemia. STUDY DESIGN: We analyzed all PICCs and conventional tunneled catheters placed in patients aged <18 years and admitted to our institute for leukemia treatment between February 2008 and April 2014. Cases of symptomatic CAT were confirmed by ultrasound and treated with low-molecular-weight heparin. RESULTS: During the study period, 157 PICCs and 138 conventional tunneled catheters were placed in 192 patients with leukemia. CAT incidence was 1.5% (n = 2) in the conventional tunneled catheter group and 10.2% (n = 16) in the PICC group. The OR for CAT occurrence after PICC vs conventional tunneled catheter placement was 5.6 (95% CI, 1.2-26.5). CONCLUSION: Our results suggest that the use of PICCs in children with leukemia increases the risk of CAT in comparison with the use of conventional tunneled catheters. Further randomized controlled studies are needed to characterize this risk and to better define indications.

Impact of a change in protected environment on the occurrence of severe bacterial and fungal infections in children undergoing hematopoietic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a procedure with a high infection risk. Strict isolation of patients is the rule to prevent such condition. OBJECTIVE: We compared the occurrence of severe infections (bacteremia and invasive fungal infection, IFI) in children undergoing alloHSCT before and after the move to a new protected unit with decreases in isolation methods. METHODS: The study was conducted over a 10-year period. Unit 1 (2002-2007) consisted of laminar airflow rooms where caregivers were required to wear a sterile outfit (gown, gloves, hat, and mask). Unit 2 (2008-2012) included spacious positive air pressure rooms with HEPA filters where only a clean gown and mask were required to be worn. RESULTS: Two hundred eighty-six alloHSCTs were performed (144 in Unit 1 and 142 in Unit 2). We reported a total incidence of 4.78 infections/1000 hospital-days including 4.4 episodes of bacteremia and 0.38 episodes of IFI. There was no statistical difference in the incidence of infections: n = 4.98/1000 hospital-days in Unit 1 vs. n = 4.6/1000 in Unit 2 (P = 0.63). CONCLUSION: The lack of difference in the occurrence of severe infection supports our decision to decrease unnecessary high protection in alloHSCT units to improve children's daily life.

Accurately Achieving Target Busulfan Exposure in Children and Adolescents With Very Limited Sampling and the BestDose Software.

BACKGROUND: Busulfan dose adjustment is routinely guided by plasma concentration monitoring using 4-9 blood samples per dose adjustment, but a pharmacometric Bayesian approach could reduce this sample burden. METHODS: The authors developed a nonparametric population model with Pmetrics. They used it to simulate optimal initial busulfan dosages, and in a blinded manner, they compared dosage adjustments using the model in the BestDose software to dosage adjustments calculated by noncompartmental estimation of area under the time-concentration curve at a national reference laboratory in a cohort of patients not included in model building. RESULTS: Mean (range) age of the 53 model-building subjects was 7.8 years (0.2-19.0 years) and weight was 26.5 kg (5.6-78.0 kg), similar to nearly 120 validation subjects. There were 16.7 samples (6-26 samples) per subject to build the model. The BestDose cohort was also diverse: 10.2 years (0.25-18 years) and 46.4 kg (5.2-110.9 kg). Mean bias and imprecision of the 1-compartment model-predicted busulfan concentrations were 0.42% and 9.2%, and were similar in the validation cohorts. Initial dosages to achieve average concentrations of 600-900 ng/mL were 1.1 mg/kg (≤12 kg, 67% in the target range) and 1.0 mg/kg (>12 kg, 76% in the target range). Using all 9 concentrations after dose 1 in the Bayesian estimation of dose requirements, the mean (95% confidence interval) bias of BestDose calculations for the third dose was 0.2% (-2.4% to 2.9%, P = 0.85), compared with the standard noncompartmental method based on 9 concentrations. With 1 optimally timed concentration 15 minutes after the infusion (calculated with the authors' novel MMopt algorithm) bias was -9.2% (-16.7% to -1.5%, P = 0.02). With 2 concentrations at 15 minutes and 4 hours bias was only 1.9% (-0.3% to 4.2%, P = 0.08). CONCLUSIONS: BestDose accurately calculates busulfan intravenous dosage requirements to achieve target plasma exposures in children up to 18 years of age and 110 kg using only 2 blood samples per adjustment compared with 6-9 samples for standard noncompartmental dose calculations.

Improvement in the Outcome of Invasive Aspergillosis in a Pediatric Hematology Department: A 10-Year Review.

BACKGROUND: Invasive aspergillosis (IA) is associated with a high mortality rate despite the introduction of new antifungal agents. Several therapeutic strategies have been proposed to improve mortality rates in IA, including combination of drugs. METHODS: Here, we report the outcome of treatments based on a combination of antifungal agents on IA, including voriconazole and liposomal amphotericin B, in a pediatric population from 2001 to 2010. Our population included children with diverse hematological diseases or with bone marrow transplantation. RESULTS: Over a 10-year period, we diagnosed 19 cases (2,8%) of invasive pulmonary aspergillosis with an overall survival rate of 58%. CONCLUSION: Compared with the previous study conducted from 1986 to 2000, the overall survival rate (bone marrow transplantation excluded) greatly improved (12.5% to 58%), especially for patients treated for acute leukemia.

Salvage therapy of refractory severe aplastic anemia by decreasing cyclosporine dose regimen.

Optimal modalities for immunosuppressive therapy (IST) for severe aplastic anemia (SAA) have to be determined, and especially cyclosporine (CyA) dosing to promote regulatory T cells (Treg) which are lacking and which account for physiopathological mechanisms. We are reporting on three cases of pediatric patients suffering from SAA, initially without hematological response between 4 and 7 months after IST, and who have responded 2 months after the decrease in CyA target trough blood levels to 100 ng/mL, and one case which has early responded by applying low trough blood levels from the beginning. As it has been demonstrated that Treg increase in IST responders and that Treg are stimulated only by low CyA concentrations, these case series suggest that lower CyA doses than actually recommended could be more efficient to enhance the proportion of responders. This report highlights a new field of perspectives for the treatment for SAA.

Pharmacokinetic drug interaction between cyclosporine and imatinib in bone marrow transplant children and model-based reappraisal of imatinib drug interaction profile.

BACKGROUND: Previous reports have suggested that imatinib may increase cyclosporine exposure by CYP3A4 inhibition. However, the magnitude of this drug interaction remains unclear. At present, quantitative information about the interaction profile of imatinib is scarce. METHODS: The authors report the effect of imatinib on cyclosporine exposure in 6 pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who received cyclosporine after hematopoietic stem-cell transplantation. Dose-normalized cyclosporine trough blood concentrations (TBC) were obtained before and after imatinib introduction. In addition, a validated model-based approach was used to derive quantitative predictions of CYP3A4-mediated drug interactions with imatinib as a victim or precipitant drug. RESULTS: The mean dose-normalized cyclosporine TBC significantly increased after 3 to 7 days of imatinib therapy. The modeling approach predicted weak-to-moderate effect of major CYP3A4 inhibitors on imatinib exposure. However, the inhibitory potency of imatinib was found to be similar to that of verapamil, suggesting significant influence of imatinib on the pharmacokinetics of drugs highly metabolized by CYP3A4. Observed increases in cyclosporine dose-normalized TBC of the 6 patients were compatible with model predictions. The observations and predictions suggest that imatinib may substantially increase cyclosporine exposure. CONCLUSIONS: Cyclosporine dose reduction may be necessary to avoid excessive immunosuppressive effect in case of coadministration of imatinib.

Pharmacokinetic drug-drug interaction of calcium channel blockers with cyclosporine in hematopoietic stem cell transplant children.

BACKGROUND: Cyclosporine (CsA) is frequently responsible for hypertension in bone marrow transplant children. Calcium channel blockers (CCBs) are considered to be the best treatment for CsA-induced hypertension, but they may alter the exposure and the effect of CsA by inhibiting the CYP3A4 pathway of CsA metabolism or P-gp. However, the inhibitory effect on CYP3A4 may vary among CCBs. METHODS: This study aimed to quantify the pharmacokinetic drug-drug interaction between CsA and nicardipine, amlodipine, and lacidipine. In all, 51 children who received CsA and CCB concomitantly were included. RESULTS: Dose-normalized CsA trough blood concentrations significantly increased in patients treated with nicardipine and amlodipine, whereas they remained stable in patients treated with lacidipine. CONCLUSIONS: Because lacidipine appears to have no effect on CsA exposure, it may be the best option among CCBs for treating high blood pressure caused by CsA in children.

How could proton pump inhibitors de-prescription be managed in geriatric long-term care?

BACKGROUND: Evaluate the misuse of proton pump inhibitors (PPIs) in geriatric long-term care (LTC) patients and improve caregiving by de-prescribing non-relevant PPIs in this population. AIM: This study was conducted in the long-term care department of the geriatric hospital Pierre-Garraud in Lyon. All patients receiving PPI for more than 8 weeks were included. A reassessment form was filled to evaluate the treatment benefit/risk ratio during a collegial consultation between the patient's referring physicians and pharmacists. During these consultations, the following possible decisions were taken: continuation, dose adjustment or gradual discontinuation of treatment. Patients' monitoring were performed one month and three months after discontinuation to detect any relapses and causes. RESULTS: Among the 113 patients included, 97 patients had their treatment re-evaluated by collegial consultation. Forty-four (45.4%) patients were treated in accordance with recommendations. For 24 of them, the indication was symptomatic recurrent gastroesophageal reflux disease. The treatment of more than half of the re-evaluated patients (54.6%) was gradually stopped. After the 3-month follow-up post-discontinuation, excluding patients who died during this period, 80.9% of the discontinuations were well-tolerated and only nine were resumed (19.1%). CONCLUSION: This study allowed a re-evaluation of PPI treatments in a high-risk population and offered a decision support tool focused on the benefit/risk balance of PPIs; 55% of treatments were considered irrelevant and could be stopped with 80% of good tolerance.

A pharmacodynamic model of ganciclovir antiviral effect and toxicity for lymphoblastoid cells suggests a new dosing regimen to treat cytomegalovirus infection.

In bone marrow transplantation, the efficacy of ganciclovir in cytomegalovirus (CMV) disease treatment or prophylaxis remains partial. Because its hematological toxicity is dose limiting, optimization of the dosing schedule is required to increase its therapeutic index. The goal of our study was to describe the influence of the ganciclovir concentration and duration of exposure on cell survival and antiviral efficacy. The study was carried out in vitro on cultures of lymphoblastoid cells infected or not with the CMV AD169 reference strain and exposed to ganciclovir at different concentrations for 1, 2, 7, or 14 days. The data were analyzed by a mathematical model that allowed a quantitative characterization of ganciclovir pharmacodynamics and its variability. Simulations of the model were undertaken to determine the optimal concentration profile for maximizing the ganciclovir therapeutic index. Ganciclovir had very little toxic and antiviral effect, even at 20 mg liter(-1), when the duration of exposure was ≤ 7 days. A biologically significant effect was observed only with a 14-day exposure. Complete inhibition of viral replication was obtained at 20 mg liter(-1). The utility function, assuming equal weights for antiviral effect and toxicity, showed that maximal utility was reached around 10 mg liter(-1). The optimal ganciclovir concentration profile consisted of maintaining the concentration at 20 mg liter(-1) at the intervals 0 to 2 days and 7.58 to 9.58 days and a null concentration at other times. This optimal profile could be obtained by intravenous (i.v.) ganciclovir at 10 mg/kg of body weight twice daily (b.i.d.) at days 1, 2, 8.5, and 9.5 in stem cell transplant patients with normal renal function.

Pharmacokinetic behavior and appraisal of intravenous busulfan dosing in infants and older children: the results of a population pharmacokinetic study from a large pediatric cohort undergoing hematopoietic stem-cell transplantation.

BACKGROUND: Intravenous (IV) busulfan (Bu) dosing approved in Europe based on 5 body weight (BW) strata has been validated for targeting Bu exposures in children undergoing hematopoietic stem-cell transplantation and with mostly malignant diseases. The authors conducted an observational study aiming to investigate the behavior and ontogeny of IV Bu pharmacokinetic (PK) disposition, and to reevaluate the consistency of the BW-based dosing in very young children with rare diseases. METHODS: The observational study comprised 115 patients, mostly infants with immunodeficiencies and metabolic inherited disorders and with altered liver function and/or iron overload. Additional data (90 children, mostly malignant diseases) were pooled with the first data set. The overall data (205 children aged from 10 days to 15 years) were analyzed using population PK modeling. RESULTS: The BW remained the main determinant of IV Bu PK, and no further covariate effect was identified. Bu clearance (CL) variability was best described by BW allometric functions. Increase of drug CL with the child's growth was faster in younger children. This pattern is likely related to the maturation of GSTA1 enzymes during infancy and was accounted for in the model by estimating a higher BW allometric exponent in children <9 kg compared with that in children ≥9 kg. IV Bu PK was not modified in children with altered liver function and/or iron overload, and no disease specific difference was observed. Bu dosing either adjusted according to the final model or with the approved EU labeling yields similar targeting performances. For both dosing strategies, the percent of patients achieving the therapeutic area under the curve window (900-1500 µmole·min/L were 60% and 70%-90% in children <9 and ≥9 kg, respectively. CONCLUSIONS: A population PK model accounting for the highest Bu CL in the youngest patients was validated on training and evaluation data sets. The BW-based dosing strategy recommended in Europe proved to be consistent on a large paediatric cohort representative of the population heterogeneity observed in hematopoietic stem-cell transplantation.

Pediatric-Adult Care Transition: Perceptions of Adolescent and Young Adult Patients with Sickle Cell Disease and Their Healthcare Providers.

Introduction: The pediatric-adult care transition, which takes place during adolescence, is a high-risk period for medical care adherence in chronic diseases, this encompasses treatment adherence, attending medical consultations and following healthcare advice. Studying perceptions is needed to get a more comprehensive picture of this care transition and to propose interventions to address the gaps. The authors analyzed perceptions from patients and caregivers in adolescents with sickle cell disease. Although this is the first step to improving the actual care management, to our knowledge, no study has explored perceptions from healthcare providers and compared it to patients' perceptions. The purpose of this study was to provide an insight on the experience of adolescent and adult patients, pediatric and adult healthcare providers in the context of pediatric to adult care transition, and analyze those concerns in order to better understand medical care adherence and improve patient care. Material and Methods: Semi-structured interviews were conducted with adolescent and adult patients, as well as healthcare professionals (HCPs) in pediatric and adult departments. These interviews were audiotaped and transcribed before manual inductive content analysis. Results: A total of 15 adolescent patients, 10 adult patients, 9 pediatric HCPs and 13 adult HCPs - including 12 nurses - were interviewed. Patients and healthcare providers all agreed that the pediatric-adult care transition was poorly experienced. This was mainly due to various changes in habits, physicians, and care organization. Anticipating this transition and acquiring new skills both for patients and HCPs are essential steps for improving medical care adherence during this challenging pediatric-adult care transition. Conclusion: Propositions emerged from patients and healthcare providers to improve care and subsequently to improve medical care adherence in patients with sickle cell disease during and after the pediatric to adult care transition.

An Investigation of O-Demethyl Tramadol/Tramadol Ratio for Cytochrome P450 2D6 Phenotyping: The CYTRAM Study.

Cytochrome P450 2D6 (CYP2D6) gene polymorphisms influence the exposure to tramadol (T) and its pharmacologically active metabolite, O-demethyl tramadol (O-dT). Tramadol has been considered as a candidate probe drug for CYP2D6 phenotyping. The objective of the CYTRAM study was to investigate the value of plasma O-dT/T ratio for CYP2D6 phenotyping. European adult patients who received IV tramadol after surgery were included. CYP2D6 genotyping was performed and subjects were classified as extensive (EM), intermediate (IM), poor (PM), or ultra-rapid (UM) CYP2D6 metabolizers. Plasma concentrations of tramadol and O-dT were determined at 24 h and 48 h. The relationship between O-dT/T ratio and CYP2D6 phenotype was examined in both a learning and a validation group. Genotype data were obtained in 301 patients, including 23 PM (8%), 117 IM (39%), 154 EM (51%), and 7 UM (2%). Tramadol trough concentrations at 24 h were available in 297 patients. Mean value of O-dT/T ratio was significantly lower in PM than in non-PM individuals (0.061 ± 0.031 versus 0.178 ± 0.09, p < 0.01). However, large overlap was observed in the distributions of O-dT/T ratio between groups. Statistical models based on O-dT/T ratio failed to identify CYP2D6 phenotype with acceptable sensitivity and specificity. Those results suggest that tramadol is not an adequate probe drug for CYP2D6 phenotyping.

Agreement between a regional pharmacovigilance centre and an adjudication committee regarding adverse drug reactions on a cohort of hospitalised children.

BACKGROUND AND PURPOSE: The EREMI project was set up to collect data on adverse drug reactions (ADRs) occurring due to off-label and/or unlicensed drugs prescribed to hospitalised children in France. These events were evaluated by a regional pharmacovigilance centre (RPC) and an adjudication committee (AC). The aim of this study was to assess the agreement between these two different entities on their evaluation of ADRs. EXPERIMENTAL APPROACH: The RPC first validated the ADRs and assessed their causality using the Naranjo scale. The AC assessed then ADRs using all available information, including the RPC evaluation. The agreement on severity and nature of ADRs, role of treatment (suspect or concomitant) and drug causality was calculated using Cohen's nonparametric kappa coefficient (k). KEY RESULTS: Three hundred and eighty-six events were reported in 219 children. The RPC excluded 65 events and validated 321 ADRs. Agreement was very good on nature of ADRs (k=0.85) and role of treatment (k=0.81), moderate on severity of ADRs (k=0.60) and very poor on drug causality (k=0.05). CONCLUSION AND IMPLICATIONS: Agreement between the RPC and the AC was not constant throughout this evaluation. They troubled to agree on severe ADRs and on drug causality.