Impact of a Bayesian Individualization of Cyclosporine Dosage Regimen for Children Undergoing Allogeneic Hematopoietic Cell Transplantation: A Cost-Effectiveness Analysis.

BACKGROUND: Cyclosporine A (CsA) is the main drug used to prevent graft-versus-host disease in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). CsA therapeutic drug monitoring (TDM) has been performed for ages, with studies revealing clinical benefits, but failing to examine its economic impact. In this article, the main objective was to evaluate the economic impact of the CsA TDM strategy, based on a Bayesian approach, by assessing costs related to its clinical impact. Furthermore, TDM effectiveness was analyzed for pharmacokinetics and clinical outcomes. METHODS: A cost-effective, nonrandomized, retrospective, single-center study compared 2 CsA monitoring and dose adaptation strategies in pediatric patients undergoing HSCT. From 2014 to 2016, CsA TDM was performed using a population pharmacokinetics model-coupled Bayesian approach by a pharmacist ["pharmacist-assisted individualization" (PAI)]. From 2017 to 2018, CsA TDM was performed by the clinician without a Bayesian approach (non-PAI group). HSCT costs were evaluated from the French National Insurance perspective. Economic and clinical outcomes were assessed by measuring incremental cost-effectiveness ratios. RESULTS: The study included 144 patients: 90 and 54 patients in PAI and non-PAI groups, respectively. Both groups were comparable for sociodemographic and clinical characteristics. The mean total cost per patient was significantly lower (P < 0.01) in the PAI group (€85,947) than in the non-PAI group (€100,435). Multivariate analysis revealed that TDM based on the Bayesian approach was a protective factor (odds ratio = 0.86) for severe acute graft-versus-host disease. We noted that pharmacist-based TDM was the dominant strategy. Bayesian method-based TDM allowed an increase in the percentage of target attainment at any period post-HSCT. CONCLUSIONS: CsA TDM with a Bayesian approach is a cost-effective procedure, and highlighted clinical benefits encourage the development of new TDM strategies for HSCT.

A Generic Model for Quantitative Prediction of Interactions Mediated by Efflux Transporters and Cytochromes: Application to P-Glycoprotein and Cytochrome 3A4.

BACKGROUND AND OBJECTIVE: The In Vivo Mechanistic Static Model (IMSM) is a powerful method used to predict the magnitude of drug-drug interactions (DDIs) mediated by cytochromes. The objective of this study was to extend the IMSM paradigm to DDIs mediated by efflux transporters and cytochromes. METHODS: First, a generic model for this kind of interaction was devised. A flexible approach was then developed to estimate the characteristic parameters [the contribution ratios (CRs) and inhibition or induction potencies (IXs)] from clinical data by non-linear regression. Next, this approach was applied to the DDIs mediated by P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4/3A5 in a large set of victim drugs and interactors. Lastly, the model and associated parameters were used to identify the DDIs most at risk of overexposure. RESULTS: A total of 25 substrates and 26 interactors (three inducers, 23 inhibitors) could be considered in the regression analysis. The number of observations [area under the plasma concentration-time curve ratios or renal clearance ratios (Robs)] was 138. Fifty CRs and 57 IXs were estimated. The proportions of predictions within 0.67- to 1.5-fold Robs and within 0.5- to 2-fold Robs were 79% and 93% for the internal validation and 76% and 88% for the external validation, respectively. The median fold error was 0.98 (the ideal value is 1) and the interquartile range of the fold error was 0.36. The relative standard error of parameter estimates was a maximum of 15%. CONCLUSIONS: The IMSM approach was successfully extended to DDIs mediated by P-gp and CYP3A4/3A5. The method revealed good predictive performances by internal and external validation.

A Model for Predicting the Interindividual Variability of Drug-Drug Interactions.

Pharmacokinetic drug-drug interactions are frequently characterized and quantified by an AUC ratio (Rauc). The typical value of the AUC ratio in case of cytochrome-mediated interactions may be predicted by several approaches, based on in vitro or in vivo data. Prediction of the interindividual variability of Rauc would help to anticipate more completely the consequences of a drug-drug interaction. We propose and evaluate a simple approach for predicting the standard deviation (sd) of Ln(Rauc), a metric close to the interindividual coefficient of variation of Rauc. First, a model was derived to link sd(Ln Rauc) with the substrate fraction metabolized by each cytochrome and the potency of the interactors, in case of induction or inhibition. Second, the parameters involved in these equations were estimated by a Bayesian hierarchical model, using the data from 56 interaction studies retrieved from the literature. Third, the model was evaluated by several metrics based on the fold prediction error (PE) of sd(Ln Rauc). The median PE was 0.998 (the ideal value is 1) and the interquartile range was 0.96-1.03. The PE was in the acceptable interval (0.5 to 2) in 52 cases out of 56. Fourth, a surface plot of sd(Ln Rauc) as a function of the characteristics of the substrate and the interactor has been built. The minimal value of sd(Ln Rauc) was about 0.08 (obtained for Rauc = 1) while the maximal value, 0.7, was obtained for interactions involving highly metabolized substrates with strong interactors.

Improved outcome of children transplanted for high-risk leukemia by using a new strategy of cyclosporine-based GVHD prophylaxis.

There is currently a major concern regarding the optimal immunosuppression therapy to be administered after hematopoietic stem cell transplantation (HSCT) to reduce both the toxicity of GvHD and the rate of relapse. We report the outcome of high-risk leukemia children transplanted with a new way of managing cyclosporine (CsA)-based GvHD prophylaxis. A total of 110 HSCT in 109 ALL or AML children who received CsA without mycophenolate or methotrexate in matched related as well as in matched or mismatched unrelated stem cell transplantation were included. CsA dosage regimens were individualized to obtain specific trough blood concentrations values. The incidences of grade I-II and III-IV acute GvHD were 69.1% and 1.8%, respectively, and 8.4% for chronic GvHD. GvHD was neither more frequent nor severe in unrelated than in related HSCT. GvHD occurred in 87% of patients with a mean CsA trough concentration ⩽120 ng/mL versus 43% with concentration >120 ng/mL (P<0.0001). Five-year disease-free survival (DFS) and overall survival were 78% and 83.6%, respectively. DFS was 76.9% for ALL and 80.4% for AML patients. There was no difference in DFS between matched siblings and matched unrelated or mismatched unrelated HSCT. DFS in patients with minimal residual disease (MRD) ⩾10(-3) and in those with MRD <10(-3) before SCT was comparable. Our results indicate that a GvHD prophylaxis regimen based on CsA without mycophenolate or methotrexate is safe and effective whatever the donor compatibility is. These results suggest that GvL effect may be enhanced by this strategy of GvHD prophylaxis.

Should busulfan therapeutic range be narrowed in pediatrics? Experience from a large cohort of hematopoietic stem cell transplant children.

Busulfan, the corner stone of hematopoietic stem cell transplantation regimens, has a narrow therapeutic window. Therapeutic drug monitoring (TDM)-guided dosing to reach the conventional area under the concentration-time curve (AUC) target range of 900-1500 µmol min/L is associated with better outcomes. We report our experience with busulfan TDM in a large cohort of children. The aims were to investigate the relevance of using a more restricted therapeutic range and investigate the association between busulfan therapeutic range and clinical outcome. This study includes 138 children receiving 16 doses of intravenous busulfan, with the first dose assigned based on weight and doses adjusted to a local AUC target range of 980-1250 µmol min/L. Busulfan TDM combined with model-based dose adjustment was associated with an increased probability of AUC target attainment, for both target range: 90.8% versus 74.8% for the conventional target range and 66.2% versus 43.9% for the local target range (P<0.001). The median follow-up was 56.2 months. Event-free survival was 88.5%, overall survival was 91.5% and veno-occlusive disease occurred in 18.3% of patients. No difference was observed for clinical outcomes depending on the selected target range. Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving target attainment, but using a restricted target range has no impact on clinical outcomes.

High methotrexate exposure and toxicity in children with t(9;22) positive acute lymphoblastic leukaemia treated with imatinib.

WHAT IS KNOWN AND OBJECTIVE: Although there is one report on the possible reduced clearance of methotrexate in an adult patient when given concomitantly with imatinib, there is little information on the possible pharmacokinetic interaction. We report on three cases of delayed elimination of methotrexate in children with chromosome Philadelphia-positive acute lymphoblastic leukaemia treated concomitantly with imatinib. CASE SUMMARY: Three patients, aged 9-17 years, presented with high methotrexate blood levels following co-administration of imatinib and high-dose methotrexate. Two patients presented with clinical symptoms (nausea, epigastric pain and mucositis, acute renal failure, liver cytolysis). One patient required extra supplementary folinic acid doses than used in the standard protocol and one child required the use of carboxypeptidase-G2. WHAT IS NEW AND CONCLUSION: There is an apparent pharmacokinetic interaction between imatinib and methotrexate in children. Several mechanisms could explain this interaction, including competition for BCRP or ABCB transporters. Temporary withdrawal of imatinib may be necessary for preventing severe methotrexate-related adverse events.

[Lacidipine efficacy and safety for high blood pressure treatment in pediatric oncohematology]. / Efficacité et tolérance de la lacidipine dans le traitement de l'hypertension artérielle en onco-hématologie pédiatrique.

In adults, lacidipine seems to have no CYP3A4-inhibiting action. This particular characteristic makes it advantageous when combined with drugs metabolized by CYP3A4, such as cyclosporine. Until now, no data on the efficacy or safety of this calcium antagonist have been available in children. Thirty-nine hypertensive children (age: 0.13-14 years) receiving lacidipine in oncohematology for a mean of 75 days were included in this retrospective study. The causes of high blood pressure were renal tumor (n=7), catecholamine-secreting tumor (n=4), corticoid treatment (n=5), and cyclosporine treatment (n=23). An initial dosage of 0.05 mg/kg/day was sufficient for 41% of the patients. The remaining patients needed to increase the dosage, by steps of 0.03 mg/kg/day, until reaching an average effective dosage of 0.1 mg/kg/day. Lacidipine significantly decreased blood pressure by 30 (±14) mmHg for systolic blood pressure and by 26 (±13) mmHg for diastolic blood pressure. A medication plan with twice-daily administration was not significantly more effective than a single administration per day. Lacidipine was well tolerated, and no toxicity-related withdrawal of treatment occurred. For 22 patients treated with both cyclosporine and lacidipine, renal function was not disturbed over time, suggesting its preservation by lacidipine. No significant increase in cyclosporine blood concentration was detected. Lacidipine seems to be an effective calcium antagonist in pediatric oncohematology, is well tolerated, has a kidney-protector effect and no drug interaction when combined with cyclosporine.

Cytomegalovirus infection in pediatric allogenic hematopoietic stem cell transplantation. A single center experience.

We report a retrospective analysis of Cytomegalovirus (CMV) infection: incidence, recurrence, resistance, and subsequent disease of 81 children who underwent allogenic hematopoietic stem cell transplantation (HSCT). The recipient and/or donor's CMV serology was positive prior to transplant [recipient (R+) and/or donor (D+)]. CMV was monitored by RT-PCR starting from the first week post transplant. Forty patients showed CMV infection (49, 5%). Of them 10 manifested CMV disease leading to four deaths. In univariate analysis, factors associated with CMV infection were CMV R+ P < .01, CMV R+/D+ pair P < .01, nonbone marrow (BM) stem cell source P < .05, nonirradiation conditioning regimen P < .05, Antithymocyte globulin (ATG) P < .01. Factors associated with CMV resistance were: >1 HLA allele mismatch P < .05, CMV R +/D-pair P < .01, CMV D-P < .01, non-BM P < .05, nongenoidentical transplant P < .01. CMV disease was influenced by >1 HLA allele mismatch (P < .001), non-BM (P < .01). On multivariate analysis, CMV R+/D- (P < .05), corticosteroids ≥2 mg/kg P < .01, ATG P < .01 and non-BM (P < .05) were independent factors for CMV infection. CMV R+ transplant is associated with more CMV infection and resistance to preemptive treatment. Prolonged immune suppression (IS) worsens outcome of CMV infection and should be shortened whenever possible.

[Invasive fungal infections in oncology and haematology unit care: review of literature and costs analysis]. / Infection fongique invasive en oncologie et hématologie pédiatrique : analyse de la littérature et étude médicoéconomique des coûts de prise en charge.

Invasive fungal infections are an important cause of mortality in oncology and haematology unit care. Immunosuppression allows the occurrence of Candida or Aspergillus infectious disease. Treatment is based on antifungal agents (liposomal amphotericin B, azoles and caspofungin) administrated alone. The lack of study does not yet validate the combination of two drugs which are not recommended in medical practice. The aim of this pharmacoeconomics study is to assess different therapeutic strategies compared to standard treatment. Health care system point of view is used. Results show that liposomal amphotericin B is the reference standard drug during no documented infection in term of cost. But, voriconazole does not have significative cost variation for Aspergillus disease. Same conclusion can be showed, in case of candidosis for caspofungin. The sensitivity analysis shows that daily cost treatment and body weight are variables with important impact on results. This preliminary analysis must be continued by a clinical study in order to assess different antifungal treatments.

[Vancomycin: what dosages are needed to achieve efficacy in paediatric hematology/oncology?]. / Vancomycine : quelles doses pour une meilleure efficacité en hémato-oncologie pédiatrique?

INTRODUCTION: In children and infants, the determination of optimal dosages is essential from the beginning of treatments with vancomycin because of the high risk of inadequate serum concentrations and bacterial resistance. Bayesian pharmacokinetic methods can be used to adjust dosages according to serum vancomycin concentrations and the patients' physiopathological characteristics. The aim of this retrospective study was to review the effective dosages of vancomycin in paediatric hematology/oncology, using a bayesian pharmacokinetic method. PATIENTS AND METHODS: One hundred and sixty-one patients in paediatric hematology/oncology units, aged from 1 month to 18 years, who were treated with vancomycin in continuous infusion, were selected between 2000 and 2010. The influence of initial vancomycin dosages on serum steady-state concentrations (S(sc)) before bayesian adaptation was studied on the basis of dosing recommendations in children and infants (i.e., 40 mg/kg/day). In addition, the S(sc) before bayesian adaptation and the effective dosages determined after bayesian adaptation (E(db)) were analysed according to the patients' age, for an identical dosage of 40 mg/kg/day (± 10%). RESULTS: The percentage of patients with low S(sc) (i.e.,<10mg/L) was 28.6%, 16%, and 0 when treatment was initiated at less than 40 mg/kg/day (± 10%), at 40 mg/kg/day (± 10%), and at more than 40 mg/kg/day (± 10%), respectively. For an identical initial dosage of 40 mg/kg/day (± 10%), the S(sc) gradually increased as the patients' age increased. The S(sc) were optimal (i.e., between 15 and 20mg/L) in adolescents and children from 6 to 12 years of age, but less than 15 mg/L in children from 2 to 6 years of age and infants. The E(db) gradually increased as the patients' age decreased. DISCUSSION AND CONCLUSIONS: The choice of initial dosages of vancomycin treatment must take greater account of the patient's age in order to reduce the frequency of inadequate S(sc) before titration. In the absence of nephrotoxic cofactors, we suggest an increase in initial vancomycin dosages in continuous infusion between 40 and 45 mg/kg/day in children from 6 to 12 years old, between 45 and 50mg/kg/day in children from 2 to 6 years old, and between 50 and 55 mg/kg/day in infants, in hematology/oncology. For teenage patients, the standard dosage (i.e., 40 mg/kg/d) seems appropriate.

[Assessment of adherence to Afssaps guidelines for the prescription of antifungals in pediatric hemato-oncology]. / Évaluation de l'adhésion au référentiel Afssaps sur les antifongiques, en hémato-oncologie pédiatrique.

OBJECTIVE: This study had for aim to identify factors limiting the implementation of clinical guidelines related to the use of expensive antifungal drugs in pediatric hemato-oncology. DESIGN: A retrospective study was conducted in a Lyon teaching hospital (France), from February to December 2008. The compliance of antifungal prescription to French guidelines was assessed. Audit findings were interpreted using both semi-directed interviews of six prescribers (qualitative approach) and statistical analysis of prescriptions (quantitative approach). RESULTS: Fifty antifungal prescriptions were studied. The compliance with clinical guidelines reached 66% (CI 95% 52-80%). The semi-directed interviews revealed that five issues may have influenced the adherence of prescribers with recommended practices: the guidelines, the molecule, the prescriber, the child, and practice settings. The statistical analysis did not reveal any link between the prescriber's activities or his department and the compliance with guidelines. A significant association was found between the documentation of infection and the non-conformity of antifungal prescriptions (p=0.02). CONCLUSIONS: This study, combining qualitative and quantitative assessments, addressed potential issues related to the implementation of guidelines in specific patient groups or to their adaptation in the context of pediatric hematology-oncology. Harmonization of practices related to the widespread use of antifungal associations is required.

The use of pharmacokinetic models in paediatric onco-haematology: effects on clinical outcome through the examples of busulfan and cyclosporine.

Overall survival after allogeneic haematopoietic stem cell transplantation (HSCT) is reduced by the high rate of transplantation-related mortality (TRM), especially because of liver veno-occlusive disease (VOD) or acute graft-vs.-host disease (GVHD) because of the toxicity or inefficacy of busulfan and cyclosporine (CsA), respectively. Results of clinical outcome of previous studies performed to optimize busulfan and CsA therapy by controlling their pharmacokinetic variability by means of maximum a posteriori (MAP) Bayesian individualization of both drugs are presented. The 90-day VOD-free survival was significantly higher in patients with individualized busulfan doses: 97% vs. 76%. Monitoring CsA trough blood concentrations allowed us to obtain a successful GVHD outcome (mild or moderate GVHD and graft vs. leukaemia effect (GVL) in malignant diseases and no GVHD (in non-malignant ones) in the majority of our patients. Severe GVHD occurred in <5% of patients. TRM in children can be significantly decreased by using population pharmacokinetic models and MAP Bayesian individualization of dose regimens for drugs such as CsA and busulfan.

Influence of underlying disease on busulfan disposition in pediatric bone marrow transplant recipients: a nonparametric population pharmacokinetic study.

Busulfan is an alkylating agent used in a conditioning regimen prior to bone marrow transplantation. Busulfan has a narrow therapeutic index, giving rise to major liver toxicity (veno-occlusive disease), and a wide interpatient and intrapatient pharmacokinetic variability. This report presents the results of a population pharmacokinetic analysis leading to models based on underlying diseases requiring bone marrow transplantation. One hundred children received oral busulfan-based conditioning regimens between March 1998 and February 2006. Busulfan pharmacokinetic parameter estimates (Ka, first order absorption rate constant; Vs, volume of distribution related to the body weight; and Cl/F, apparent clearance) were estimated by using the nonparametric adaptative grid (NPAG) algorithm in patients divided into four groups according to initial diagnosis: metabolic diseases, hemoglobinopathies, hematological malignancies, and immune deficiencies. Ka and Vs did no differ significantly in the four subgroups. Cl/F and areas under the plasma concentration curve were significantly different in the four groups. Cl/F was significantly higher in the hemoglobinopathies group (P = 0.002), with a mean value of 7.78 L . h, whereas the immune deficiencies group was characterized by the lowest Cl/F (3.59 L . h). Interindividual variability was shown by high interindividual parameter percent coefficients of variation (CV%) but, nevertheless, with less diversity in the population parameter distributions for Vs in the three subgroups-metabolic diseases, hemoglobinopathies, and malignant diseases-and in Cl/F for patients with hemoglobinopathies. The fit was good for busulfan concentration predictions based on Bayesian individual posterior values, with little bias and good precision. In comparison with the overall population, the only model of subgroup presenting a greater precision was patients with hemoglobinopathies (P = 0.002). Use of these more specific models of a given disease may well result in more accurate individualization of busulfan dose regimens, especially in very sparse blood sampling situations.

[Human herpesvirus 6 encephalitis after bone marrow transplantation]. / Un cas d'encéphalite à herpès virus humain de type 6 après transplantation de moelle osseuse.

Human herpesvirus 6 (HHV-6) encephalitis may induce neurological sequelae and death; the diagnosis is difficult because of an initially poor symptomatology and of the absence of specific biochemical, electric and radiological signs. We report on a 7-year-old boy with relapsed acute lymphoblastic leukaemia, who developed HHV-6 encephalitis after bone marrow transplantation; the patient recovered after treatment with ganciclovir.

Efficacy and plasma levels of ropivacaine for children: controlled regional analgesia following lower limb surgery.

BACKGROUND: Continuous regional analgesia (CRA) is considered a safe and efficacious technique for postoperative pain relief in children after lower limb surgery. We recently evaluated the feasibility of patient-controlled regional analgesia (PCRA) in a similar acute pain situation and we concluded that PCRA might be advantageous over CRA in terms of lower costs, risk of systemic toxicity while producing similarly adequate analgesia. We therefore prospectively compared both techniques in the paediatric population. METHODS: In total, 30 children undergoing lower limb orthopaedic surgery were randomized to receive PCRA or CRA with ropivacaine 0.2%. Visual analogue scale scores, rescue analgesia, overall satisfaction, motor blockade and plasma ropivacaine concentrations were recorded for 48 h. RESULTS: Adequate analgesia was achieved with both techniques. No significant difference was noted for rescue analgesia, overall satisfaction and motor blockade. In contrast, children in the PCRA group received significantly less local anaesthetics than those in the CRA group. In addition, total plasma concentrations of ropivacaine were significantly reduced in the PCRA group as compared with the CRA group during the 48 h postoperative period. CONCLUSIONS: Both techniques are efficacious and satisfactory. However, PCRA with ropivacaine 0.2% can provide adequate postoperative analgesia for paediatric orthopaedic procedures with smaller doses of ropivacaine than CRA.

Low incidence of sepsis due to viridans streptococci in a ten-year retrospective study of pediatric acute myeloid leukemia.

BACKGROUND: Infections remain an important cause of morbidity and mortality in children with acute myeloid leukemia (AML), and particularly viridans group streptococci (VGS) sepsis. The present study, conducted between 1993 and 2003 in children with AML, sought to assess the frequency and characteristics of infectious complications (ICs), the incidence of VGS sepsis, the interest of preventive decontamination, and a possible cytarabine dose-effect on the occurrence of ICs. METHODS: Medical charts of 78 children treated according to the EORTC 58921 clinical trial were analyzed retrospectively. Patients were isolated in laminar air flow rooms, received non-absorbable gut decontamination, gum decontamination with vancomycin mouthwash, and trimethoprim-sulfamethoxasole. ICs were categorized as microbiologically documented infections (MDI), clinically documented infections (CDI), or fever of unknown origin (FUO). RESULTS: Overall, 268 ICs occurred: 57.5% FUO, 8.5% CDI, and 34% MDI. Bloodstream infections occurred in 58 febrile episodes: Gram-positive bacteria represented 83% of the pathogens including 66.1% Staphylococcus species and 8.5% Streptococcus species (6.8% VGS), Gram-negative bacteria represented 13.5% of the pathogens and yeasts 3.5%. Five patients died of infection (6.4%). None died from bacterial infection and no case of VGS sepsis required intensive care. Invasive fungal infection was proven in four patients. Number of ICs was significantly different according to gum and gut decontamination status, and according to the cytarabine dose during the first intensification. No resistant strains were detected in spite of the use of local antibiotics. CONCLUSION: The low rate of VGS and enterobacteriaceae sepsis was probably due to the effective decontamination. Our supportive care strategy could potentially help enhance overall survival in children with AML.

Antileukemic and long-term effects of two regimens with or without TBI in allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia.

Between September 1986 and June 1997, 24 children with high-risk ALL in CR1 were allografted after TAM (fractionated TBI, high-dose Ara-C, and melphalan; n = 10) or BAM protocol (busulfan, high-dose Ara-C, and melphalan; n = 14). The EFS for transplants from sibling donors was 33% with TAM and 62% with BAM (P = 0.148). The probability of acute GvHD was 70% with TAM and 15% with BAM (P = 0.003). Four of 17 evaluable patients relapsed: one after TAM and three after BAM. In all, 46 other children transplanted in CR beyond CR1 were studied for sequelae. Long-term side effects were more frequent in TAM vs BAM. In children with ALL, busulfan may be a good alternative to TBI to improve the quality of life.