Gilles Aulagner

Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens.

In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 μg.h.ml+1. Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan–Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 ± 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients. Bone Marrow Transplantation (2001) 28, 743–751.

Clinical and pharmacological risk factors for acute graft-versus-host disease after paediatric bone marrow transplantation from matched-sibling or unrelated donors

Summary:The aim of this study was to identify the risk factors for acute graft-versus-host disease (aGVHD) in children transplanted from a matched-sibling donor (MSD) or an unrelated donor (UD). In all, 87 children consecutively underwent allogeneic bone marrow transplantation (BMT) from MSD (n=36), and UD (n=51). GVHD prophylaxis included CsA alone (n=33) or with MTX (n=51). ATG was added in UD-BMT and thalassemic recipients. CsA whole-blood concentrations were measured by EMIT and the dosing regimen was monitored by Bayesian pharmacokinetic modelling. Trough blood concentration (TBC) during the first 2 weeks post transplantation was lower in children who developed grade II–IV aGVHD than those developing no GVHD or only grade I (57±9 vs 94±8u2009ng/ml, P=0.007), whereas peak blood concentration and area under concentration curve vs time were similar in both groups. TBC <85u2009ng/ml and ‘use of MTX’ were associated with aGVHD in MSD-SCT (P=0.003 and 0.007, respectively) as well as in UD-SCT (P=0.006 and 0.003). Donor age ⩾8 years was significant only in MSD-BMT. Our results have shown the significant decisive role of pharmacological factors such as CSA TBC or use of MTX in the occurrence of GVHD in MSD as well as in UD paediatric BMT.

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−1, whereas the immune deficiencies group was characterized by the lowest Cl/F (3.59 L · h−1). 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.

Rapid and sensitive high-performance liquid chromatographic method for busulfan assay in plasma.

A reversed-phase liquid chromatographic method with ultraviolet detection has been developed to determine busulfan concentrations in plasma of children undergoing bone marrow transplantation. Plasma samples (200 microl) containing busulfan and 1,6-bis(methanesulfonyloxy)hexane as an internal standard were prepared by a simple derivatization method with diethyldithiocarbamate followed by extraction with ethyl acetate and solid-phase purification on C8 columns conditioned with methanol and water and eluted with acetonitrile (recovery 99%). Chromatography was accomplished using a Hypersil octadecylsilyl column (10 cm x 4.6 mm I.D.) and a mobile phase of acetonitrile, tetrahydrofuran and distilled water (65:5:30, v/v). The limit of detection was 25 ng/ml (signal-to-noise ratio of 5). Calibration curves were linear up to 25,000 ng/ml. Intra-day and inter-day coefficients of variation of the assay were < or =5%. This method was used to analyse busulfan plasma concentrations after oral administration within the framework of therapeutic drug monitoring and pharmacokinetic studies in children.

Relationship between CsA trough blood concentration and severity of acute graft-versus-host disease after paediatric stem cell transplantation from matched-sibling or unrelated donors

Summary:In order to determine optimal CsA trough blood concentrations (TBC) in the early post transplantation period, we analysed relationships between TBC and acute graft-versus-host disease (aGVHD) in paediatric SCT. A total of 94 children consecutively underwent allogeneic stem cell transplantation (SCT) from: matched-sibling (MSD) (n=36), mismatched-related (MMRD) (n=3) and unrelated donors (UD) (n=55). GVHD prophylaxis usually included CsA alone or with methotrexate. Antithymocyte globulin was added in UD-SCT. TBC during the first weeks of post transplantation were estimated retrospectively by a Bayesian pharmacokinetic method and statistically associated with aGVHD. In MSD-SCT, the mean TBC during the first 2 weeks post transplantation were 42±10 and 90±7u2009ng/ml, respectively, in patients with grade II–IV and 0–I aGVHD (P=0.001). In SCT from UD and MMRD, TBC were 73±4 vs 95±8u2009ng/ml (P=0.284). For TBC >85u2009ng/ml, no patient developed grade II–IV aGVHD, 10 developed mild aGVHD and 30 had no aGVHD. For TBC <65u2009ng/ml, 7/11 patients receiving an MSD-SCT and 4/18 receiving an UD- or MMRD-SCT developed grade II–IV aGVHD. The mean TBC corresponding to each grade were: no GVHD: 101±10u2009ng/ml, mild: 77±11u2009ng/ml, moderate: 61±13u2009ng/ml, severe: 56±15u2009ng/ml (P<0.001). These results reveal a strong relationship between TBC during the early post transplantation period and the severity of aGVHD in paediatric SCT.

Assessment of acyclovir intraindividual pharmacokinetic variability during continuous hemofiltration, continuous hemodiafiltration, and continuous hemodialysis.

The use of intravenous acyclovir can be particularly complicated in pediatric patients with evolving renal impairment, because of intraindividual pharmacokinetic variability linked to the patients clinical condition. The objective of this study was to use therapeutic drug monitoring data to assess acyclovir intraindividual pharmacokinetic variability during several types of renal replacement therapy. Bayesian adaptive control of acyclovir dosage regimen was performed in a pediatric patient with bone marrow transplant who developed severe renal impairment. Acyclovir pharmacokinetic parameter values corresponding to the different techniques and periods of renal replacement therapy were estimated using USCPACK PC Clinical Programs and therapeutic drug monitoring data. Results showed a wide intraindividual pharmacokinetic variability during CAVH, CAVHDF, and CVVHD, reflecting not only the performance of each dialysis technique but also the difficulty in making use of each one. The acyclovir elimination rate constant was higher during CVVHD compared to CAVH or CAVHDF. Bayesian method appears to be valuable in assessing intraindividual pharmacokinetic variability, as it allows the clinician to deal with sparse routine patient data.

Effect of duration and intensity of ganciclovir exposure on lymphoblastoid cell toxicity.

Introduction: Human cytomegalovirus infection is still a major complication after pediatric bone marrow transplantation and could be fatal in some cases. The toxicity of the drug in dividing transplanted haematopoietic cells combined with the suppression of cell growth caused by the virus remains a major problem in managing human cytomegalovirus infection. Methods: The aim of the current in vitro study was to evaluate the effect of the intensity (1–20 mg/l) and duration (1, 2, 7 or 14 days) of ganciclovir exposure on toxicity in B lymphoblastoid cells (using cell counting and viability measurements). Results: A correlation was found between the dose of ganciclovir exposure and a decrease in total cell number when duration exceeded 2 days (r2=0.92 and 0.93 after 7 and 14 days, respectively). High levels (20 mg/l) of ganciclovir were not more toxic than lowest levels (1 mg/l) for the shortest durations of ganciclovir exposure (1 and 2 days). Moreover, 50% cytotoxic concentrations markedly decreased with the duration of ganciclovir exposure (374–3 mg/l from 1 to 14 days respectively) after 14 days of culture. Conclusions: This in vitro study demonstrated for the first time that ganciclovir exhibited an in vitro duration-dependent toxicity on haematopoietic-derived cells when in vivo doses of the drug were used.

Control of Intra and Inter-Patient Variability by Bayesian Forecasting of Busulfan Dosage Regimens in Pediatric BMT

Control of Intra and Inter-Patient Variability by Bayesian Forecasting of Busulfan Dosage Regimens in Pediatric BMT

Low Dosing of Sandimmun® and Neoral® When Switching IV-PO Cyclosporin in Pediatric Bone Marrow Transplantation

Low Dosing of Sandimmun® and Neoral® When Switching IV-PO Cyclosporin in Pediatric Bone Marrow Transplantation

Individualization of Amikacin (AMK) Therapy in Neonates (NN) less than 2-day old 1421

Introduction: Considering a very large inter-individual pharmacokinetic (PK) variability in neonates, a standard amikacin dosage regimen does not allow to obtain efficacy or safety in all cases of suspected spesis especially in just-born ones. This study was aimed to elaborate and validate an once-a-day amikacin dosing nomogram for the first days of life, using population PK models. Patients/material and methods: We used three population PK models built using NPEM2 algorithm from 63 NNdivided into 3 groups according to gestational age (G1: 34 SA, n = 31) were prospectively included for the nomogram validation. AMK doses given by the nomogram, depending on gestational age and body weight, were determined by simulation of target plasma levels on USCPACK software. Target AMK peak levels were between 28 and 34 μg/ml for G1 and G2, between 33 and 37 μg/ml for G3, and target trough levels < 7 μg/ml for G1,< 5 μg/ml for G2 and G3. The nomogram was used in the 55 NN and validated by comparing estimated and observed AMK peak and trough levels. Percentage of accurately predicted plasma levels were evaluated in each NN group after the first D1 and second D2 doses. Results: 62% of satisfying AMK peak levels after D1 and 100% after D2 were obtained in S1, 80% after D1 and 80% after D2 in S2, 63% after D1 and 90% after D2 in S3. Non toxic AMK plasma levels were obtained in 100% of NN. Conclusion: The nomogram allows the use of once-a-day AMK dosage regimens adapted to each NN in the first two days of life. These regimens guarantee a better efficiency and a better safety than conventional regimens, despite a persistent intra-individual variability.