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Purpose: Serum creatinine (SCr) is used as a marker of kidney function to guide dosing of renally eliminated drugs. Serum Cystatin C (S-CysC) has been suggested as a more reliable kidney marker than SCr in adults and children. Purpose of this study was to investigate S-CysC as alternative renal marker to SCr for estimating vancomycin clearance in neonates undergoing intensive care. Methods: Vancomycin pharmacokinetics (PK), SCr and S-CysC data were collected in patients undergoing vancomycin treatment in the neonatal intensive care unit of Robert Debré Hospital - Paris. A population PK analysis was performed utilizing routine therapeutic drug monitoring samples. S-CysC and SCr were compared as covariates on vancomycin clearance using stepwise covariate modeling (forward inclusion [ p < 0.05] and backward elimination [ p < 0.01]). Model performance was evaluated by graphical and statistical criteria. Results: A total of 108 vancomycin concentrations from 66 patients (postmenstrual age [PMA] of 26–46 weeks) were modeled with an allometric one-compartment model. The median (range) values for SCr and S-CysC were 41 (12–153) µmol/l and 1.43 (0.95–2.83) mg/l, respectively. Following stepwise covariate model building, SCr was retained as single marker of kidney function (after accounting for weight and PMA) in the final model. Compared to the final model based on SCr, the alternative model based on S-CysC showed very similar performance (e.g. BIC of 578.3 vs. 576.4) but included one additional covariate: impact of mechanical ventilation on vancomycin clearance, in addition to the effects of size and maturation. Conclusion: ill neonates. However, if using S-CysC for this purpose mechanical ventilation needs to be taken into account.

Objective: To develop a population pharmacokinetic model for valganciclovir in paediatric renal transplant recipients, identify covariates that explain variability, and determine valganciclovir dosage regimens for cytomegalovirus (CMV) prophylaxis in children. Methods: The pharmacokinetics of valganciclovir were described with plasma concentrations from 22 patients (age range 3–17 years) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with lag-time and first-order absorption and elimination was developed. The final model was validated using a bootstrap and visual predictive check. The dosage regimens of valganciclovir for CMV prophylaxis in children were simulated using the final model. Results: The mean population pharmacokinetic parameters were apparent systemic clearance (CL) 10.1 L/h, apparent central volume of distribution 5.2 L, apparent peripheral volume of distribution 30.7 L, inter-tissue clearance 3.97 L/h, absorption rate constant 0.369 h −1 and lag-time 0.743 h. The covariate analysis identified creatinine clearance (CL CR ) and bodyweight (WT) as individual factors influencing the apparent oral clearance: CL = 8.04 · (CL CR /89) 2.93 + 3.62 · (WT/28) L/h. The results of the simulation showed that for a typical patient (WT 28 kg and CL CR 89 mL/min), an area under the plasma concentration-time curve of 43 ± 10.6 mg · h/mL will be achieved with valganciclovir 500 mg once daily. Conclusion: The dosage regimens of valganciclovir for CMV prophylaxis have been defined using the final population pharmacokinetic model based on WT and CL CR for paediatric renal transplantation patients.

BackgroundClinical trials are conducted during pregnancy to evaluate benefits and risks of medicines for mother and child. The safety of maternal treatments is a key issue for healthcare professionals and parents.ObjectiveTo analyse offspring data reported in clinical trials in pregnant women with diabetes, HIV infection or hypertension (three of the most common diseases in women of childbearing potential) and either treated prior to pregnancy for these chronic diseases or diagnosed and treated during pregnancy.MethodsPubMed and Embase (1 January 1997 to 31 December 2017) were searched for drug trials in pregnant women with diabetes, HIV infection or hypertension. Titles and abstracts were screened, followed by a full-text review of eligible articles. Inclusion criteria were interventional clinical trials in pregnant women treated with medication and full text in English. Trial characteristics, maternal and offspring data were extracted. Data were summarised by disease and study. Twelve key items were considered for the offspring.ResultsOverall, 196 articles reporting 132 clinical trials (diabetes n=55; HIV n=59; hypertension n=18) were included. Key offspring data were frequently not reported, for example, number of births (diabetes: 22/55, 40%; HIV: 14/59, 24%; hypertension: 10/18, 56%). Congenital malformations were often not reported with sufficient detail (diabetes: 40/55, 73%; HIV: 39/59, 66%; hypertension: 17/18, 94%). Similar observations were made for other key items (eg, fetal losses, neonatal deaths).ConclusionUnder-reporting of key data for the offspring was frequent in publications of clinical trials in pregnant women with diabetes, HIV infection or hypertension making the assessment of the benefit-risk ratio of treatment options during pregnancy difficult.Trial registration numberCRD42017057024.

IntroductionMycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), has become a major therapeutic option in juvenile systemic lupus erythematosus (jSLE). Monitoring MPA exposure using area under curve (AUC) has proved its value to increase efficacy and safety in solid organ transplantation both in children and adults, but additional data are required in patients with autoimmune diseases. In order to facilitate MMF therapeutic drug monitoring (TDM) in children, Bayesian estimators (BE) of MPA AUC0–12 h using limited sampling strategies (LSS) have been developed. Our aim was to conduct an external validation of these LSS using rich pharmacokinetics and compare their predictive performance.MethodsPharmacokinetic blood samples were collected from jSLE treated by MMF and MPA plasma concentrations were determined using high-performance liquid chromatography system with ultraviolet detection (HPLC–UV). Individual AUC0–12 h at steady state was calculated using the trapezoid rule and compared with two LSS: (1) ISBA, a two-stage Bayesian approach developed for jSLE and (2) ADAPT, a non-linear mixed effects model with a parametric maximum likelihood approach developed with data from renal transplanted adults.ResultsWe received 41 rich pediatric PK at steady state from jSLE and calculated individual AUC0–12 h. The external validation MPA AUC0–12 h was conducted by selecting the concentration–time points adapted to ISBA and ADAPT: (1) ISBA showed good accuracy (bias: − 0.8 mg h/L), (2) ADAPT resulted in a bias of 6.7 mg L/h. The corresponding relative root mean square prediction error (RSME) was 23% and 43% respectively.ConclusionAccording to our external validation of two LSS of drug exposure, the ISBA model is recommended for Bayesian estimation of MPA AUC0–12 h in jSLE. In the literature focusing on MMF TDM, an efficacy cut-off for MPA AUC0–12 h between 30 and 45 mg h/L is proposed in jSLE but this requires additional validation.

Ganciclovir (GCV) is effective in preventing and treating cytomegalovirus (CMV) infection in solid organ transplant recipients. The aims of the present study were to determine the pharmacokinetics of GCV administered intravenously (IV) and orally (p.o.) as pre-emptive anti-CMV therapy in pediatric renal transplant recipients and to monitor trough levels and side-effects during pre-emptive therapy. Eleven pediatric renal transplant recipients (aged 11.0+/-3.9 years) were included. The diagnosis of CMV infection, based on two positive pp-65 CMV blood antigen tests at 1 week apart, was made at 39+/-12 days post renal transplantation. They received IV GCV at a dose of 5.0+/-0.3 mg/kg per 12 h for 15 days, followed by GCV p.o. at a dose of 46.7+/-8.2 mg/kg per 12 h for 3 months. Pharmacokinetics (PK) were studied at steady state and GCV plasma concentrations were measured by high-performance liquid chromatography. After IV GCV administration, PK parameters were: C(0)=0.84+/-0.66 microg/ml; C(max)=11.77+/-2.82 microg/ml; AUC(0-12 h)=42.29+/-17.57 microg/ml per hour; Cl=0.13+/-0.05 l/h per kg. After p.o. GCV administration, PK parameters were: C(0)=1.08+/-0.68 microg/ml; C(max)=2.70+/-1.07 microg/ml; AUC(0-12 h)=18.97+/-9.36 microg/ml per hour; Cl/F=2.97+/-1.42 l/h per kg. Bioavailability (F) was 4.9+/-1.2%. Pre-dose concentrations (C(0)) measured under p.o. GCV (n=51) were 1.29+/-0.80 microg/ml (8 C(0) values were below 0.5 microg/ml). Pp-65 CMV blood antigen tests became negative after 16+/-11 days of treatment. GCV was well tolerated. Because of the limited bioavailability, the recommended high doses of p.o. GCV (50 mg/kg per 12 h) were administered and were associated with trough levels over 0.5 microg/ml. In 1 patient who received an erroneously low dosage p.o., CMV resistance to GCV appeared, requiring foscarnet.

BackgroundChildren with haematological malignancy represent an identified subgroup of the paediatric population with specific pharmacokinetic parameters. In these patients, inadequate empirical antibacterial therapy may result in infection-related morbidity and increased mortality, making optimization of the dosing regimen essential. As paediatric data are limited, our aim was to evaluate the population pharmacokinetics of teicoplanin in order to define the appropriate dosing regimen in this high-risk population.MethodsThe current dose of teicoplanin was evaluated in children with haematological malignancy. Population pharmacokinetics of teicoplanin was analysed using NONMEM software. The dosing regimen was optimised based on the final model.ResultsEighty-five children (age range: 0.5 to 16.9 years) were included. Therapeutic drug monitoring and opportunistic samples (n=143) were available for analysis. With the current recommended dose of 10mg/kg/day, 41 children (48%) had sub-therapeutic steady-state trough concentrations (Css,min<10mg/liter). A two-compartment pharmacokinetic model with first-order elimination was developed. Systematic covariate analysis identified that bodyweight (size) and creatinine clearance significantly influenced teicoplanin clearance. The model was validated internally. Its predictive performance was further confirmed in an external validation. In order to reach the target AUC of 750mg.h/L, 18mg/kg was required for infants, 14mg/kg for children and 12mg/kg for adolescents. A patient-tailored dose regimen was further developed and reduced variability in AUC and Css,min values compared to the mg/kg-basis dose, making the modelling approach an important tool for dosing individualization.ConclusionsThis first population pharmacokinetic study of teicoplanin in children with haematological malignancy provided evidence-based support to individualize teicoplanin therapy in this vulnerable population.

Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to the active immunosuppressant mycophenolic acid (MPA). The drug is now widely prescribed for adult renal transplant recipients and its use has been extended to pediatric patients, although pharmacological data in this age group are limited. Nine pediatric renal transplant recipients received MMF with corticosteroids and either cyclosporine or tacrolimus a median of 55 months (range 7.5-124 months) months after transplantation. The pharmacokinetic parameters of MPA and MPA glucuronide (MPAG) were determined at steady state by high-performance liquid chromatography after administration of MMF at the oral dose of 494+/-142 mg/m(2) twice daily. MPA was rapidly absorbed, with a peak concentration at 1.4 h. The mean plasma concentration of MPA at steady state was 4.7+/-1.3 microg/ml. The areas under the plasma concentration-time curves (AUCs) over 12 h (between two administrations) were 57.0+/-15.3 microg.h/ml for MPA and 1,515+/-722 microg.h/ml for MPAG, and the apparent oral clearance was 11.7+/-7.0 and 0.5+/-0.4 l/h for MPA and MPAG, respectively. Assuming that the pharmacokinetics of MPA was dose dependent, the mean concentration at steady state and the AUC for MPA were calculated for the recommended dosage schedule of 600 mg/m(2) every 12 h and were 6.3+/-2.7 microg/ml and 75.2+/-32.9 microg.h/ml, respectively. The tolerance of MMF was studied prospectively with a follow-up of 1.1+/-0.2 years. Gastrointestinal disorders requiring dosage reduction or discontinuation of therapy, observed in five of nine patients, occurred at an incidence higher than expected from adult data. Our results suggest that the dose of 600 mg/m(2) every 12 h extrapolated from adult data for use in pediatric patients would be associated with plasma levels and AUCs higher than expected and may be associated with a higher incidence of side-effects, primarily gastrointestinal.

The objectives of this study were to characterize the population pharmacokinetics of MTX in patients with acute lymphoblastic leukemia (ALL) with ages ranging from 2 to 16 years and to propose a limited sampling strategy to estimate individual pharmacokinetic parameters. Seventy-nine children were enrolled in this study; they received 1-4 courses of chemotherapy. MTX was administered at a dose of 5 g/m2. MTX population parameters were estimated from 61 patients (231 courses; age range: 2-16 years). The data were analyzed by nonlinear mixed-effect modeling with use of a two-compartment structural model. The interoccasion variability was taken into account in the model. Eighteen additional patients (70 courses) were used to evaluate the predictive performances of the Bayesian approach and to devise a limited sampling strategy. The following population parameters were obtained: total clearance (CL) = 8.8 l/h (inter-individual variability: 43%), initial volume of distribution (V1) = 17.3 l (48%), k12 = 0.0225 h(-1) (41%), and k21 = 0.0629 h(-1) (24%). The inter-individual variability in the initial volume of distribution was partially explained by the fact that this parameter was weight-dependent. Intercourse variability was limited, with a mean variation of 13.2%. The protocol involving two sampling times, 24 and 48 h after the beginning of infusion, allows precise and accurate determination of individual pharmacokinetic parameters and consequently, it was possible to predict the time at which the MTX concentration reached the predicted threshold (0.2 microM) below which the administration of folinic acid could be stopped. The results of this study combine the relationships between the pharmacokinetic parameters of MTX and patient covariates that may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing pediatric patient care.