Evelyne Jacqz-Aigrain

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial

Mycophenolate mofetil (MMF) has emerged as a new therapeutic option in steroid-dependent nephrotic syndrome (SDNS). We conducted a phase II Bayesian trial of MMF in children with SDNS. Phase II trials, usually single-arm studies, investigate the effect of new treatments. Standard Fleming’s procedure relies on observed results (relapse rate during the trial), whereas Bayesian approach combines observed results with prior information (expected relapse rate according to prior studies and clinical experience). All patients were required to have received prior alkylating-agent treatment. Sixty-seven percent of them had also received levamisole. Patients received MMF (1,200xa0mg/m2/day) and prednisone according to a defined schedule [reduction of alternate-day (e.o.d) dose to 50% of pre-MMF dose at 3xa0months, 25% at 6xa0months]. Twenty-four children (median age 6.0xa0years, 2.8–14.4) entered the study and 23 completed it. Bayesian analysis showed that adding four patients would not change significance of results, allowing stopping inclusions. Four patients relapsed during the first 6xa0months (estimated probability 17.6%, 95% credibility interval: 5.4–35.0%) and two at months 8 and 11.5. In the 19 patients free of relapse during the first 6xa0months, median (Q1–Q3) prednisone maintenance dose decreased from 25 (10–44) to 9 (7.5–11.2) mg/m2 e.o.d (pu2009<u20090.001) and cumulative dose from 459 (382–689) to 264 (196–306) mg/m2/month (pu2009<u20090.001) before and on MMF respectively. Pre-MMF patient characteristics and MMF pharmacokinetics did not differ between patients with or without relapse. MMF reduces relapse rate and steroid dose in children with SDNS and should be proposed before cyclosporine and cyclophosphamide.

Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia

BackgroundThe backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability.AimThis review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.

A novel maturation function for clearance of the cytochrome P450 3A substrate midazolam from preterm neonates to adults

Background and objectiveMajor changes in cytochrome P450 (CYP) 3A activity may be expected in the first few months of life with, later, relatively limited changes. In this analysis we studied the maturation of in vivo CYP3A-mediated clearance of midazolam, as model drug, from preterm neonates of 26xa0weeks gestational age (GA) to adults.MethodsPharmacokinetic data after intravenous administration of midazolam were obtained from six previously reported studies. Subjects were premature neonates (nxa0=xa024; GA 26–33.5xa0weeks, postnatal age (PNA) 3–11xa0days, and nxa0=xa024; GA 26–37xa0weeks, PNA 0–1xa0days), 23 children after elective major craniofacial surgery (age 3–23xa0months), 18 pediatric intensive-care patients (age 2xa0days–17xa0years), 18 pediatric oncology patients (age 3–16xa0years), and 20 healthy male adults (age 20–31xa0years). Population pharmacokinetic modeling with systematic covariate analysis was performed by use of NONMEM v6.2.ResultsAcross the entire lifespan from premature neonates to adults, bodyweight was a significant covariate for midazolam clearance. The effect of bodyweight was best described by use of an allometric equation with an exponent changing with bodyweight in an exponential manner from 0.84 for preterm neonates (0.77xa0kg) to 0.44 for adults (89xa0kg), showing that the most rapid maturation occurs during the youngest age range.ConclusionsAn in-vivo maturation function for midazolam clearance from premature neonates to adults has been developed. This function can be used to derive evidence-based doses for children, and to simulate exposure to midazolam and possibly other CYP3A substrates across the pediatric age range in population pharmacokinetic models or physiologically based pharmacokinetic models.

Safety of fluconazole in paediatrics: a systematic review

PurposeTo determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment.MethodsA search of EMBASE (1950–January 2012), MEDLINE (1946–January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982–2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17xa0years) was performed. Only articles with sufficient quality of safety reporting after patients’ exposure to fluconazole were included.ResultsWe identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6xa0%) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95xa0% confidence interval (CI) 0.87–2.14, Pu2009=u20090.175 and RR 1.43, 95xa0% CI 0.67–3.03, Pu2009=u20090.352, respectively]. Complete resolution of hepatoxicity was achieved by 84xa0% of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95xa0% CI 0.12–5.60, P =u20090.831 and RR 1.23, 95xa0%CI 0.87–1.71, Pu2009=u20090.235, respectively). There were 41 drug withdrawals, 17 (42xa0%) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children.ConclusionFluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity.

Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates

OBJECTIVESnCoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens.nnnMETHODSnA hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations.nnnRESULTSnThere was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mgu200a·u200ah/L. Simulations predicted that neonates <29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups.nnnCONCLUSIONSnThe AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial.

Covariate effects and population pharmacokinetics of lamivudine in HIV‐infected children

AIMnLamivudine is used as first line therapy in HIV-infected children. Yet, like many other paediatric drugs, its dose rationale has been based on limited clinical data, without thorough understanding of the effects of growth on drug disposition. Here we use lamivudine to show how a comprehensive population pharmacokinetic model can account for the influence of demographic covariates on exposure (i.e. AUC and Cmax ).nnnMETHODSnData from three paediatric trials were used to describe the pharmacokinetics across the overall population. Modelling was based on a non-linear mixed effects approach. A stepwise procedure was used for covariate model building.nnnRESULTSnA one compartment model with first order elimination best described the pharmacokinetics of lamivudine in children. The effect of weight on clearance (CL) and volume of distribution (V) was characterized by an exponential function, with exponents of 0.705 and 0.635, respectively. For a child with median body weight (17.6 kg), CL and V were 16.5 (95% CI 15.2, 17.7) l h⁻¹ and 46.0 (95% CI 42.4, 49.5) l, respectively. There were no differences between formulations (tablet and solution). The predicted AUC(0,12 h) after twice daily doses of 4 mgu2009kg⁻¹ ranged from 4.44 mgu2009l⁻¹ u2009h for children <14 kg to 7.25 mgu2009l⁻¹ u2009h for children >30 kg.nnnCONCLUSIONSnThe use of meta-analysis is critical to identify the correct covariate-parameter relationships, which must be assessed before a model is applied for predictive purposes (e.g. defining dosing recommendations for children). In contrast to prior modelling efforts, we show that the covariate distribution in the target population must be considered.

The impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia.

PurposeLow-dose methotrexate (MTX) therapy is the cornerstone treatment of acute lymphoblastic leukemia (ALL) and may enhance the activation of 6-mercaptopurine (6-MP) to 6-thioguanine nucleotides (6-TGN). Yet, data have established that high-dose MTX (HDMTX) hampers the accumulation of 6-TGN in red blood cells (RBC) and lymphoblasts.MethodsTo clarify the pharmacokinetic interactions between these two antimetabolites, we serially measured RBC 6-TGN and MTX polyglutamates (MTXPG) levels following repeated courses of HDMTX (5xa0g/m² over 24xa0h) with daily oral 6-MP (25xa0mg/m²) during interval therapy in 20 children with ALL.ResultsHDMTX produced a rapid reduction in RBC 6-TGN 24xa0h after the start of MTX, and this effect was sustained at least by the third day (median decrease −21%; Pxa0<xa00.001). However, a return to pre-infusion of 6-TGN levels was observed by the time of the following HDMTX course 14xa0days later (Pxa0<xa00.001). RBC MTX polyglutamates accumulation followed Michaelis–Menten kinetics but was not associated with the change in pre-infusion 6-TGN levels which remained stable during the interval period.ConclusionHDMTX does not appear to enhance 6-MP activation to 6-TGN. Moreover, given that the deleterious effect of HDMTX on intracellular 6-MP disposition has been shown to be several folds greater in lymphoblasts than in RBC. Our data warrant additional studies elucidating the optimal MTX dose synergizing with 6-MP.

A model-based approach for the evaluation of once daily dosing of lamivudine in HIV-infected children

AIMnLittle attention has been paid to the effects of compliance and prescription practice on treatment outcome in HIV-infected children. In this context, an evaluation of the role of covariates on pharmacokinetics is required to establish the impact of differences in dosing regimens. Here we investigate whether a once daily dosing regimen of lamivudine provides comparable exposure to the currently approved paediatric regimen.nnnMETHODSnA hypothetical group of 180 patients between 3 months and 12 years old was used to evaluate the impact of body weight on systemic exposure to lamivudine. Simulation scenarios were evaluated using AUC and Cmax as parameters of interest. The analysis was performed using a population pharmacokinetic model previously implemented in nonmem v.6.2.nnnRESULTSnThe simulations show that once daily dosing of lamivudine yields comparable exposure to historical values observed in children and adults, both for liquid and solid dosage forms. Simulated steady-state AUC(0-24 h) and Cmax values after once daily doses ranged respectively from 9.9 u2009mgu2009l⁻¹ u2009h and 1.9 mgu2009l⁻¹ for children lighter than 14u2009kg to 13.75u2009mgu2009l⁻¹ u2009h and 3.0u2009mgu2009l⁻¹ for children heavier than 30 kg. These values are comparable or higher than historical values observed after once daily dosing in children and adults.nnnCONCLUSIONSnOur findings illustrate how dosing regimens can be evaluated taking into account the effects of developmental growth on drug disposition. Most importantly, they suggest that the reduction in dosing frequency to once daily leads to comparable lamivudine exposure, as observed after administration of a twice daily dosing regimen.

Neonatal adverse drug reactions: an analysis of reports to the French pharmacovigilance database

AIMnTerm and preterm neonates are at high risk for serious adverse drug reactions (ADRs).nnnMETHODSnA descriptive study of reports registered in the French pharmacovigilance database from 1986 to 2012 were obtained. All reports concerning neonates (≤1xa0month of life) with direct drug exposure were retrieved. Characteristics of the reports, including reported ADR(s), drug(s) and the causality assessment using the French causality assessment method, were described.nnnRESULTSnA total of 1688 reports were analyzed and more than half of them were classified as serious (nxa0=xa0995). Median age at ADR occurrence was 9xa0days. Overall, 3127 ADRs were described in these reports in relation to 2238 suspect/interacting drugs. The most commonly reported system organ classes (SOCs) were injury, poisoning and procedural complications (16%), general disorders and administration site conditions (12.5%) and blood and lymphatic system disorders (12%). In the majority of ADRs reported (73%), infants fully recovered and less than 4% of neonates deceased as a consequence of the reported ADR. One out of five ADRs was associated with drug administration errors. Therapeutic classes commonly incriminated were anti-infectives, nervous system and alimentary tract drugs. Substances most frequently related to serious ADRs were zidovudine, ibuprofen and nevirapine. Among the 10 most frequently encountered drug-ADR pairs, two substances were mainly implicated, zidovudine in haematological adverse reactions and phytomenadione in maladministrations.nnnCONCLUSIONSnAnti-infective drugs, mainly antiretroviral therapy, account for the majority of ADRs reported in neonates. The specific issue of drug maladministration and medication errors remains to be addressed in neonates.

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV-infected infants and toddlers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTnAbacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8u2003mgu2003kg(-1) twice daily up to a maximum of 300u2003mg twice daily. Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children.nnnWHAT THIS STUDY ADDSnA population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. A maximum a posteriori probability Bayesian estimator of AUC(0-) (t) based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration-time curve (AUC) targeted individualized therapy in infants and toddlers.nnnAIMSnTo develop a population pharmacokinetic model for abacavir in HIV-infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration-time curve (AUC) targeted dosage and individualize therapy.nnnMETHODSnThe pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment model with first-order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross-validation and simulation-estimation method.nnnRESULTSnThe typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 () h−1 (RSE 6.3%), apparent central volume of distribution 4.94 () (RSE 28.7%), apparent peripheral volume of distribution 8.12 () (RSE14.2%), apparent intercompartment clearance 1.25 () h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t.nnnCONCLUSIONSnThe population pharmacokinetic model developed for abacavir in HIV-infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC(0-) (t) was developed from the final model and can be used routinely to optimize individual dosing.