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Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione‐s‐transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model‐based, first‐dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu‐based conditioning regimen. External model validation used data from 100 patients. The relationship between body weight and Bu clearance (CL) was best described by an age‐dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based on GSTA1 polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first‐dose CL in the external cohort, with 81% of predicted area under the curves within the therapeutic window. The final model showed minimal bias (mean prediction error, −0.5%; 95% confidence interval [CI], −3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%–20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of GSTA1 polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.

Given a high pharmacokinetic inter-individual variability and a low exposure target achievement, ganciclovir (GCV) therapeutic drug monitoring is sometimes used in children. We aimed to develop and validate Bayesian estimators based on limited sampling strategies for the estimation of GCV area under the concentration–time curve from 0 to 24 h in pediatric transplant recipients treated with valganciclovir (VGCV) or GCV. Solid organ transplant or stem-cell transplant recipients who received GCV or VGCV and had available GCV concentrations per standard of care were retrospectively included in this study for pharmacokinetic modeling and development of Bayesian estimators using the iterative two-stage Bayesian method. Validation datasets included additional child recipients of a solid organ transplant or stem-cell transplant, and child recipients of a kidney or liver transplant enrolled in a previous study. Various combinations of three or two sampling times, applicable in clinical practice, were assessed based on the relative mean bias, standard deviation, and the root mean square error in a development dataset and three independent validation datasets. In the development dataset, the mean bias/standard deviation/root mean square error for the 1 h/2 h/3 h and 1 h/3 h limited sampling strategies were − 1.4%/9.3%/9.1% and − 3.5%/12.2%/12.3%, respectively for GCV, while for VGCV, the mean bias/standard deviation/root mean square error for the 1 h/2 h/6 h and 1 h/6 h limited sampling strategies were 0.7%/13.5%/13.3% and − 0.1%/12.1%/11.8%, respectively. In the independent validation datasets, seven (13%) and five (14%) children would have had misclassifications of their exposure using these Bayesian estimators and limited sampling strategies for VGCV and GCV, respectively. Three plasma samples collected at 1 h/2 h/3 h and 1 h/2 h/6 h post-dose for GCV and VGCV respectively, are sufficient to accurately determine GCV area under the concentration–time curve from 0 to 24 h for pharmacokinetic-enhanced therapeutic drug monitoring.

In busulfan-based conditioning regimen for hematopoietic stem cell transplantation in children, accurate a priori determination of the first dose is important because of its narrow therapeutic window. Sickle cell disease (SCD) influences pharmacokinetics of the commonly used drugs by affecting organs responsible for drug metabolism and elimination. This pharmacokinetics study assesses the influence of SCD on the metabolic pathway of busulfan that is mainly metabolized in the liver. In this retrospective cross-sectional case-control study, 16 patients with SCD were matched to 50 patients without SCD on known busulfan clearance's covariates (glutathione-S-transferase alpha1 polymorphisms, age, weight). Clearance of the first dose of busulfan was not significantly different independently of genetic or anthropometric factors in patients with or without SCD.

AIMS Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are first-line agents to prevent and treat cytomegalovirus in transplant recipients. There is high pharmacokinetic (PK) interindividual variability and PK data are scarce, especially in paediatric stem cell transplant (SCT) recipients. We sought to determine the optimal GCV and VGCV dosing in transplanted children. METHODS We conducted a single-centre retrospective population PK (POPPK) study of IV GCV and enteral VGCV in paediatric solid organ transplant (SOT) and SCT recipients. We included children who were transplanted and had available plasma GCV concentrations, done per standard of care. POPPK analysis was performed using a nonlinear mixed effects modelling approach with NONMEM. Optimal dosing was determined based on the achievement of the surrogate efficacy target: GCV 24 h area under the concentration-time curve (AUC0-24h ) of 40-60 mg.h.L-1 . RESULTS Fifty children with a median [range] age of 7.5 years [0.5-17.4] contributed 580 PK samples. A two-compartment model with first-order absorption with a lag time and first-order elimination fit the data well. Creatinine clearance and body weight (WT) were significant covariates for GCV clearance (CL); and WT for the volumes of distribution. IV GCV 15-20 mg.kg-1 .day-1 divided every 12 hours achieved the highest probability of target achievement (PTA) (33.0-33.8%). Enteral VGCV 30 and 40 mg.kg-1 .day-1 divided every 12 hours in children 0

Aims The aim of this study is to develop a population pharmacokinetic (PopPK) model for intravenous busulfan in children that incorporates variants of GSTA1, gene coding for the main enzyme in busulfan metabolism. Methods Busulfan concentration-time data was collected from 112 children and adolescents (median 5.4 years old, range: 0.1-20) who received intravenous busulfan during the conditioning regimen prior to stem cell transplantation. Weight, sex, baseline disease (malignant vs. non-malignant), age, conditioning regimen and GSTA1 diplotypes were evaluated as covariates of pharmacokinetic parameters by using nonlinear mixed effects analysis. The ability to achieve the target AUC24h (3600-6000 μM min-1 ) was assessed by estimating the first dose based on the present PopPK model and by comparing the results with other available models in children. Results A one-compartment model with first-order elimination best described the data. Allometric scaling of weight and a factor of busulfan metabolism maturation were included in the base model. GSTA1 diplotypes were found to be a significant covariate of busulfan clearance, which was 7% faster in rapid metabolizers and 12% slower in poor metabolizers, in comparison with normal ones. Busulfan doses calculated using the parameters of the proposed PopPK model were estimated to achieve the target AUC in 85.2% of the cases (95% CI 78.7-91.7%). Conclusion This is the first PopPK for busulfan that successfully incorporated GSTA1 genotype in a paediatric population. Its use may contribute to better prediction of busulfan exposure in children and adolescents since the first dose, by tailoring the dose according to the individual metabolic capacity.

Busulfan (Bu) is a key component of conditioning regimens used before hematopoietic stem cell transplantation (SCT) in children. Different predictive methods have been used to calculate the first dose of Bu. To evaluate the necessity of further improvements, we retrospectively analyzed the currently available weight- and age-based guidelines to calculate the first doses in 101 children who underwent allogenic SCT in CHU Sainte-Justine, Montreal, after an intravenous Bu-containing conditioning regimen according to genetic and clinical factors. The measured areas under the curve (AUCs) were within target (900 to 1500 µM/min) in 38.7% of patients after the administration of the first dose calculated based on age and weight, as locally recommended. GSTA1 diplotypes linked to poor Bu metabolism (G3) and fludarabine-containing regimens were the only factors associated with AUC within target (OR, 4.7 [95% CI, 1.1 to 19.8, P = .04]; and OR, 9.9 [95% CI, 1.6 to 61.7, P = .01], respectively). From the 11 methods selected for dose calculation, the percentage of AUCs within the target varied between 16% and 74%. In some models G3 was associated with AUCs within the therapeutic and the toxic range, whereas rapid metabolizers (G1) were correlated with subtherapeutic AUCs when different methods were used. These associations were confirmed by clearance-prediction analysis, in which GSTA1 diplotypes consistently influenced the prediction errors of the methods. These findings suggest that these factors should be considered in Bu dose prediction in addition to the anthropometric data from patients. Furthermore, our data indicated that GSTA1 diplotypes was a factor that should be included in future population pharmacokinetic models, including similar conditioning regiments, to improve the prediction of Bu exposure after its initial dose.

Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.

Background The emergence of coagulase-negative staphylococci with reduced vancomycin susceptibility in some neonatal intensive care units has resulted in an increase of linezolid use. Linezolid pharmacokinetics (PK) and safety in premature infants still need to be better established. Methods This was a retrospective PK study. All infants who received intravenous linezolid and had linezolid plasma concentrations per standard of care were included. Linezolid concentrations were measured by high performance liquid chromatography. A population PK model was developed using nonlinear mixed effects modeling. Optimal dosing was determined based on achievement of the surrogate pharmacodynamics target for efficacy: a ratio of the area under the concentration-time curve to minimum inhibitory concentration >80. We assessed the occurrence of thrombocytopenia and lactic acidosis in relation with drug exposure. Results A total of 78 plasma concentrations were collected from 26 infants, with a median postnatal age (PNA) of 24 days (8-88) and weight of 1423 g (810-3256). A 1-compartment model described linezolid data well. The final model included PNA and weight on clearance and weight on volume of distribution. Considering an MIC90 of 1 mg/L, all infants reached an area under the concentration-time curve/minimum inhibitory concentration > 80. Although thrombocytopenia and hyperlactatemia occurred frequently, they were not sustained and were not considered related to linezolid. Conclusion and was well tolerated in critically ill premature infants. PNA was the main determinant of clearance.

// Marc Ansari 1,2 , Patricia Huezo-Diaz Curtis 1,2,* , Chakradhara Rao S. Uppugunduri 1,2,* , Mohammed Aziz Rezgui 3 , Tiago Nava 1,3,5,6 , Vid Mlakar 1,2 , Laurence Lesne 1,2 , Yves Theoret 3,4,5 , Yves Chalandon 7 , Lee L. Dupuis 8 , Tao Schechter 8 , Imke H. Bartelink 9,17 , Jaap J. Boelens 9 , Robbert Bredius 10 , Jean-Hugues Dalle 11 , Saba Azarnoush 11 , Petr Sedlacek 12 , Victor Lewis 13 , Martin Champagne 14 , Christina Peters 15 , Henrique Bittencourt 3,4,5,16 and Maja Krajinovic 3 - 5,16,18 1 Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland 2 Department of Pediatrics, Onco-Hematology Unit, Geneva University Hospital, Geneva, Switzerland 3 Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada 4 Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada 5 Clinical Pharmacology Unit, CHU Sainte-Justine, Montreal, Quebec, Canada 6 Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil 7 Department of Medical Specialties, Division of Hematology, Geneva University Hospital, Geneva, Switzerland 8 Department of Haematology/Oncology, Blood and Marrow Transplant Unit, The Hospital for Sick Children, Toronto, Ontario, Canada 9 Pediatric Blood and Marrow Transplantation Program, University Medical Center, Utrecht, The Netherlands 10 Department of Pediatrics, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands 11 Pediatric Hematology Department, Robert Debre Hospital, Assistance Publique, Hopitaux de Paris, Paris, France 12 Department of Pediatric Hematology and Oncology Teaching Hospital, 2nd Medical School, Charles University, Prague, Czech Republic 13 Department of Pediatrics, Alberta Children’s Hospital, Calgary, Alberta, Canada 14 Department of Hematology, Hospital Verdun, Montreal, Quebec, Canada 15 Department of Pediatrics, Stem Cell Transplantation Unit, St Anna Children’s Hospital, Vienna, Austria 16 Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada 17 Department of Medicine, The University of California San Francisco, San Francisco, CA, USA 18 On Behalf of the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, Leiden, The Netherlands * These authors have contributed equally to this work Correspondence to: Patricia Huezo-Diaz Curtis, email: // Keywords : busulfan, pharmacokinetics, pharmacogenetics, toxicity, hematopoietic stem cell transplantion Received : July 18, 2017 Accepted : July 23, 2017 Published : August 27, 2017 Abstract Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 ( GSTA1 ) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p

Aims The objectives of this study were to develop a population pharmacokinetic (PopPK) model for tacrolimus in paediatric liver transplant patients and determine optimal sampling strategies to estimate tacrolimus exposure accurately. Methods Twelve hour intensive pharmacokinetic profiles from 30 patients (age 0.4–18.4 years) receiving tacrolimus orally were analysed. The PopPK model explored the following covariates: weight, age, sex, type of transplant, age of liver donor, liver function tests, albumin, haematocrit, drug interactions, drug formulation and time post-transplantation. Optimal sampling strategies were developed and validated with jackknife. Results A two-compartment model with first-order absorption and elimination and lag time described the data. Weight was included on all pharmacokinetic parameters. Typical apparent clearance and central volume of distribution were 12.1 l h−1 and 31.3 l, respectively. The PopPK approach led to the development of optimal sampling strategies, which allowed estimation of tacrolimus pharmacokinetics and area under the concentration–time curve (AUC) on the basis of practical sampling schedules (three or four sampling times within 4 h) with clinically acceptable prediction error limit. The mean bias and precision of the Bayesian vs. reference (trapezoidal) AUCs ranged from −2.8 to −1.9% and from 7.4 to 12.5%, respectively. Conclusions The PopPK of tacrolimus and empirical Bayesian estimates represent an accurate and convenient method to predict tacrolimus AUC(0–12) in paediatric liver transplant recipients, despite high between-subject variability in pharmacokinetics and patient demographics. The developed optimal sampling strategies will allow the undertaking of prospective trials to define the tacrolimus AUC-based therapeutic window and dosing guidelines in this population.

BackgroundHaematopoietic stem cell transplantation (HSCT) is the only current curative treatment for Sickle Cell Disease (SCD), with potential life-threatening consequences. Busulfan is an alkylating agent used in HSCT conditioning regimen. Because of its narrow therapeutic window, determining the optimal first dose a priori remains a challenge.Busulfan is metabolized in the liver by conjugation with glutathione, which is catalyzed by Glutathione-S-Transferases (GSTs). GSTA1 is a known determinant of Busulfan clearance1 2 (just like age and weight) suggesting that those characteristics should be known a priori to adjust the first dose of Busulfan.Haemoglobinopathies (SCD and thalassemia) are not associated with changes in Busulfan clearance in a recent study.3 However, SCD is known to alter pharmacokinetics of other drugs.4 5 As it leads namely to liver dysfunction6 it may affect busulfan pharmacokinetics independently from genetic or anthropometric factors.Our aim is to compare the clearance of the first dose of Bu between patients with and without SCD, considering other constitutional factors.MethodsPatients with SCD were paired to patients without SCD on known Busulfan clearance’s covariates including GSTA1 group, age and frequency of administration.Data were collected retrospectively from the HSCT Unit database at Sainte-Justine Hospital and also used in previous studies.1 2 Weight adjusted clearance was compared between the two paired groups using a mixed procedure on SAS software.ResultsAmong the 129 patients included, 16 had SCD. Each patient was matched with up to 4 controls (total of 50 controls). Mean weight adjusted clearance was 3.04 ml/min/kg [SD:0,18] in patients with SCD versus 3.11 ml/min/kg [SD:0,14] in controls (difference 0.07 ml/min/kg F=0,14 p>F=0.714).ConclusionsThe diagnosis of SCD did not reveal to influence independently the clearance of the first dose of Bu. Consequently, no dose tailoring is needed in those patients only by the fact of being affected by SCD.ReferencesAnsari M, Curtis PH-D, Uppugunduri CRS, Rezgui MA, Nava T, Mlakar V, et al. GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study. Oncotarget 2017 Oct 31;8(53).Nava T, Kassir N, Rezgui MA, Uppugunduri CRS, Curtis PH-D, Duval M, et al. Incorporation of GSTA1 genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation. British Journal of Clinical Pharmacology. 84(7):1494–504.McCune JS, Baker KS, Blough DK, Gamis A, Bemer MJ, Kelton-Rehkopf MC, et al. Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients. Journal of Clinical Pharmacology. 2013 Mar;53(3):264–75.Maksoud E, Koehl B, Kaguelidou F, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother 2018 Apr;62(4).Dampier CD, Setty BN, Logan J, Ioli JG, Dean R. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995 Mar;126(3):461–7.Gremse DA, Fillingim E, Hoff CJ, Wells DJ, Boerth RC. Hepatic function as assessed by lidocaine metabolism in sickle cell disease. J Pediatr 1998 Jun;132(6):989–93.Disclosure(s)Nothing to disclose

BackgroundChildren with sickle cell disease (SCD) are at high risk of intractable pain and severe infections despite early and aggressive drug treatment. SCD is a multisystemic disease potentially leading to liver and renal dysfunction. Altogether, those may lead to pharmacokinetic (PK) alterations, which may contribute to therapeutic failure or drug toxicity. We performed a systematic literature review to describe the current evidence on the effect of SCD on drug disposition in children.MethodsA systematic literature search was conducted by a librarian on 5 databases until 08.2018 and independently assessed by two reviewers. All full-text articles, containing PK data in children, were included. The reported differences in PK parameters between SCD and non-SCD children were examined.ResultsAmong 4213 retrieved abstracts, 50 full-text articles were assessed and 27 studies were included (13 exclusively children). Data on 15 drugs was available from which 5 were exclusively developed for SCD (impeding any comparison). From the remaining 10 drugs, a comparison of PK parameters was available in 8. Six were investigated in adults and children. Three (37.5%) showed significant PK alterations (morphine, cefotaxime,lidocaine) while 5 did not (hydroxyurea, sulfadoxine-pyrimethamine, methadone, rofecoxib,arginine butyrate). In children with SCD, clearance was higher by 42–61% for IV morphine, and by 24–62% for cefotaxime, compared with non-SCD controls. This difference led to a new dosing recommendation only for cefotaxime (400 mg/kg/day). Hepatic drug metabolism assessed by lidocaine was impaired in children with SCD compared to healthy controls.ConclusionSCD alters drug disposition of commonly used drugs but data is scarce. A significant increase in clearance of morphine and cefotaxime, two commonly used drugs in patients with SCD, suggests that recommended doses may not be sufficient to provide adequate analgesia and antimicrobial control. PK data is urgently needed to ensure adequate drug efficacy and safety in this high-risk population.ReferencesDong M, McGann PT, Mizuno T, et al. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. Brit J Clin Pharmacol. 2016;81:742–52.Gremse DA, et al. Hepatic function as assessed by lidocaine metabolism in sickle cell disease. J Pediatr 1998;132:989–93.Dampier CD, et al. Intravenous morphine pharmacokinetics in pediatric patients with sickle cell disease. J Pediatr 1995;126:461–7.Kopecky EA, et al. Systemic exposure to morphine and the risk of acute chest syndrome in sickle cell disease. Clin Pharmacol Ther 2004;75:140–6.Maksoud E, et al. Population Pharmacokinetics of Cefotaxime and Dosage Recommendations in Children with Sickle Cell Disease. Antimicrob Agents Chemother. 2018;62: e00637–1.Disclosure(s)Nothing to disclose

Osteoarticular infections lead to significant morbidity in children. Cephalexin has in vitro activity against methicillin-susceptible Staphylococcus aureus, a predominant pathogen in osteoarticular infection. However, cephalexin pharmacokinetics (PK) and pharmacodynamics (PD) are poorly described in children. This study described cephalexin PK in children treated for osteoarticular infection and assessed the proportion of children achieving surrogate PK/PD target for efficacy in methicillin-susceptible S. aureus infection.Children with osteoarticular infection, 1 to 18 years of age, were eligible for this study if they were receiving oral cephalexin per standard of care. PK plasma samples were collected at specified times after multiple doses. PK parameters were estimated using noncompartmental analysis. PK/PD target for efficacy was calculated using the child's PK parameters, minimum inhibitory concentration (MIC) of the isolate when available and previously described MIC of 2 and 4 mg/L.Twelve children were enrolled and PK profiles were obtained from 11 of them. Median age was 7 years, and median cephalexin dose was 40 mg/kg/dose every 8 hours. Median apparent oral clearance, apparent oral volume of distribution and elimination half-life (T1/2) were 0.29 L/h/kg, 0.44 L/kg and 1.1 h, respectively. Time above MIC (TMIC) was greater than 40% of the dosing interval in 100%, 90% and 80% of the children when MICs were 0.25, 2 and 4 mg/L, respectively.Oral cephalexin achieved optimal plasma exposure and was well tolerated in children with osteoarticular infection. Correlation between osteoarticular infection clinical outcome and PK/PD parameters needs further evaluation.

BU is a key compound of conditioning regimens in children undergoing hematopoietic SCT (HSCT). Inter-individual differences in BU pharmacokinetics (PKs) might affect BU efficacy and toxicity. As BU is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship between GSTA1, GSTM1 and GSTP1 genotypes with first-dose BU PKs, and the relationship with HSCT outcomes in 69 children receiving myeloablative conditioning regimen. GSTM1 null genotype correlated with higher BU exposure and lower clearance in patients older than 4 years (P ≤ 0.04). In accordance with the suggested functional role, GSTA1*A2 haplotype was associated with lower drug levels and higher drug clearance (P ≤ 0.03). Gene-dosage effect was also observed (P ≤ 0.007). GSTA1 haplotypes were associated with HSCT outcomes. Patients with two copies of haplotype *A2 had better event free survival (P=0.03). In contrast, homozygous individuals for haplotypes *B and *B1 had higher occurrence of veno-occlusive disease (P=0.009). GSTM1 null individuals older than 4 years had more frequently graft versus host disease (P=0.03). In conclusion, we showed that GST gene variants influence BU PK and outcomes of HSCT in children. A model for the dosage adjustment with the inclusion of genetic and non-genetic factors should be evaluated in a future prospective validation cohort.

Plasma posaconazole exposure was assessed in 13 children who underwent a hematopoietic stem cell transplant. The median dosage was 12.5 mg/kg per day, divided into 3 doses. Of these 13 patients, 46.2% (6) and 30.8% (4) achieved concentrations higher than 0.7 and 1.25 mg/L, respectively. In children at high risk, a higher dosage might be needed to achieve target concentrations.

High-dose busulfan is an important component of myeloablative regimens. Variable drug exposure may occur following oral administration. Therefore, the use of intravenous busulfan has been advocated. Previous work has suggested a cumulative dosage of 16 mg/kg for haematopoietic transplantation in children less than 3 years of age, but only limited data are available in infants. Pharmacokinetics of intravenous busulfan administered at the suggested dosage were studied in 14 infants (median age 4.7 months). Busulfan plasma concentrations were measured by either GC-MS or HPLC-UV. In seven patients, the dose was decreased to target an area- under- the- curve of 600-1300 micromol min. The median total dose given was 13.8 mg/kg. All patients engrafted. Severe veno-occlusive disease occurred in one patient. Our study demonstrates that a cumulative dosage of 16 mg/kg is associated with higher exposure than expected in infants. We suggest an initial dose of 0.8 mg/kg followed by pharmacokinetically guided dose adjustment.

BACKGROUND The optimal monitoring strategy for cyclosporine (CsA) in pediatric hematopoietic stem cell transplantation (HSCT) patients remains unclear. Although there is a growing interest in the use of the area under the concentration-time curve (AUC), measurement of AUC in clinical settings is often impractical. The objective of this study was to identify and validate limited sampling strategies (LSSs) for the prediction of CsA AUC after intravenous (IV) and oral (PO) administration in this population. METHODS Sixty-eight pediatric patients who underwent HSCT and received CsA were investigated. Twelve-hour pharmacokinetic profiles (n = 138) performed per standard of care were collected. Weighted multiple linear regression was used to investigate all possible LSSs consisting of 4 or less concentration-time points. Their predictive performance was evaluated by leave one out cross validation and external validation by measuring the root mean squared relative error (RMSE%) and the 95th percentile of the absolute relative error (AE%). Values less than 20% were considered clinically acceptable. RESULTS Nine LSSs (4 IV and 5 PO) convenient for clinical application proved to have clinically acceptable performance. Notably, LSS based on C0, C2, and C4 was found to be accurate for estimation of CsA exposure after both IV and PO administration with the 95th percentile of AE% of 19.7% and 17.5%, respectively. CONCLUSIONS LSSs using 3 or 4 concentration-time points obtained within 4 hours postdose provide a convenient and reliable method to estimate CsA exposure in this population. These LSSs may facilitate future research aiming at better defining the relationship between AUC and clinical outcomes.

We report the case of a patient highly susceptible to invasive aspergillosis who received treatment with voriconazole (VRC). As part of therapeutic drug monitoring, VRC plasma trough concentrations were measured, showing undetectable levels (

We evaluated the pharmacokinetic profile of intravenous ganciclovir and oral valganciclovir in transplant children. Median AUC0-24 concentrations obtained after intravenous and oral formulations were 22.9 µg•h/mL (range, 17-65.2) and 34.55 µg•h/mL (range, 20.8-84.2), respectively. After normalization on a 20 mg/kg/d valganciclovir dosage, the median AUC0-24 concentration was 37.6 µg•h/mL (range, 23.6-68).

Objective To develop and validate limited sampling strategies (LSSs) for tacrolimus in pediatric liver transplant recipients. Methods Thirty-six 12-hour pharmacokinetic profiles from 28 pediatric liver transplant recipients (0.4-18.5 years) were collected. Tacrolimus concentrations were measured by immunoassay and area under the curve (AUC0-12) was determined by trapezoidal rule. LSSs consisting of 1, 2, 3, or 4 concentration-time points were developed using multiple regression analysis. Eight promising models (2 per category) were selected based on the following criteria: r2 ≥ 0.90, inclusion of trough concentration (C0), and time points within 4 hours postdose. The predictive performance of these LSSs was evaluated in an independent set of data by measuring the mean prediction error and the root mean squared prediction error. Results Five models including 2-4 time points predicted AUC0-12 with a ±15% error limit. Bias (mean prediction error) and precision (root mean squared prediction error) of LSS involving C0, C1, and C4 (AUCpredicted = 9.30 + 3.69 × C0 + 2.19 × C1 + 4.69 × C4) were -4.98% and 8.29%, respectively. Among single time point LSSs, the model using C0 had a poor correlation with AUC0-12 (r2 = 0.53), whereas the one with C4 had the highest correlation with tacrolimus exposure (r2 = 0.84). Conclusions Trough concentration is a poor predictor of tacrolimus AUC0-12 in pediatric liver transplant recipients. However, LSSs using 2-4 concentration-time points obtained within 4 hours postdose provide a reliable and convenient method to predict tacrolimus exposure in this population. The proposed LSSs represent an important step that will allow the undertaking of prospective trials aiming to better define tacrolimus target AUC in pediatric liver transplant recipients and to determine whether AUC-guided monitoring is superior to C0-based monitoring in terms of efficacy and safety.

A high-performance liquid chromatographic method with ultraviolet detection has been developed for the determination of bretylium in plasma. Following a single-step solid-phase extraction procedure, bretylium is selectively isolated and well recovered from plasma. The assay sensitivity is 0.156 micrograms/ml from 250-microliters plasma samples and its linearity was assessed up to 40 micrograms/ml. The method is accurate (101.0 +/- 5.4%) and precise (maximum coefficient of variation of 8%). It provides a simple and time-saving alternative to existing methods and is particularly suitable for pharmacokinetic studies.

A simple and sensitive high-performance liquid chromatographic procedure to determine spironolactone and its three major metabolites in biological specimens is described. The assay involves sequential extraction on C18 and CN solid phases, and subsequent separation on a reversed-phase column. In plasma samples, spironolactone and its metabolites were completely separated within 8 min using an isocratic mobile phase, while in urine samples a methanol gradient was necessary to achieve a good separation within 14 min. Recoveries for all analytes were greater than 80% in plasma and 72% in urine. Linear responses were observed for all compounds in the range 6.25–400 ng/ml for plasma and 31.25–2000 ng/ml for urine. The plasma and urine methods were precise (coefficient of variation from 0.8 to 12.5%) and accurate (−12.1% to 7.4% of the nominal values) for all compounds. The assay proved to be suitable for the pharmacokinetic study of spironolactone in healthy human subjects.

Busulfan (BU) is a key compound in conditioning myeloablative regimens for children undergoing hematopoietic stem cell transplantation (HSCT). There are wide interindividual differences in BU pharmacokinetics, which increase the risk of veno-occlusive disease, graft rejection and disease relapse. As BU is mainly metabolized by glutathione S-transferase (GST), it is hypothesized that functional polymorphisms in GST genes may explain in part the variability in BU pharmacokinetics. We analyzed polymorphisms in GSTA1 (C-69T, A-513G, G-631T, C-1142G), GSTM1 (deletion) and GSTP1 (A1578G, C2293T) genes in 28 children undergoing HSCT. All patients had individualized dosing based on pharmacokinetics after the first dose of intravenous BU. GSTM1-null individuals had higher drug exposure (P(Cmax)=0.008; P(AUC)=0.003; P(Css)=0.02) and lower clearance (P(CL)=0.001). Multivariate regression models showed that, other than the drug dose and age, the GSTM1 genotype was the best predictor of first-dose pharmacokinetic variability. GSTM1-null patients also received lower cumulative BU doses (P=0.02). No association was found between BU exposure and major GSTA1 or GSTP1 gene variants. In children, GSTM1 polymorphism seems to modify BU pharmacokinetics after intravenous drug administration.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The use of intravenous pantoprazole, a proton pump inhibitor, has been increasing in the paediatric intensive care unit. • Despite this increased use, data on the disposition of intravenous pantoprazole in paediatric intensive care patients are very scarce. WHAT THIS STUDY ADDS • Our population approach has determined the pharmacokinetic parameters of intravenous pantoprazole in paediatric intensive care patients and the relative importance of factors influencing its disposition. • Pantoprazole clearance was significantly influenced by developmental changes and by the presence of systemic inflammatory syndrome, hepatic dysfunction and CYP2C19 inhibitors. AIMS To characterize the pharmacokinetics of intravenous pantoprazole in a paediatric intensive care population and to determine the influence of demographic factors, systemic inflammatory response syndrome (SIRS), hepatic dysfunction and concomitantly used CYP2C19 inducers and inhibitors on the drug's pharmacokinetics. METHODS A total of 156 pantoprazole concentration measurements from 20 patients (10 days to 16.4 years of age) at risk for or with upper gastrointestinal bleeding, who received pantoprazole doses ranging from 19.9 to 140.6 mg/1.73 m2/day, were analysed using a population pharmacokinetic approach (nonmem program). RESULTS The best structural model for pantoprazole was a two-compartment model with zero order infusion and first-order elimination. Body weight, SIRS, age, hepatic dysfunction and presence of CYP2C19 inhibitors were significant covariates affecting clearance (CL), accounting for 75% of interindividual variability. Only body weight significantly influenced central volume of distribution (Vc). In the final population model, the estimated CL and Vc were 5.28 l h−1 and 2.22 l, respectively, for a typical 5-year-old child weighing 20 kg. Pantoprazole CL increased with weight and age, whereas the presence of SIRS, CYP2C19 inhibitors and hepatic dysfunction, when present separately, significantly decreased pantoprazole CL by 62.3, 65.8 and 50.5%, respectively. For patients aged between 6 months and 5 years without SIRS, CYP2C19 inhibitor or hepatic dysfunction, the predicted pantoprazole CL is faster than that reported in adults. CONCLUSION These results provide important information for physicians regarding selection of a starting dose and dosing regimens of pantoprazole for paediatric intensive care patients based on factors frequently encountered in this population.

The pharmacokinetics and pharmacodynamics of atracurium, a nondepolarizing neuromuscular blocking agent, were compared between morbidly obese patients and nonobese patients. Atracurium besylate (0.2 mg/kg) was administered intravenously as a bolus to patients who had received anesthesia. The force of contraction of the adductor pollicis was measured and plasma samples were collected for a 2-hour period. The concentrations of atracurium and its major end product, laudanosine, were determined by use of a chromatographic method. The pharmacokinetic-pharmacodynamic relationship was characterized by use of several models. No difference was observed between obese patients and nonobese patients in atracurium elimination half-life (19.8 ± 0.7 versus 19.7 ± 0.7 minutes), volume of distribution at steady state (8.6 ± 0.7 versus 8.5 ± 0.7 L), and total clearance (444 ± 29 versus 404 ± 25 ml/min). However, if values were expressed on a total body weight basis, there was a difference between obese and nonobese patients in the volume of distribution at steady state (0.067 versus 0.141 L/kg) and total clearance (3.5 ± 0.2 versus 6.6 ± 0.5 ml/min/kg). Although atracurium concentrations were consistently higher in obese patients than in nonobese patients, there was no difference in the time of recovery from neuromuscular blockade between the two groups. Consequently, the median effective concentration was higher in obese than in nonobese patients (470 ± 46 versus 312 ± 33 ng/ml). Clinical Pharmacology and Therapeutics (1990) 48, 18–25; doi:10.1038/clpt.1990.112

Introduction: Busulfan (Bu) is a component of several conditioning regimens before hematopoietic stem cell transplant (HSCT). Bu has a narrow therapeutic window. High exposure was associated to higher rates of GVHD, VOD and mortality and low exposure to relapse or graft failure. Pharmacokinetic (PK) studies demonstrated high intra- and inter-patient variability. Several factors such as age, gender and weight have been associated to this variability (Vassal 1993, McCune 2009, Lee 2012, Veal 2012). The contribution of GSTA1 polymorphisms has been also documented. Haplotype *A2 was associated to higher clearance and less SCT-related complications, whereas haplotype *B (-69T) was associated to more frequent VOD occurrence (Ansari 2013). This study aims to analyse the influence of GSTA1 genotypes/haplotypes on Bu clearance. Methods: Eighty-nine patients underwent a SCT after Bu-based conditioning with therapeutic drug monitoring (TDM) from October 2000 to August 2010 at our center CHU Sainte Justine, Montreal. The median age was 8.2 (IQR 1.6 to 13.9) years, 50.6% were males, most with malignancies (64.4%). Most patients received BuCy (77%) as conditioning regimen. Bu four times daily dose was given as previously described (Ansari 2014) and ulterior doses were calculated depending on the TDM. Bu AUC, steady-state concentration (Css) and Clearance were assessed after the first dose in all patients. New PK studies could be performed between sixth and ninth dose. Adjusted doses were calculated assuming a linear correlation between dose and desired AUC. Bu clearancewas expressed in base to an allometric representation of patients' size accounting for age, body weight and body composition: Normal Fat Mass (NFM). The NFM of 62Kg corresponds to an allometrically-scaled body weight of 70kg. Then, clearance was normalized by 62Kg NFM as described previously (McCune 2014). GSTA1 genotypes was classified as carriers of *A/*B haplotypes and their subtypes (Ansari 2013). Continuous data was expressed as median and interquartile range (IQR). A linear mixed model was performed to evaluate the association of normalized clearance to GSTA1 genotypes/haplotypes. Subjects were considered as random effects of repeated measures. Results: Two hundreds and eighty PK measurements were performed (from one to 5 times per patient during the Bu exposure time). Median of Bu prescribed doses during the conditioning was 0.97mg/Kg. A TDM-based change of dose was possible from the 6th dose (30 hours after Bu initial dose). A dose change was made in 69.3% of patients. Median change was +32% (IQR 0 to +48.3%) of the initial dose. Eight percent of doses had to be decreased. Overall normalized clearance was 16.8 l/h/62 Kg NFM (IQR 13.7 to 19.4). Eighty-six percent were genotyped by GSTA1. In a model including age, gender and NFM normalized dose, clearance was significantly associated with GSTA1 haplotypes (p Conclusion: We have demonstrated that GSTA1 *B1a haplotype is an independent factor related to diminished Bu clearance. We suggest that GSTA1 genotyping should be included in the work-up before Bu-based conditioning regimens. Adjusted doses depending on *B1a status would limit the exposure to Bu in patients with lower rates of elimination and higher risk of HSCT-related complications, ensuring a more individualized and safer conditioning. However, it lacks Bu first dose prediction models accounting for genetics components such as GSTA1 haplotypes. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction: Busulfan (Bu) is a component of conditioning before stem cell transplant (SCT). Bu has a narrow therapeutic window. High exposure was associated to higher rates of GVHD, VOD and mortality and low exposure to relapse or graft failure. Pharmacokinetic (PK) studies demonstrated high intra- and inter-patient variability. Several factors such as age, gender, weight and genetic components have been associated to this variability (McCune 2009, Vassal 1993, Ansari 2013). Certain models and nomograms have been used to predict Bu first dose, in theory precluding need of further adjustments. Recent comparison of 12 different models showed acceptable performances but high coefficients of variation (CV) and failure to reach target AUC in at least 24% of cases (Zao 2015). The present study aims to evaluate the role of GSTA1 haplotypes on different methods' performances in predicting of Bu first dose. Methods: A hundred and ten patients underwent a SCT after Bu based conditioning from October 2000 to October 2011 and 104 had PK data. Median of age was 6.9 (IQR 2 to 13.7) years, 55.5% were males and most had malignancies (69%). Most received Bucy (78.2%) as conditioning regimen. Four-time daily dose of Bu was calculated as previously described (Ansari 2014). Bu AUC, steady-state concentration (Css) and Clearance (Cl) were assessed for all patients after the first dose. The same parameters were predicted based on 11 other methods previously described (Zao 2015) to calculate the initial dose of Bu assuming a linear relationship between predicted doses and AUC. For each model that predicted individualized clearances, a mean prediction error (MPE) was calculated as follows: MPE=(Clpredicted-Clobserved)/Clobserved. Target AUC was from 900μM.min through 1500μM.min. Two haplotypes, found previously to influence Cl were included in the analysis: haplotype *B1a (-1142G, -631G, -513C, -69T) and *A2 (-1142C, -631G, -513T, -69C) in heterozygous and homozygous state (Ansari 2013). X2 test was used to compare methods' performances and observed values. Continuous data was expressed as median and interquartile range (IQR). Multivariate linear model was used to evaluate the association of Cl MPE and the GSTA1 haplotypes. Results: Initial doses of Bu, calculated by the different methods, varied from 0.47 to 1.6mg/kg. Predicted AUCs varied from 392 to 2,968μ.min with CV ranging from 21.5 to 37.1%. Ability to predict the target AUC was from 28.8% to 76%, with 0 to 20% of measures above the range. Bartelink's (p Conclusion: Bartelink's and McCune's models seemed to be adequate methods to calculate the initial dose of Bu and demonstrated better performances than the method used in our center. For the clearance-predictor methods, although McCune's seemed to be the most reliable model for most patients, it had limited performance in GSTA1 haplotypes previously associated to extreme clearances. It suggests that genetic factors such as GSTA1 genotyping should be included in a future model design to better predict the initial dose of Bu. Disclosures No relevant conflicts of interest to declare.

The use of proton pump inhibitors (PPIs) has become widespread in children and infants for the management of paediatric acid-related disease. Pharmacokinetic profiles of only omeprazole and lansoprazole have been well characterised in children over 2 years of age with acid-related diseases. Few data have been recently published regarding the pharmacokinetics of pantoprazole in children, and none are available for rabeprazole or esomeprazole. The metabolism of PPI enantiomers has never been studied in the paediatric population. A one-compartment model best describes the pharmacokinetic behaviour of omeprazole, lansoprazole and pantoprazole in children, with important interindividual variability for each pharmacokinetic parameter. Like adults, PPIs are rapidly absorbed in children following oral administration; the mean time to reach maximum plasma concentration varies from 1 to 3 hours. Since these agents are acid labile, their oral formulations consist of capsules containing enteric-coated granules. No liquid formulation is available for any of the PPIs. Thus, for those patients unable to swallow capsules, extemporaneous liquid preparations for omeprazole and lansoprazole have been reported; however, neither the absolute nor the relative bioavailabilities of these oral formulations have been studied in children. Intravenous formulations are available for omeprazole (in Europe), lansoprazole and pantoprazole. PPIs are rapidly metabolised in children, with short elimination half-lives of around 1 hour, similar to that reported for adults. All PPIs are extensively metabolised by the liver, primarily by cytochrome P450 (CYP) isoforms CYP2C19 and CYP3A4, to inactive metabolites, with little unchanged drug excreted in the urine. Similar to that seen in adults, the absolute bioavailability of omeprazole increases with repeated dosing in children; this phenomenon is thought to be due to a combination of decreased first-pass elimination and reduced systemic clearance. The apparent clearance (CL/F) of omeprazole, lansoprazole and pantoprazole appears to be faster for children than for adults. A higher metabolic capacity in children as well as differences in the extent of PPI bioavailability are most likely responsible for this finding. This may partly account for the need in children for variable and sometimes considerably greater doses of PPIs, on a per kilogram basis, than for adults to achieve similar plasma concentrations. Furthermore, no studies have been able to demonstrate a statistically significant correlation between age and pharmacokinetic parameters among children. Despite the small number of very young infants studied, there is some evidence for reduced PPI metabolism in newborns. The limited paediatric data regarding the impact of CYP2C19 genetic polymorphism on PPI metabolism are similar to those reported for adults, with poor metabolisers having 6- to 10-fold higher area under the concentration-time curve values compared with extensive metabolisers. Finally, because a pharmacokinetic/pharmacodynamic relationship exists for PPIs, the significant interindividual variability in their disposition may partly explain the wide range of therapeutic doses used in children. Further studies are needed to better define the pharmacokinetics of PPIs in children

Abstract 4143 Myeloablative unrelated cord blood transplantation (MAC-UCBT) is an alternative to transplant in children with acute leukemia or myelodisplastic syndrome (MDS) when a donor is not available. Intravenous (iv) busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used and is associated with higher EFS, lower transplant-related mortality (TRM) and toxicity. Even if iv Bu has a more predictable bioavailability comparing with oral Bu, there is still an important variation in Bu pharmacokinetics (PK) between patients that may cause treatment failure and toxicity. In order to analyze the impact of PK parameters of the first iv Bu dose on the different outcomes of MAC-UCBT for acute leukemia and MDS, we analyzed 34 consecutive transplants performed in children between dec/2000 and dec/2011. Patients or parents provided an informed consent. Median age at transplant was 5.9 (0.6–19) years, and 19 (56%) were male. There were 20 AML, 2 ALL and 12 MDS. A total of 10 and 12 patients with acute leukemia were transplanted in first remission (CR1), second remission (CR2)/advanced phase of disease, respectively. Thirty-one patients received a single UCBT. Eight, and twelve patients received a 6/6, or 5/6HLA-matched graft. Median infused nucleated cells and CD34+ cells were 5.5 × 10⋀7/kg and 2.1 × 10⋀5/kg, respectively. Cyclosporin A and steroids were used as graft versus host disease (GvHD) prophylaxis for all patients and 33 patients received ATG. Conditioning regimen consisted of first-dose PK-adapted Bu (targeted steady-state concentration - Css - between 600–900 ng/ml) and Cy 200 mg/kg (n=30), Melphalan 135 mg/m2 (n=2) or Cy 120 mg/kg and etoposide 30 mg/kg (n=2). Median follow-up was 36 months. After iv Bu first dose, median Css was 555 ng/ml, AUC was 188,901 min*ng/ml and clearance was 4.61 ml/min/kg. Cumulative incidence (CI) of neutrophil (>0.5×10⋀9/L) at D+60 and platelet recovery (>50×10⋀9/L) at D+150 were both 87%. Median time to neutrophil and platelet recovery was 20 days and 67 days, respectively. There were six primary or secondary graft failure. CI of acute GVHD grade II-IV at D+180 was 16%. There were two cases of VOD. Five-years CI of transplant-related mortality (TRM) was 12%. CI of relapse at 5 years was 25%. Estimated event-free survival (EFS) at 5 years was 49%. Estimated overall survival (OS) at 5 years was 64%. First dose Css significantly influenced neutrophil recovery (100% vs. 70% for Css < and > 600 ng/ml, respectively - P=0.002), TRM (0% vs. 27% for Css < and > 600 ng/ml, respectively - P=0.02), EFS (73% vs. 18% for Css < and > 600 ng/ml, respectively- P 600 ng/ml, respectively - P=0.005). There was no influence of Css on the incidence of platelet recovery, grade 2–4 aGVHD or relapse. In conclusion, first dose iv Bu PK seems to be a significant prognostic factor after UCBT for malignancies in children, influencing neutrophil recovery, TRM, EFS and OS. A direct toxic effect of Bu and/or a synergistic toxic effect with Cy might explain the worst outcome when first dose iv Bu has a Css higher than 600 ng/ml. It will be important to validate these results in a multicentre study and also to compare these results with patients that received a fixed dose of Bu. Finally, our data reinforces the importance of Bu therapeutic drug monitoring-guided dosing in pediatric HSCT patients. Disclosures: No relevant conflicts of interest to declare.

A high-performance liquid chromatographic assay coupled with electrochemical detection has been developed for the determination of vecuronium and its three putative deacetylated metabolites in human plasma. A novel solid-phase extraction procedure allowed good recovery of both vecuronium and its metabolites, together with ease and speed of execution. This method was sensitive, reproducible and accurate over the therapeutic range of concentrations of vecuronium and its metabolites, and was applied successfully to a study of the pharmacokinetics of vecuronium in anaesthetized patients.

To determine the influence of sampling site on atracurium pharmacokinetic-pharmacodynamic relationships, blood was drawn simultaneously from the radial artery and a peripheral vein during a 20-minute period after injection of atracurium, 0.2 mg/kg, in eight patients. Atracurium and laudanosme concentrations were measured by HPLC. Neuromuscular blockade was measured at the adductor pollicis, after stimulation of the ulnar nerve. Venous levels were lower than corresponding arterial values for up to 20 minutes, and this difference was marked for the early samples. Neuromuscular blockade was maximum after 5 to 7 minutes, much later than the peak venous concentration (1 to 3 minutes). Nonparametric analysis yielded (mean ± SEM) a rate constant, concentration for 50% blockade, and slope of the effect-concentration relationship of 0.092 ±0.01 min−1, 379 ± 27 ng/ml, and 7.3 ± 1.67, respectively, when based on arterial samples. The values were statistically different (0.135 ± 0.011 min−1, 235 ± 42 ng/ml, and 3.41 ± 0.37, respectively) when venous levels were used (p < 0.05). It is concluded that forearm venous levels do not correspond to adductor pollicis neuromuscular blockade and the kinetics and kinetic-dynamic relationship for atracurium are heavily dependent on sampling site. Clinical Pharmacology and Therapeutics (1991) 49, 515–522; doi:10.1038/clpt.1991.62

A high-performance liquid chromatographic method coupled with fluorometric detection has been developed for the determination of atracurium and its major end-product laudanosine in human plasma. The method enables good separation of atracurium from its metabolites after direct precipitation of plasma proteins. The assay is sensitive, reproducible and linear for atracurium concentrations ranging from 31.25 to 8000 ng/ml. In a clinical setting, drugs commonly administered during anesthesia did not interfere with the assay. This method provides a simple and time-saving alternative to existing methods.

median pH was: P: 0.95 (0.5-6.9), O 2.9 (1.0-64), R 3.8 (06-7.3). The duration ofpH < 4was: P: 88.3% (14.4-100.0), O: 73.7% (21.0-93.1), R: 556 (0.0-100.0). Eriedman's analys~s for all parameters cluring all periods demonstrated significant differences between the three treatments, except for the nocturnal duration of pH < 4. Wilcoxon's comparisons between 0 and R showed no significant differences for both 24h and nocturnal intragastric pH and the duration of pH < 4. In the daytime there was a significant difference for both median intragastfic pH (P=0.041) and the duration of pH < 4 (P= 0.033). Conclusion: Oral rabeprazole and iv. omeprazole are comparable in their potency to inhibit gastric acid production. Omeprazole may be shghtly more effective during the daytime.

We currently calculate area under the busulfan concentration time curve (AUC) using 7 plasma busulfan concentrations (AUC7) drawn after the first of 16 i.v. busulfan doses given as a 2-hour infusion every 6 hours. The aim of this study was to develop and validate limited sampling strategies (LSSs) using 3 or fewer busulfan concentration values with which to reliably calculate AUC in children undergoing hematopoietic stem cell transplant (HSCT). Children in the development group (44) received i.v. busulfan at Sick Kids; the validation group consisted of 35 children who received care at CHU Ste-Justine. Busulfan doses given and subsequent plasma busulfan concentrations were recorded. LSSs using 1 to 3 concentration-time points were developed using multiple linear regression. LSS were considered to be acceptable when adjusted r2 > 0.9, mean bias 1500 or

Background The objectives of this study were to investigate pharmacokinetic and pharmacogenetic parameters during the conversion on a 1:1 (mg:mg) basis from a twice-daily (Prograf) to once-daily (Advagraf) tacrolimus formulation in pediatric kidney transplant recipients. Methods Twenty-four-hour pharmacokinetic profiles were analyzed before and after conversion in 19 stable renal transplant recipients (age 7–19 years). Tacrolimus pharmacokinetic parameters [area under the concentration-time curve (AUC0–24), minimum whole-blood concentration (Cmin), maximum whole-blood concentration (Cmax), and time to achieve maximum whole-blood concentration (tmax)] were compared between Tac formulations and between CYP3A5 and MDR1 genotypes after dose normalization. Results Both AUC0–24 and Cmin decreased after conversion (223.3 to 197.5 ng.h/ml and 6.5 to 5.6 ng/ml; p = 0.03 and 0.01, respectively). However, the ratio of the least square means (LSM) for AUC0–24 was 90.8 %, with 90 % CI limits of 85.3 to 96.7 %, falling within bioequivalence limits. The CYP3A5 genotype influences the dose-normalized Cmin with the twice-daily formulation only. Conclusions Both tacrolimus formulations are bioequivalent in pediatric renal recipients. However, we observed a decrease in AUC0–24 and Cmin after the conversion, requiring close pharmacokinetic monitoring during the conversion period.