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AIMS We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant disorders (NMD) undergoing allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) containing alemtuzumab, fludarabine and melphalan. METHODS Patients received test-dose melphalan (10% of planned full-dose) prior to conditioning. Blood samples for PK were obtained around test and full-dose melphalan (140 mg/m2 or 4.7 mg/kg in patients

Chronic intrauterine exposure to psychoactive drugs often results in neonatal opioid withdrawal syndrome (NOWS). When nonpharmacologic measures are insufficient in controlling NOWS, morphine, methadone, and buprenorphine are first-line medications commonly used to treat infants with NOWS because of in utero exposure to opioids. Research suggests that buprenorphine may be the leading drug therapy used to treat NOWS when compared with morphine and methadone. Currently, there are no consensus or standardized treatment guidelines for medications prescribed for NOWS. Opioids used to treat NOWS exhibit large interpatient variability in pharmacokinetics (PK) and pharmacodynamic (PD) response in neonates. Organ systems undergo rapid maturation after birth that may alter drug disposition and exposure for any given dose during development. Data regarding the PK and PD of opioids in neonates are sparse. Pharmacometric methods such as physiologically based pharmacokinetic and population pharmacokinetic modeling can be used to explore factors predictive of some of the variability associated with the PK/PD of opioids in newborns. This review discusses the utility of pharmacometric techniques for enhancing precision dosing in infants requiring opioid treatment for NOWS. Applying these approaches may contribute to optimizing the outcome by reducing cumulative drug exposure, mitigating adverse drug effects, and reducing the burden of NOWS in neonates.

Aims Fanconi anaemia (FA) is a rare disorder characterized by progressive bone marrow failure that requires haematopoietic cell transplantation (HCT). Busulfan is used in conditioning regimens prior to HCT. Doses used in non‐FA patients cause life‐threatening toxicities in FA patients and data on busulfan pharmacokinetics (PK) in this population are limited. This study characterized busulfan PK in paediatric FA patients using population PK modelling and evaluated the effect of body composition on steady‐state concentrations (C ss). Methods A total of 200 busulfan plasma concentrations in 29 FA patients from a recent study (http://Clinicaltrials.gov; NCT01082133) were available for population PK modelling. The effect of different body size‐scaled doses and body compositions on C ss was investigated using population PK modelling. Results Fat free mass (FFM) was identified as the best size descriptor in a two‐compartment busulfan PK model in FA patients. Conventional dosing, based on an amount of busulfan per kilogram of total body mass, resulted in higher C ss in FA patients with higher body mass index (BMI). A newly proposed FFM‐based dosing strategy would eliminate the observed trend of higher concentrations in high BMI patients, and achieve consistent C ss across a wide BMI spectrum. Conclusions This is the first study to describe the population PK of busulfan in paediatric FA patients. The proposed model will facilitate PK model‐informed precision dosing. FFM‐based dosing is expected to improve the probability of achieving target C ss, particularly in obese patients, while minimizing the risk of overdosing.

Chronic intrauterine exposure to psychoactive drugs often results in neonatal abstinence syndrome (NAS). NAS is the symptomatic drug withdrawal in newborns that generally occurs after in utero chronic opioid exposure. Methadone is an opioid analgesic commonly prescribed for pharmacologic management of NAS. It exhibits high pharmacokinetic (PK) variability. The current study used physiologically based PK modeling to predict the PK profile of methadone in 20 newborns treated for NAS. The physiologically based PK simulations adequately predicted the PK profile of the clinical data for 45% of the patients. Sensitivity analyses were conducted to explore contributing factors to methadone PK variability. The data suggest that P450 enzymatic activity impacts the clearance of methadone in virtual adults and neonates, while the contribution of cardiac output may be negligible. Understanding maturational and/or pharmacogenetic changes in cytochrome P450 enzymatic activity may further explain the large PK variability of methadone in newborns with NAS and will help individualized treatment.

Morphine has large pharmacokinetic variability, which is further complicated by developmental changes in neonates and small infants. The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood‐flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP‐glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood‐flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling. The implementation of these three age‐dependent factors into the pediatric system platform resulted in reasonable prediction for an age‐dependent increase in morphine CL in these populations. Sensitivity of morphine CL to changes in cardiac output increased with age up to 3 years, whereas sensitivity to changes in UGT2B7 activity decreased. This study suggests that morphine exhibits age‐dependent extraction, likely due to the developmental increase in OCT1 and UGT2B7 protein expression/activity and hepatic blood‐flow.

Simultaneous changes in several physiological factors may contribute to the large pharmacokinetic (PK) variability of vancomycin. This study was designed to systematically characterize the effects of multiple physiological factors to the altered PK of vancomycin observed in special populations. A vancomycin physiologically based pharmacokinetic (PBPK) model was developed as a PK simulation platform to quantitatively assess the effects of changes in physiologies to the PK profiles. The developed model predicted the concentration-time profiles in healthy adults and diseased patients. The implementation of developmental changes in both renal and non-renal elimination pathways to the pediatric model improved the predictability of vancomycin clearance. Simulated PK profiles with a 50% decrease in cardiac output (peak plasma concentration (Cmax ), 59.9 ng/mL) were similar to those observed in patients before bypass surgery (Cmax , 55.1 ng/mL). The PBPK modeling of vancomycin demonstrated its potential to provide mechanistic insights into the altered disposition observed in patients who have changes in multiple physiological factors.

Morphine shows large interindividual variability in its pharmacokinetics; however, the cause of this has not been fully addressed. The variability in morphine disposition is considered to be due to a combination of pharmacogenetic and physiological determinants related to morphine disposition. We previously reported the effect of organic cation transporter (OCT1) genotype on morphine disposition in pediatric patients. To further explore the underlying mechanisms for variability arising from relevant determinants, including OCT1, a physiologically based pharmacokinetic (PBPK) model of morphine was developed. The PBPK model predicted morphine concentration-time profiles well, in both adults and children. Almost all of the observed morphine clearances in pediatric patients fell within a twofold range of median predicted values for each OCT1 genotype in each age group. This PBPK modeling approach quantitatively demonstrates that OCT1 genotype, age-related growth, and changes in blood flow as important contributors to morphine pharmacokinetic (PK) variability.

Sirolimus is increasingly being used in neonates and infants, but the mechanistic basis of age‐dependent changes in sirolimus disposition has not been fully addressed yet. In order to characterize the age‐dependent changes, serial sirolimus clearance (CL) estimates in individual young pediatric patients were collected and analyzed by population modeling analysis. In addition, sirolimus metabolite formation was also investigated to further substantiate the corresponding age‐dependent change in CYP3A activity. The increasing pattern over time of allometrically size‐normalized sirolimus CL estimates vs. age was well described by a sigmoidal Emax model. This age‐dependent increase was also observed within each individual patient over a 4‐year study period. CYP3A‐dependent sirolimus metabolite formation changed in a similar fashion. This study clearly demonstrates the rapid increase of sirolimus CL over time in neonates and infants, indicating the developmental change. This developmental pattern can be explained by a parallel increase in CYP3A metabolic activity.

During the past decades significant progress has been made in our understanding of the importance of age-appropriate development of new drug therapies in children. Importantly, several regulatory initiatives in Europe and the US have provided a framework for a rationale. In the US, most notably the enactment of the Best Pharmaceuticals for Children Act (BPCA) and Product Research and Equity Act (PREA) has facilitated the studying of on-patent and off-patent drugs in children. The biggest challenge in pediatric studies is defining a safe and effective dose or dose range in a patient population that can span from premature neonates to adolescents. From a mechanism-based perspective, advances in the science of quantitative pharmacology and pharmacometrics have resulted in the development of model-based approaches to better describe and understand important age-related factors influencing drug disposition and response in pediatric patients. The application of modeling and simulation has been shown to result in better estimates of pediatric doses as evidenced by several studies, although the optimal approach is still being debated. The extrapolation of efficacy findings from adults to the pediatric population has streamlined the development process especially for studies in older children. However, a focus on developmental changes in neonates and infants as well as further developing a paradigm for conducting pharmacodynamic studies in neonates, infants, and children remain important unmet needs. In this overview we will review current approaches for age-appropriate dose selection and highlight ongoing efforts to define exposure-response and clinical outcome relationships across the pediatric age spectrum.

This study describes the maturation of sirolimus clearance in a cohort of very young pediatric patients with vascular anomalies. The relationship between allometrically scaled in vivo clearance and age was described by the Emax model in patients aged 1 month to 2 years. Consistent with the observed increase, in vitro intrinsic clearance of sirolimus using pediatric liver microsomes showed a similar age-dependent increase. In children older than 2 years, allometrically scaled sirolimus clearance did not show further maturation. Simulated clearance estimates with a sirolimus physiologically based pharmacokinetic model that included CYP3A4/5/7 and CYP2C8 maturation profiles were in close agreement with observed in vivo clearance values. In addition, physiologically based pharmacokinetic model-simulated sirolimus pharmacokinetic profiles predicted the actual observations well. These results demonstrate the utility of a physiologically based pharmacokinetic modeling approach for the prediction of the developmental trajectory of sirolimus metabolic activity and its effects on total body clearance in neonates and infants.

Aim The purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK−PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post-transplant period. Methods A total of 214 MPA plasma concentrations−time data points from 24 patients were available for PK model development. In 17 out of a total of 24 patients, inosine monophosphate dehydrogenase (IMPDH) enzyme activity measurements (n = 97) in peripheral blood mononuclear cells were available for PK−PD modelling. The PK−PD model was developed using non-linear mixed effects modelling sequentially by 1) developing a population PK model and 2) incorporating IMPDH activity into a PK−PD model using post hoc Bayesian PK parameter estimates. Covariate analysis included patient demographics, co-medication and clinical laboratory data. Non-parametric bootstrapping and prediction-corrected visual predictive checks were performed to evaluate the final models. Results A two compartment model with a transit compartment absorption best described MPA PK. A non-linear relationship between dose and MPA exposure was observed and was described by a power function in the model. The final population PK parameter estimates (and their 95% confidence intervals) were CL/F, 22 (14.8, 25.2) l h−1 70 kg−1; Vc/F, 45.4 (29.6, 55.6) l; Vp/F, 411 (152.6, 1472.6)l; Q/F, 22.4 (16.0, 32.5) l h−1; Ka, 2.5 (1.45, 4.93) h−1. Covariate analysis in the PK study identified body weight to be significantly correlated with CL/F. A simplified inhibitory Emax model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK−PD parameter estimates (and their 95% confidence intervals) were: E0, 3.45 (2.61, 4.56) nmol h−1 mg−1 protein and EC50, 1.73 (1.16, 3.01) mg l−1. Emax was fixed to 0. There were two African-American patients in our study cohorts and both had low IMPDH baseline activities (E0) compared with Caucasian patients (mean value 2.13 mg l−1 vs. 3.86 mg l−1). Conclusion An integrated population PK−PD model of MPA has been developed in paediatric renal transplant recipients. The current model provides information that will facilitate future studies and may be implemented in a Bayesian algorithm to allow a PK−PD guided therapeutic drug monitoring strategy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Despite its increased use, the pharmacokinetics (PK) of mycophenolic acid (MPA) and the relationship between dose, plasma concentration and exposure are poorly understood, especially in children. • The PK of MPA are associated with high inter- and intra-individual variability. • MPA and its metabolites, like the inactive 7-O-MPA-β-glucuronide (MPAG) undergo enterohepatic circulation (EHC), which can contribute to an increase in exposure to MPA of 40% (range 10–60%). WHAT THIS STUDY ADDS • Thisis the first report of MPA PK in adolescents with childhood-onset systemic lupus erythematosus (cSLE). • The proposed final population PK model successfully incorporates the physiological aspects associated with MPA disposition, which includes MPA and its main metabolite MPAG, and adequately reflects the complex processes of absorption and enterohepatic circulation associated with mycophenolate mofetil (MMF) oral dosing in patients with cSLE. • This model provides a basis for further development of a model-based Bayesian estimator for individualized MPA dosing in paediatric patients treated for cSLE. AIM This study aimed to develop a population pharmacokinetic (PK) enterohepatic recycling model for MPA in patients with childhood-onset systemic lupus erythematosus (cSLE). METHODS MPA concentration–time data were from outpatients on stable oral mycophenolate mofetil (MMF) and collected under fasting conditions, with standardized meals (1 and 4 h post-dose). Sampling times were pre-dose, 20, 40 min, 1, 1.5, 2, 3, 4, 6 and 9 h, post dose. The population PK analysis simultaneously modelled MPA and 7-O-MPA-β-glucuronide (MPAG) concentrations using nonlinear mixed effect modelling. RESULTS PK analysis included 186 MPA and MPAG concentrations (mg l–1) from 19 patients. cSLE patients, age range 10–28 years, median 16.5 years were included. Mean ± SD disease duration was 3.8 ± 3.7 years. The final PK model included a gallbladder compartment for enterohepatic recycling and bile release time related to meal times, with first order absorption and single series of transit compartments. The PK estimates for MPA were CL1/F 25.3 l h–1, V3/F 20.9 l, V4/F 234 l and CL2/F 19.8 l h–1. CONCLUSION The final model fitted the complex processes of absorption and enterohepatic circulation (EHC) in those treated with MMF for cSLE and could be applied in Bayesian dose optimization algorithms.

Infants and children are unique patient populations compared with adults as they not only differ physiologically and anatomically but also experience rapid changes in growth and development over the course of their childhood. These dynamic and variable developmental changes can have major impact on the pharmacokinetic and pharmacodynamic profile of a drug from its absorption, distribution, metabolism and elimination (ADME) properties to its effects [1]. Since oral administration is one of the primary routes for giving a drug to children, many studies have been implemented to provide evidence for developmental differences in the absorption of drugs [1, 2]. As is well known, the bioavailability of orally administered drugs is regulated by various metabolic enzymes and transporters expressed in the small intestine. Therefore, the developmental changes in activity of metabolic enzymes and transporters could explain developmental differences in absorption. To date, several studies have characterized the ontogeny of metabolic enzymes in tissues including the small intestine [1–3]. However, there is little information on the ontogeny of drug transporters in the human intestine. P-glycoprotein (MDR1/ABCB1), an ATP-binding cassette transporter, located in the small intestine mediates the efflux of substrates from the epithelial cells to the intestinal lumen [4]. Thus, the inter-individual variability in the expression of intestinal ABCB1 is an important factor which determines the bioavailability of ABCB1 substrates, as has been shown for tacrolimus [5]. Since many drugs used in neonates, infants and children are substrates of ABCB1, it is important to characterize the effects of developmental changes of intestinal ABCB1 on drug disposition in children [1, 2]. Here, we evaluate ABCB1 mRNA expression patterns in human small intestine tissues collected from children to provide fundamental information on the age-dependent expression. mRNA expression data were obtained as part of a previous study at Kyoto University Hospital, Japan [5]. In short, 206 paediatric patients undergoing living donor liver transplantation were enrolled in the study. All mucosal specimens of the upper jejunum were obtained from a part of the Roux-en-Y limb for biliary reconstruction or around the bile drainage tube during surgery. Samples were immediately frozen in liquid nitrogen and stored at −80°C until analysis. ABCB1 mRNA expression was determined by quantitative RT-PCR as previously described [5]. The amount was determined with a standard curve generated using known amounts of standard plasmid DNA. To verify the quality of the total cellular RNA extracted, GAPDH mRNA expression was also quantified as an internal standard. Demographics of patients were as follows: median age (range) 1.27 years (62 days–18.9 years), median body weight (range) 8.5 kg (3.7–70 kg), 85 male and 121 female patients. The study was approved by the Institutional Review Board and all participants, patients and/or care givers, gave written informed consent or assent. Large inter-individual variability in intestinal ABCB1 expression was observed across all ages (Figure 1). Over the studied age range from 62 days to 18.9 years, no clear maturation trajectory of ABCB1 expression was observed. This may indicate that the expression of intestinal ABCB1 has reached at the certain level by at least 2 months after the birth. A most recent report showed no significant difference in intestinal ABCB1 mRNA expression between neonates and adults [6]. Although our data are not completely comparable due to the lack of samples in neonates, the report indirectly supports our observation. On the other hand, there is an earlier study demonstrating a very weak or no expression of ABCB1 in the fetal intestine [7]. Furthermore, a study using enterocyte cell lines demonstrated that breast milk induces ABCB1 expression in a dose-and time-dependent manner [8]. An animal study also demonstrated that the ABCB1 expression in the small intestine of neonatal rodents dramatically increased shortly after initiation of breastfeeding [8]. Since lactation is generally started right after the birth, the expression of intestinal ABCB1 is anticipated to initiate at the same time and rapidly reach levels comparable with those seen in adults. Figure 1 Age related changes of intestinal ABCB1 mRNA expression. Data represent individual ABCB1 mRNA expression As with the small intestine, developmental changes in hepatic ABCB1 expression has been of great interest as an important consideration in the development of age-appropriate dosing strategies. In a recent preliminary report, it was noted that hepatic ABCB1 mRNA expression in fetuses, neonates, infants and children was 25–60-fold lower compared with adult values [9]. In addition, in a recent review article, Klaassen & Aleksunes also reported that mRNA expression of ABCB1 in perinatal human liver samples was very low and gradually increased over time until the age of 7 years [10]. The maturation pattern of ABCB1 expression is most likely organ-specific and needs to be studied in each organ. In conclusion, this analysis suggests that the maturation of intestinal ABCB1 mRNA expression is completed relatively soon after birth. This finding contributes to an improved understanding of the age dependent maturation of ABCB1 transporter mRNA expression and its potential effect on the disposition of drug substrates.

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Rs6295C/G SNP in the 5-HT1A gene (HTR1A) has been found to affect the expression and function of HTR1A. In fact rs6295C/G is in strong linkage disequilibrium with other polymorphisms of HTR1A suggesting that those functional effects could be associated with polymorphisms other than or together with the synonymous rs6295C/G. In the present study we examined the possible association of a panel of markers in strong linkage disequilibrium of the HTR1A with SSRI/SNRI response in 137 Japanese major depression subjects followed for 6 weeks. We observed a significant association of better response to antidepressant in rs10042486C/C (P

Background: The number of studies of long-term follow up to adolescence is very low on spontaneous closure (SC) of perimembranous ventricular septal defects (P-VSD) in children not undergoing surgical closure because of small left-to-right shunting. Methods: Seventy patients with a P-VSD with pulmonary-to-systemic flow ratio (Qp/Qs)

BACKGROUND Estrogen sulfotransferase (EST) and steroid sulfatase (STS) are known to be involved in in situ estrogen production in estrogen dependent human cancer such as breast cancer, but unknown in prostate cancer. MATERIALS AND METHODS We first examined whether these enzymes above were expressed and actually involved in estrogen production and metabolism in prostate cancer cell lines (LNCaP, DU-145, and PC-3). We than examined the expression of EST and STS in human prostate cancer tissues obtained from surgery (n = 52) using immunohistochemistry. RESULTS mRNAs of both enzymes were detected in all prostate cancer cell lines examined, and the synthesis of estrone (E1) and estradiol (E2) was also confirmed in these cell lines. In addition, STS immunoreactivity was detected in 44 cases (85%) and EST in 39 cases (75%), respectively. CONCLUSIONS STS and EST are expressed and may be involved in local production and metabolism of estrogens in human prostate cancers. Prostate 66: 1005–1012, 2006. © 2006 Wiley-Liss, Inc.

The role was studied of ephrin-B3, a ligand of the Eph family of tyrosine kinase receptors, in the formation of cortical connectivity. In situ hybridization and immunohistochemistry showed that EphA4, a receptor of ephrin-B3, was expressed in the lateral thalamus (visual and somaotosensory thalamus) of the developing rat brain, but not in the medial thalamic nuclei which project to the limbic cortex. Correspondingly, ephrin-B3 was expressed strongly in the developing limbic cortex including amygdala, entorhinal cortex and hippocampus. To examine the action of ephrin-B3 on thalamic axons, either lateral or medial thalamic explants were cultured on membranes obtained from ephrin-B3-expressing COS cells. Axonal growth was inhibited for cells from the lateral thalamus but not from the medial thalamus. These results suggest that ephrin-B3 contributes to regional specificity by suppressing axonal growth of lateral thalamic neurons.

Background Severe obesity has been shown to limit access to renal transplantation in patients with end stage renal disease (ESRD). Laparoscopic sleeve gastrectomy (LSG) has been performed in the ESRD population to assist in achieving waitlist and transplant eligibility. Little is known about how LSG impacts the bioequivalence tacrolimus products and immunosuppression pharmacokinetics. Methods This was a prospective, open-label, single-dose, crossover, two-period pharmacokinetic (PK) study. The purpose of this study was to assess single-dose PK of immediate-release tacrolimus (IR-TAC), extended-release tacrolimus (ER-TAC), and mycophenolic acid (MPA) in adult ESRD patients post-LSG. Results Twenty-three subjects were included in the 24-hour PK assessments. The ratio of geometric means between ER-TAC and IR-TAC was 103.5% (90% CI 89.6 – 119.6%) for AUC0-24 and 92.5% (90% CI 80.4 – 106.4%) for Cmax. PK parameters were similar between ER-TAC and IR-TAC, except for Cmin (p=0.004) and Cmax (p=0.04). MPA AUC0-24 was similar when given with either ER-TAC or IR-TAC (p=0.32). Patients expressing CYP3A5*1 genotypes had lower tacrolimus AUC0-24 values versus those with CYP3A5*3/*3 (IR-TAC p

Aims Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O-desmethylvenlafaxine (ODV). Therefore, the influence of the CYP2D6 genotypes on venlafaxine pharmacokinetics was examined in a Japanese population. Methods Twelve adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotypes were determined by codon 188C/T, 1934G/A, 2938G/A and 4268G/C mutations using endonuclease tests based on PCR and by Xba I-RFLP analysis. Subjects were categorized into the following 3 groups (n=4 in each group); Group1: CYP2D6*10/*10, *5/*10, Group2: CYP2D6*1/*10, *2/*10 and Group3: CYP2D6*1/*1, CYP2D6*1/*2. Venlafaxine (25 mg, n=6; 37.5 mg, n=6) was administered orally at 09.00 h following an overnight fast. Plasma concentrations of venlafaxine and ODV were monitored by h.p.l.c. for 48 h. Results The Cmax and AUC of venlafaxine were 184% and 484% higher in the group 1 subjects than in the group 3 subjects, and 101% and 203% higher in the group 1 than in the group 2, respectively. Conclusions These results suggest that CYP2D6*10 influences the pharmacokinetics of venlafaxine in a Japanese population.

A novel biotinyl derivative containing a carbodiimide group (Carb-Bio) has been newly synthesized and this compound has been applied for non-radioactive labeling of DNA. The result suggests that this reagent can be used for labeling a probe DNA for Southern analysis.

Percutaneous balloon aortic valvuloplasty (BAV) was performed in 14 patients, including one critically ill infant with congenital valvular aortic stenosis (AS). BAV was effective in 13 patients (except the infant). The peak systolic pressure gradient between the left ventricle (LV) and the ascending aorta decreased from 76.6 +/- 21.6 to 29.5 +/- 15.3 mmHg (P less than 0.001). Follow-up cardiac catheterization was performed for eight patients between 1 and 3 years (1.6 +/- 1.1 years) after BAV. Restenosis was found in only one patient, and the efficacy of BAV continued significantly. Aortic regurgitation developed or increased in severity in 5 of 13 children immediately after BAV. Any other severe complication was not observed. Dilatation by BAV was not sufficient for the infant with critical AS, and acute myocardial infarction (AMI) in the lateral wall of the LV occurred during the BAV procedure. The infant died 3 days after the procedure due to AMI. It was concluded that the retrograde double balloon technique was superior to the retrograde single balloon technique. In two cases, the single balloon technique was ineffective because it was impossible to fix the balloon at the aortic annulus. However, the double balloon technique was effective in every patient. BAV is effective for AS in children, and an optional repeat trial may enable BAV to be the first choice for AS. Although BAV may be effective for neonates and infants with critical AS as an emergency treatment, much attention must be paid during the procedure.

Background/Purpose: Mycophenolate mofetil (MMF) is a prodrug that is pre-systemically hydrolyzed by esterases to the biologically active mycophenolic acid (MPA) and is mainly inactivated by UDP-glucuronosyltransferases (UGTs) in the liver, intestine and kidney. MMF has been used off-label in SLE because of its favorable side effect spectrum. Optimal MMF dosing in childhood-onset SLE (cSLE) is not well-established. Little is known about the pharmacokinetics (PK) and pharmacogenetics (PG) of MPA in cSLE although in pediatric transplant populations, graft survival is more closely related to individualized dosing based on systemic exposure (PK) to MPA rather than weight-adjusted dosing. Transplant literature has also elucidated the potential influence of genetic variants in UGTs on the large variability of MPA exposure and the occurrence of common MMF-associated adverse events. The purpose of this study is to explore the importance and potential benefits of individualized MMF therapy in cSLE by determining whether MPA PK correlates with cSLE therapeutic response and whether MPA PG influences MMF exposure. Methods: Full 9-hour pharmacokinetic profiles were obtained from cSLE patients (n = 18; F:M = 17:1; age 10–30 years, 43% Caucasian, 57% African-American, 81% non-Hispanic) who were on stable MMF therapy. The MPA PK parameters dose-normalized area under the curve from 0 to 12 hours (AUC0–12h), peak concentration (Cmax), time to peak concentration (Tmax) and oral clearance (CL/F) were assessed and analyzed by non-compartmental analysis. Genomic DNA was extracted using standard procedures and genotyped for UGT1A8*3 (830G>A), UGT1A9*3 (98T>C), 1A9–2152T>C, 1A9–440C>T, 1A9–331T>C, 1A9–275T>A and UGT2B7–900A>G by TaqMan assay and direct sequencing. Change in SLE disease activity while on MMF was measured using the British Isles Lupus Assessment Group (BILAG) index. Results: Large inter-patient variability in AUC0–12h (mean + S.D.: 38.7 + 19.8 mg hr/L/gMPA, range: 14.9–95.4) and oral clearance (CL/F) of MPA (mean + S.D.: 27.9 + 13.7 L/hr, range: 8.3–59.3) was observed. The AUC0–12h and weight-adjusted MMF dosing were only moderately correlated (r = 0.56, P = 0.01). An AUC0–12h of >30 mg hr/L was associated with decreased BILAG scores while on MMF (P = 0.002). Patients with UGT1A9 –440T (–331C) or UGT2B7 –900G appeared to have a trend toward lower CL/F and higher MPA exposure (AUC) than the wild-type of all evaluated single nucleotide polymorphisms. Patients with UGT1A9 –275A showed relatively high CL/F over a wide range. In an exploratory fashion, wild-type and –275A-carriers were analyzed and showed significantly higher CL/F compared to the rest of the carriers of SNPs 1A9 –440T (–331C) or 2B7 –900G (p < 0.05, Mann-Whitney's U test). Conclusion: Our data suggest that weight-adjusted MMF dosing alone does not reliably allow for the prediction of exposure to MPA in cSLE and that MPA exposure measured as AUC0–12h of at least 30 mg hr/L is required for cSLE improvement. UGT1A9 and UGT2B7 polymorphisms accounted in part for inter-individual differences in MPA exposure in patients with cSLE.

Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) and is increasingly being used in transplantation and cancer therapies. Sirolimus has low oral bioavailability and exhibits large pharmacokinetic variability. The underlying mechanisms for this variability have not been explored to a large extent. Sirolimus metabolism was characterized by in vitro intrinsic clearance estimation. Pathway contribution ranked from CYP3A4 > CYP3A5 > CYP2C8. With the well stirred and Qgut models sirolimus bioavailability was predicted at 15%. Interindividual differences in bioavailability could be attributed to variable intestinal CYP3A expression. The physiologically-based pharmacokinetics (PBPK) model developed in Simcyp predicted a high distribution of sirolimus into adipose tissue and another elimination pathway in addition to CYP-mediated metabolism. PBPK model predictive performance was acceptable with Cmax and area under the curve (AUC) estimates within 20% of observed data in a dose escalation study. The model also showed potential to assess the impact of hepatic impairment and drug-drug interaction (DDI) on sirolimus pharmacokinetics.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e59; doi:10.1038/psp.2013.33; published online 24 July 2013.