Valentina Shakhnovich

Anti-TNF, infliximab, and adalimumab can be effective in eosinophilic bowel disease.

Background: Eosinophilic enterocolitis (EEC) is an emerging distinct inflammatory bowel disease of unknown etiology. There are no published data on the effect of infliximab (IFX) or adalimumab (ADA) for the treatment of refractory cases. Methods: A report of all pediatric cases with EEC treated with anti-tumor necrosis factor, identified after an open international call. Results: We describe here the first 8 children with refractory EEC who were treated with IFX (75% boys; mean age at diagnosis 8.6 ± 4.03 [range 1.6–14 years]; mean age at IFX treatment 11.7 ± 4.4 [range 4.2–16 years]). Allergic and infectious causes of EEC were excluded in all cases. Rapid and complete clinical remission was documented in 6 (75%) children following the induction infusions: 3 (38%) with endoscopic remission, 2 (25%) with endoscopic improvement, and 1 unknown. Four of the 6 responders had secondary loss of response and were switched to ADA, 3 of whom with sustained remission using high doses. Overall, the 6 responders were followed for a median of 7 years (range 4–12; interquartile range 6.4–8.8 years) without evidence of developing Crohn disease or ulcerative colitis. The only case with macroscopic findings on endoscopy was a primary nonresponder. Conclusions: IFX and ADA may be effective in cases of refractory idiopathic EEC; however, because this is an uncontrolled report, further prospective studies are warranted.

Decreased Pregnane X Receptor Expression in Children with Active Crohn’s Disease

Expression of the pregnane X receptor (PXR) has been reported to be decreased in animal models of inflammatory bowel disease (IBD). To investigate the differential expression of PXR in children with Crohn’s disease, a type of IBD, RNA was extracted from archived intestinal biopsies from 18 children with Crohn’s disease (CD) and 12 age- and sex-matched controls (aged 7–17yrs). The aim of this investigation was to compare the relative mRNA expression of PXR, cytochrome p450 3A4 (CYP3A4), and villin 1 (VIL1) (a marker of epithelial cell integrity) in the inflamed terminal ileum (TI) versus noninflamed duodenum of children with CD. Relative expression was determined via reverse transcription real-time quantitative polymerase chain reaction, data normalized to glyceraldehyde 3-phosphate dehydrogenase, and differences in gene expression explored via paired t tests. PXR expression was decreased in the inflamed TI versus noninflamed duodenum (TI = 1.88 ± 0.89 versus duodenum = 2.5 ± 0.67; P < 0.001) in CD, but not controls (TI = 2.11 ± 0.41 versus duodenum = 2.26 ± 0.61; P = 0.52). CYP3A4 expression was decreased in CD (TI = –0.89 ± 3.11 versus duodenum = 1.90 ± 2.29; P < 0.05), but not controls (TI = 2.46 ± 0.51 versus duodenum = 2.60 ± 0.60; P = 0.61), as was VIL1 (CD TI = 3.80 ± 0.94 versus duodenum = 4.61 ± 0.52; P < 0.001; controls TI = 4.30 ± 0.35 versus duodenum = 4.47 ± 0.40; P = 0.29). PXR expression correlated with VIL1 (r = 0.78, P = 0.01) and CYP3A4 (r = 0.52, P = 0.01) expression. In conclusion, PXR, CYP3A4, and VIL1 expression was decreased only in the actively inflamed small intestinal tissue in children with CD. Our findings suggest that inflammation has the potential to influence expression of genes, and potentially intestinal proteins, important to drug disposition and response. The observed differential patterns of gene expression support further investigation of the role of PXR in the pathogenesis and/or treatment of pediatric Crohn’s disease.

Use of pharmacokinetic modelling to individualize FFP dosing in factor V deficiency

Therapy with fresh frozen plasma (FFP) confers serious risks, such as contraction of blood‐borne viruses, allergic reaction, volume overload and development of alloantibodies. The aim of this study was to apply principles of pharmacokinetic (PK) modelling to individual factor content of FFP to optimize individualized dosing, while minimizing potential risks of therapy. We used PK modelling to successfully target individual factor replacement in an 8‐month‐old patient receiving FFP for treatment of a severe congenital factor V (FV) deficiency. The model fit for the FV activity vs. time data was excellent (r = 0.98) and the model accurately predicted FV activity during the intraoperative and postoperative period. Accurate PK modelling of individual factor activity in FFP has the potential to provide better targeted therapy, enabling clinicians to more precisely dose patients requiring coagulation products, while avoiding wasteful and expensive product overtreatment, minimizing potentially life‐threatening complications due to undertreatment and limiting harmful product‐associated risks.

Obese Children Require Lower Doses of Pantoprazole Than Nonobese Peers to Achieve Equal Systemic Drug Exposures

Objective To assess appropriate pantoprazole dosing for obese children, we conducted a prospective pharmacokinetics (PK) investigation of pantoprazole in obese children, a patient population that is traditionally excluded from clinical trials. Study design A total of 41 obese children (6‐17 years of age), genotyped for CYP2C19 variants *2, *3, *4, and *17, received a single oral dose of pantoprazole, ˜1.2 mg/kg lean body weight (LBW), with LBW calculated via a validated formula. Ten post‐dose pantoprazole plasma concentrations were measured, and PK variables generated via noncompartmental methods (WinNonlin). Linear and nonlinear regression analyses and analyses of variance were used to explore obesity, age, and CYP2C19 genotype contribution to pantoprazole PK. PK variables of interest were compared with historic nonobese peers treated with pantoprazole. Results Independent of genotype, when normalized to dose per kg total body weight, pantoprazole apparent clearance and apparent volume of distribution were significantly lower (P < .05) and systemic exposure significantly higher (P < .01) in obese vs nonobese children. When normalized per kg LBW, these differences were not evident in children ≥12 years of age and markedly reduced in children <12 years of age. Conclusions LBW dosing of pantoprazole led to pantoprazole PK similar to nonobese peers. Additional factors, other than body size (eg, age‐related changes in CYP2C19 activity), appear to affect pantoprazole PK in children <12 years of age. Trial registration ClinicalTrials.gov: NCT02186652

Lean body weight dosing avoids excessive systemic exposure to proton pump inhibitors for children with obesity: PPI dosing for children with obesity

Children with obesity are more likely to suffer gastroesophageal reflux disease, requiring acid‐suppression therapy with proton pump inhibitors (PPIs) and no guidelines regarding dosing.

It's Time to Reverse our Thinking: The Reverse Translation Research Paradigm

In contrast, reverse translation, also called bedside-tobenchtop research, begins with actual, real-life patient experiences in the clinic, or during a clinical trial, and works backward to uncover the mechanistic basis for these experiences and clinical observations. In the reverse translation paradigm, research becomes a seamless, continuous, cyclical process, in which each new patient observation stimulates new testable hypotheses that help refine and direct the next iteration of benchtop therapeutics research, which, in turn, leads to the next clinical trial and the next human experience (Figure 1).1 The beauty of reverse translation, unlike benchtop-tobedside research, is that there is no such thing as a failed clinical trial; only expected and unexpected therapeutic outcomes, and the inevitable variability in the observed human therapeutic response that needs further explanation and exploration. The reverse translation issue of Clinical and Translational Science embraces this broad view of reverse translation, which encompasses awide range of topics highly relevant to clinical pharmacology and patient-centered translational therapeutics research.

PANTOPRAZOLE PHARMACOKINETICS IN OBESITY: WHERE GENES AND SIZE COLLIDE

Background Limited dosing guidelines exist for overweight children (≈30% pediatric population). This prospective study examines the pharmacokinetics (PK) of pantoprazole (CYP2C19 substrate) in overweight vs. normal-weight children. Methods Using TaqMan techniques, 51 children (6–17 yrs) were genotyped for CYP2C19 loss-of-function (*2, *3, *4) and gain-of-function (*17) alleles. After a single oral dose of pantoprazole (1.2 mg/kg lean body weight), 10 plasma samples were collected over 8hrs, pantoprazole/metabolite concentrations measured by HPLC-UV, and PK parameters generated via non-compartmental methods. Using a two-tailed unpaired t-test, parameters were compared between overweight/obese (n=24) and normal-weight (n=25) children, and the effect of CYP2C19 genotype (*1/*1, n=24; *1/*17, n=15; *1/*2, n=7; *2/*17, n=3; *2/*2, n=2) on drug disposition was analyzed using a one-way ANOVA; α=0.05. Results Dose-adjusted AUCtot, CL/F and other PK parameters were not significantly different between overweight/obese and normal-weight children. Independent of weight, mean AUCtot for pantoprazole was 2-fold greater in children with 1 loss-of-function vs. 1 gain-of-function allele (p=0.01). CL/F was increased only in children with *1/*17 genotype compared to all other genotypes (p<0.03), except *2/*17. In children with *1/*1 genotype (n=24), CL/F was significantly reduced (0.25±0.1 vs. 0.41±0.23 L/h/kg; p<0.05) and AUCtot increased (5.3±3.5 vs. 3.1±1.5 mg*h/L; p=0.05) in overweight/obese vs. normal-weight children. AUCtot was significantly increased in obese vs. normal-weight children (8.1±4.6 vs. 3.1±1.5 mg*h/L; p<0.05), with a positive correlation observed between AUCtot and BMI (r2=0.4; p=0.01). Conclusions CYP2C19 genotype appears to be the primary determinant of pantoprazole PK in children, whereas BMI may explain individual variability within genotype groups.

General Considerations for Pediatric Oral Drug Formulation

In pediatrics, the absorption of a perorally administered drug depends on the ability of the formulation to overcome the chemical, physical, mechanical, and biological barriers of the developing gastrointestinal tract. The differences between the pediatric and adult digestive systems are subtle, but physiologically important, and encompass organs from mouth to anus. Although the exact age of GI function maturation remains to be defined, clinically relevant developmental changes that influence drug absorption occur primarily during early childhood. This chapter reviews the developmental changes in gastrointestinal physiology that occur throughout childhood and discusses their relevance to formulation development and drug delivery.