Population Pharmacokinetic Modeling of Risperidone and 9-Hydroxyrisperidone to Estimate CYP2D6 Subpopulations in Children and Adolescents

Sherwin, Catherine M.T.; Saldaña, Shannon N.; Bies, Robert R.; Aman, Michael G.; Vinks, Alexander A.

doi:10.1097/ftd.0b013e318261c240

Cited by 25 publications

(40 citation statements)

References 41 publications

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“…This quantitative ‘bottom-up’ approach includes physiologically-based in vitro – in vivo extrapolation (IVIVE) and has gained momentum due to our increased understanding of the contributing factors (e.g., physical chemistry, systems physiology and pharmacogenetics) and advances in quantitative modeling using mechanistic models. 2,33,54–62 …”

Section: Physiology- and Population-based Pharmacokinetic Modeling (Pmentioning

confidence: 99%

Summary of the National Institute of Child Health and Human Development–Best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop–Pediatric Biopharmaceutics Classification System Working Group

Abdel‐Rahman

Amidon

Kaul

et al. 2012

Clinical Therapeutics

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The Biopharmaceutics Classification System (BCS) allows compounds to be classified based on their in vitro solubility and intestinal permeability. The BCS has found widespread use in the pharmaceutical community as an enabling guide for the rational selection of compounds, formulation for clinical advancement and generic biowaivers. The Pediatric Biopharmaceutics Classification System (PBCS) working group was convened to consider the possibility of developing an analogous pediatric based classification system. Since there are distinct developmental differences that can alter intestinal contents, volumes, permeability and potentially biorelevant solubilities at the different ages, the PBCS working group focused on identifying age specific issues that would need to be considered in establishing a flexible, yet rigorous PBCS. Objective To summarize the findings of the PBCS working group and provide insights into considerations required for the development of a pediatric based biopharmaceutics classification system. Methods Through several meetings conducted both at The Eunice Kennedy Shriver National Institute of Child Health, Human Development (NICHD)-US Pediatric Formulation Initiative (PFI) workshop (November 2011) and via teleconferences, the PBCS working group considered several high level questions that were raised to frame the classification system. In addition, the PBCS working group identified a number of knowledge gaps that would need to be addressed in order to develop a rigorous PBCS. Results It was determined that for a PBCS to be truly meaningful, it would need to be broken down into several different age groups that would account for developmental changes in intestinal permeability, luminal contents, and gastrointestinal transit. Several critical knowledge gaps where identified including: 1) a lack of fully understanding the ontogeny of drug metabolizing enzymes and transporters along the gastrointestinal (GI) tract, in the liver and in the kidney; 2) an incomplete understanding of age-based changes in the GI, liver and kidney physiology; 3) a clear need to better understand age-based intestinal permeability and fraction absorbed required to develop the PBCS; 4) a clear need for the development and organization of pediatric tissue biobanks to serve as a source for ontogenic research; and 5) a lack of literature published in age-based pediatric pharmacokinetics in order to build Physiologically- and Population-Based Pharmacokinetic (PBPK) databases. Conclusions To begin the process of establishing a PBPK model, ten pediatric therapeutic agents were selected (based on their adult BCS classifications). Those agents should be targeted for additional research in the future. The PBCS working group also identified several areas where a greater emphasis on research is needed to enable the development of a PBCS.

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Section: Physiology- and Population-based Pharmacokinetic Modeling (Pmentioning

confidence: 99%

Summary of the National Institute of Child Health and Human Development–Best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop–Pediatric Biopharmaceutics Classification System Working Group

Abdel‐Rahman

Amidon

Kaul

et al. 2012

Clinical Therapeutics

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“…Plasma (pCr) or serum creatinine (sCr) and blood urea nitrogen (BUN) have usually been used as indicators, or biomarkers, for kidney injury in human GPSH intoxication (El-Shenawy, 2009;Lee et al, 2008;Moon and Chun, 2010;Talbot et al, 1991;Tominack et al, 1991). Recently, several studies have suggested that pCr is not sensitive enough to detect early kidney injury or predict subsequent functional change (Sherwin et al, 2012;Toto, 1995;Vaidya et al, 2008b;Woitas et al, 2000). Other biomarkers including interleukin-18 (IL-18), cystatin-C (Cys-C), kidney injury molecule-1 (KIM-1), 2-microglobulin (2-M), albumin (Alb), neutrophil gelatinaseassociated lipocalin (NGAL) and osteopontin (Opn) have been proposed for the early and sensitive detection of AKI and functional loss Ferguson et al, 2008;Nguyen and Devarajan, 2008;Noiri et al, 2009;Vaidya et al, 2008a;Vaidya et al, 2008b), and may have greater sensitivity than pCr.…”

Section: Introductionmentioning

confidence: 99%

Use of a glyphosate-based herbicide-induced nephrotoxicity model to investigate a panel of kidney injury biomarkers

et al. 2014

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Accidental or intentional ingestion of glyphosate surfactant-based herbicides, like Roundup, leads to nephrotoxicity as well as death. In this study, a panel of kidney injury biomarkers was evaluated in terms of suitability to detect acute kidney injury and dysfunction. The Roundup intoxication model involved oral administration of glyphosate to rats at dose levels of 250, 500, 1200 and 2500 mg/kg. Urinary and plasma biomarker patterns were investigated at 8, 24 and 48 hours after dosing.Biomarkers were quantified by absolute concentration; by normalising to urine creatinine; and by calculating the excretion rate. The diagnostic performances of each method in predicting of acute kidney injury were compared. By Receiver Operating Characteristic (ROC) analysis of the selected biomarkers, only urinary kidney injury molecule-1 (KIM-1) best predicted histological changes at 8 h (best cut-off point > 0.00029 µg/ml). Plasma creatinine performed better than other biomarkers at 24 h (best cut-off point > 0.21 mg/dl). Urinary KIM-1 was the best early biomarker of kidney injury in this glyphosate-induced nephrotoxicity model.

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“…Sherwin et al [ 31 ] investigated differences in risperidone clearance between metabolic phenotypes. Decreases in relative clearance correlated with decreases in CYP2D6 metabolic activity, though no UM phenotype subjects were included in the study.…”

Section: Resultsmentioning

confidence: 99%

A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment in children and adolescents

Dodsworth

Kim

Procyshyn

et al. 2018

Child Adolesc Psychiatry Ment Health

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The second generation antipsychotic drug risperidone is widely used in the field of child and adolescent psychiatry to treat conditions associated with disruptive behavior, aggression and irritability, such as autism spectrum disorders. While risperidone can provide symptomatic relief for many patients, there is considerable individual variability in the therapeutic response and side-effect profile of the medication. One well established biological factor that contributes to these individual differences is genetic variation in the cytochrome P450 enzyme 2D6. The 2D6 enzyme metabolizes risperidone and therefore affects drug levels and dosing. In the present review, we summarize the current literature on 2D6 variants and their effects on risperidone responses, specifically in children and adolescents. Relevant articles were identified through systematic review, and after irrelevant articles were discarded, ten studies were included in the review. Most prospective studies were well controlled, but often did not have a large enough sample size to make robust statements about rarer variants, including those categorized as ultra-rapid and poor metabolizers. Individual studies demonstrated a role for different genetic variants in risperidone drug efficacy, pharmacokinetics, hyperprolactinemia, weight gain, extrapyramidal symptoms and drug–drug interactions. Where studies overlapped in measurements, there was typically a consensus between results. These findings indicate that the value of 2D6 genotyping in the youth population treated with risperidone requires further study, in particular with the less common variants.

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Population Pharmacokinetic Modeling of Risperidone and 9-Hydroxyrisperidone to Estimate CYP2D6 Subpopulations in Children and Adolescents

Cited by 25 publications

References 41 publications

Summary of the National Institute of Child Health and Human Development–Best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop–Pediatric Biopharmaceutics Classification System Working Group

Summary of the National Institute of Child Health and Human Development–Best Pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop–Pediatric Biopharmaceutics Classification System Working Group

Use of a glyphosate-based herbicide-induced nephrotoxicity model to investigate a panel of kidney injury biomarkers

A systematic review of the effects of CYP2D6 phenotypes on risperidone treatment in children and adolescents

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