Exposure-response modeling for extrapolation from adult to pediatric patients who differ with respect to prognostic factors: Application to everolimus.
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ABSTRACT:
SUBMITTER: Dumortier T
PROVIDER: S-EPMC8213418 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:During drug development, matching adult systemic exposures of drugs is a common approach for dose selection in pediatric patients when efficacy is partially or fully extrapolated. This is a systematic review of approaches used for matching adult systemic exposures as the basis for dose selection in pediatric trials submitted to the US Food and Drug Administration (FDA) between 1998 and 2012. The trial design of pediatric pharmacokinetic (PK) studies and the pediatric and adult systemic exposure data were obtained from FDA publicly available databases containing reviews of pediatric trials. Exposure-matching approaches that were used as the basis for pediatric dose selection were reviewed. The PK data from the adult and pediatric populations were used to quantify exposure agreement between the 2 patient populations. The main measures were the pediatric PK studies' trial design elements and drug systemic exposures (adult and pediatric). There were 31 products (86 trials) with full or partial extrapolation of efficacy with an available PK assessment. Pediatric exposures had a range of mean Cmax and AUC ratios (pediatric/adult) of 0.63 to 4.19 and 0.36 to 3.60, respectively. Seven of the 86 trials (8.1%) had a predefined acceptance boundary used to match adult exposures. The key PK parameter was consistently predefined for antiviral and anti-infective products. Approaches to match exposure in children and adults varied across products. A consistent approach for systemic exposure matching and evaluating pediatric PK studies is needed to guide future pediatric trials.
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Project description:BackgroundThe development of generic ophthalmic drug products is challenging due to the complexity of the ocular system, and a lack of sensitive testing to evaluate the interplay of physiology with ophthalmic formulations. While measurements of drug concentration at the site of action in humans are typically sparse, these measurements are more easily obtained in rabbits. The purpose of this study is to demonstrate the utility of an ocular physiologically based pharmacokinetic (PBPK) model for translation of ocular exposure from rabbit to human.MethodThe Ocular Compartmental Absorption and Transit (OCAT™) model within GastroPlus® v9.8.2 was used to build PBPK models for levofloxacin (Lev), moxifloxacin (Mox), and gatifloxacin (Gat) ophthalmic solutions. in the rabbit eye. The models were subsequently used to predict Lev, Mox, and Gat exposure after ocular solution administrations in humans. Drug-specific parameters were used as fitted and validated in the rabbit OCAT model. The physiological parameters were scaled to match human ocular physiology.ResultsOCAT model simulations for rabbit well described the observed concentrations in the eye compartments following Lev, Mox, and Gat solution administrations of different doses and various administration schedules. The clinical ocular exposure following ocular administration of Lev, Mox, and Gat solutions at different doses and various administration schedules was well predicted.ConclusionEven though additional case studies for different types of active pharmaceutical ingredients (APIs) and formulations will be needed, the current study represents an important step in the validation of the extrapolation method to predict human ocular exposure for ophthalmic drug products using PBPK models.
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Project description:This study aims to investigate differences in imaging, procedure utilization, and clinical outcomes of severely injured adolescents treated at adult versus pediatric trauma centers.The National Trauma Data Bank was queried retrospectively for adolescents, 15-19years old, with a length of stay (LOS) >1day and Injury Severity Score (ISS) >25 treated at adult (ATC) or pediatric (PTC) Level 1 trauma centers from 2007 to 2011. Patient demographics and utilization of imaging and procedures were analyzed. Univariate and multivariate regression analysis was used to compare outcomes.Of 12,861 adolescents, 51% were treated at ATC. Older age and more nonwhites were seen at ATC (p<0.01). Imaging and invasive procedures were more common at ATC (p<0.01). Shorter LOS (p=0.03) and higher home discharge rates (p<0.01) were seen at PTC. ISS and mortality did not differ. Age, race, ATC care (all p<0.01), and admission systolic blood pressure (SBP) (p=0.03) were predictors of CT utilization. ISS, SBP, and race (p<0.01) were risk factors for overall mortality; SBP (p=0.03) and ISS (p<0.01) predicted death from penetrating injury.Severely injured adolescents experience improved outcomes and decreased imaging and invasive procedures without additional mortality risk when treated at PTC. PTC is an appropriate destination for severely injured adolescents.
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Project description:Regulatory toxicology testing has traditionally relied on in vivo methods to inform decision-making. However, scientific, practical, and ethical considerations have led to an increased interest in the use of in vitro and in silico methods to fill data gaps. While in vitro experiments have the advantage of rapid application across large chemical sets, interpretation of data coming from these non-animal methods can be challenging due to the mechanistic nature of many assays. In vitro to in vivo extrapolation (IVIVE) has emerged as a computational tool to help facilitate this task. Specifically, IVIVE uses physiologically based pharmacokinetic (PBPK) models to estimate tissue-level chemical concentrations based on various dosing parameters. This approach is used to estimate the administered dose needed to achieve in vitro bioactivity concentrations within the body. IVIVE results can be useful to inform on metrics such as margin of exposure or to prioritize potential chemicals of concern, but the PBPK models used in this approach have extensive data requirements. Thus, access to input parameters, as well as the technical requirements of applying and interpreting models, has limited the use of IVIVE as a routine part of in vitro testing. As interest in using non-animal methods for regulatory and research contexts continues to grow, our perspective is that access to computational support tools for PBPK modeling and IVIVE will be essential for facilitating broader application and acceptance of these techniques, as well as for encouraging the most scientifically sound interpretation of in vitro results. We highlight recent developments in two open-access computational support tools for PBPK modeling and IVIVE accessible via the Integrated Chemical Environment (https://ice.ntp.niehs.nih.gov/), demonstrate the types of insights these tools can provide, and discuss how these analyses may inform in vitro-based decision making.
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Project description:Diagnostic radiographs, computed tomography (CT), nuclear medicine studies, and intraoperative fluoroscopy durations were analyzed for radiation exposure. Cumulative and yearly effective ionizing radiation doses, cumulative background radiation, and total radiograph studies were compared between pediatric and adult populations. In 24 patients with 1,246 imaging studies (average 5.5 years longitudinal treatment duration), the mean estimated cumulative effective radiation dose per patient was 30.0 mSv (range 2.3-115.0), with an average yearly dose of 4.9 mSv (range 0.4-24.8). Pediatric patients had significantly more radiograph studies per year than adults and greater average yearly effective radiation doses.
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Project description:It is increasingly clear that both adult and pediatric glial tumor entities represent collections of neoplastic lesions, each with individual pathological molecular events and treatment responses. In this review, we discuss the current prognostic biomarkers validated for clinical use or with future clinical validity for gliomas. Accurate prognostication is crucial for managing patients as treatments may be associated with high morbidity and the benefits of high risk interventions must be judged by the treating clinicians. We also review biomarkers with predictive validity, which may become clinically relevant with the development of targeted therapies for adult and pediatric gliomas.
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