An exploratory machine learning approach to identify placebo responders in pharmacological binge eating disorder trials.

Randomized, placebo-controlled trials for binge eating disorder (BED) have revealed highly variable, and often marked, rates of short-term placebo response. Several quantitative based analyses in patients with BED have inconsistently demonstrated which patient factors attribute to an increase in placebo response. The objective of this study is to utilize machine learning (ML) algorithms to identify moderators of placebo response in patients with BED.

Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis.

Objectives: To characterize individual participant level response distributions to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration from 1979 to 2016.

Design: Individual participant data analysis.

Population: 232 randomized, double blind, placebo controlled trials of drug monotherapy for major depressive disorder submitted by drug developers to the FDA between 1979 and 2016, comprising 73 388 adult and child participants meeting the inclusion criteria for efficacy studies on antidepressants.

Development and Use of an Ex-Vivo In-Vivo Correlation to Predict Antiepileptic Drug Clearance in Patients Undergoing Continuous Renal Replacement Therapy.

Objectives: Results from previous ex-vivo continuous renal replacement therapy (CRRT) models have successfully demonstrated similar extraction coefficients (EC) identified from in-vivo clinical trials. The objectives of this study are to develop an ex-vivo in-vivo correlation (EVIVC) model to predict drug clearance for commonly used antiepileptics and to evaluate similarity in drug extraction across different CRRT modalities to extrapolate dosing recommendations.

Methods: Levetiracetam, lacosamide, and phenytoin CRRT clearance was evaluated using the Prismaflex CRRT system and M150 hemodiafilters using an albumin containing normal saline (ALB-NS) vehicle with 3 different albumin concentrations (2 g/dL, 3 g/dL, and 4 g/dL) and a human plasma vehicle at 3 different effluent flow rates (1 L/hr, 2 L/hr, and 3 L/hr).

Evaluation of an vivo neonatal extracorporeal membrane oxygenation circuit on antiepileptic drug sequestration.

Antiepileptic dosing information used to manage neonatal patients receiving extracorporeal membrane oxygenation (ECMO) is limited. The objective of this study is to quantify the extent of sequestration of various antiepileptic drugs using an -vivo neonatal ECMO circuit. Two neonatal closed-loop ECMO circuits were prepared using a Rotaflow centrifugal pump, custom polyvinylchloride tubing and a Quadrox-i Neonatal membrane oxygenator.

Extrapolation of Efficacy and Dose Selection in Pediatrics: A Case Example of Atypical Antipsychotics in Adolescents With Schizophrenia and Bipolar I Disorder.

Pediatric labeling information for novel atypical antipsychotics can be significantly delayed as the result of time lag between initial drug approval in adults and the completion of pediatric clinical trials. This delay can lead health care providers to rely on limited evidence-based literature to make critical therapeutic decisions for pediatric patients. Effective and scientifically justified dosing recommendations are needed to improve treatment outcomes in pediatric patients with schizophrenia and bipolar I disorder.

Concordance of Exposure Changes Because of Renal Impairment Between Results of Dedicated Renal Impairment Studies and Population Pharmacokinetic Predictions.

This analysis compared the results from noncompartmental analysis and population pharmacokinetic (PopPK) predictions of exposure changes in patients with renal impairment (RI) for 27 new molecular entities (NMEs) approved between 2000 and 2015. Renal function was identified as a covariate in the final PopPK model for 17 NMEs. The final PopPK model was used to simulate (n  =  1000 replicates/individual) the results of a dedicated PK study in subjects with renal impairment.

A prospective, real-world, clinical pharmacokinetic study to inform lacosamide dosing in critically ill patients undergoing continuous venovenous haemofiltration (PADRE-02).

Aims: Although the use of continuous renal replacement therapy (CRRT) has increased, limited dosing information exists on the effect of CRRT on antiepileptic drug pharmacokinetics. The objectives of this practice-based study are to evaluate the pharmacokinetics of lacosamide and recommend individualized dosing recommendations in critically ill patients receiving continuous venovenous haemofiltration (CVVH).

Methods: Seven patients receiving lacosamide and CVVH in a neurocritical care unit were enrolled.

Evaluation of Switch-to-Brand Rates as a Potential Signal for Therapeutic Equivalency of Generic Antidepressants: A Real-World Retrospective Cohort Study.

Negative clinical outcomes after switching from brand to generic antidepressants have raised concerns regarding therapeutic equivalency. This research aims to estimate the prevalence of switching and to identify predictors for generic to brand switching for various antidepressants. This retrospective cohort study utilized data from a 10% random sample of enrollees in the IQVIA PharMetrics Plus claims database from 2007-2015.

Influence of age on the relationship between apixaban concentration and anti-factor Xa activity in older patients with non-valvular atrial fibrillation.

Background/objectives: Despite lower major bleeding rates associated with direct oral anticoagulants (DOACs) as compared to conventional warfarin therapy, bleeding rates remain higher in older patients compared to younger patients suggesting a potential role for DOAC measurements. The objective of this study is to examine the effect of age on the relationship between apixaban concentrations and anti-Factor Xa activity in patients with non-valvular atrial fibrillation (NVAF).

Methods: This is a retrospective analysis based on a database created using data from the ARISTOTLE study.

Optimizing ceftaroline dosing in critically ill patients undergoing continuous renal replacement therapy.

Background And Objectives: Currently, no dosing information exists for ceftaroline fosamil in patients undergoing continuous renal replacement therapy (CRRT). The objectives of this study are to characterize the pharmacokinetics of ceftaroline in critically ill patients undergoing CRRT modalities and to derive individualized dosing recommendations.

Methods: This pharmacokinetic study aimed to enroll critically ill patients receiving ceftaroline fosamil and any CRRT modality from adult intensive care units.

A Practice-Based, Clinical Pharmacokinetic Study to Inform Levetiracetam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemofiltration (PADRE-01).

Limited data exist on the effect of continuous renal replacement therapy (CRRT) methods on anti-epileptic drug pharmacokinetics (PK). This prospective practice-based PK study aims to assess the impact of continuous venovenous hemofiltration (CVVH), a modality of CRRT, on levetiracetam PK in critically ill patients and to derive individualized dosing recommendations. Eleven patients receiving oral or intravenous levetiracetam and CVVH in various intensive care units at a large academic medical center were enrolled to investigate the need for dosing adjustments.

Assessment of Similarity in Antipsychotic Exposure-Response Relationships in Clinical Trials Between Adults and Adolescents With Acute Exacerbation of Schizophrenia.

Despite agreement that early-onset schizophrenia is continuous with the adult-onset form, quantitative relationships between antipsychotic exposure and clinical response are relatively unexplored in adolescents, compared to adults. Clinical efficacy data from second-generation antipsychotic development programs (N = 5951 adults and N = 1035 adolescents ranging from 12 to 17 years old) were collected from available new drug applications submitted to the US Food and Drug Administration from 1993 to 2017. The developed disease-drug trial models adequately predicted the longitudinal trend in total positive and negative syndrome scale scores in both adults and adolescents using a Weibull placebo response, time-delayed drug effect, and a Weibull structural dropout model.

Vancomycin Pharmacokinetics in Obese Patients with Sepsis or Septic Shock.

Study Objectives: Obese patients with sepsis or septic shock may have altered vancomycin pharmacokinetics compared with the general population that may result in improper dosing or inadequate drug concentrations. The objective of this study was to characterize vancomycin pharmacokinetics in obese patients with sepsis or septic shock, and to develop a novel pharmacokinetic dosing model based on pharmacokinetic-pharmacodynamic target requirements.

Design: Prospective observational pharmacokinetic study.

A Population Pharmacokinetics and Pharmacodynamic Approach To Optimize Tazobactam Activity in Critically Ill Patients.

The percentage of the time that the free drug concentration remains above a concentration threshold (% > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using infection models. Similar models suggested that an 85% > concentration threshold of 2 μg/ml for tazobactam is required to demonstrate a 2-log-unit decrease in the number of CFU per milliliter from that at the baseline at 24 h for high-level β-lactamase-producing strains. The objective of this study was to characterize the tazobactam concentrations in a cohort of critically ill patients with Gram-negative bacterial infections, determine if traditional dosing regimens achieve a prespecified PK/PD target of an 80% > concentration threshold of 2 μg/ml, and propose alternative dosing regimens.

Development of point-of-care testing devices to improve clozapine prescribing habits and patient outcomes.

Although clozapine has demonstrated superior efficacy in patients with schizophrenia and other serious mental health illness, drug utilization rates are significantly low due to safety concerns and administration challenges. Previous research indicates that current barriers to clozapine use include lack of confidence and knowledge by prescriber, therapeutic monitoring requirements, lack of support and infrastructure to for adequate monitoring and patient adherence, and inadequate understanding of clozapine's benefit-risk profile by policy makers and payers. One potential solution to optimizing clozapine therapy and improving clinical outcomes is the use of point-of-care testing (POCT) devices.

An Innovative Disease-Drug-Trial Framework to Guide Binge Eating Disorder Drug Development: A Case Study for Topiramate.

As with other psychiatric disorders, development of drugs to treat binge-eating disorder (BED) has been hampered by high placebo response and dropout rates in randomized controlled trials (RCTs). Although not approved for use in BED, several RCTs have suggested that topiramate is efficacious for BED in obese individuals. Using data from a positive investigator-initiated RCT of topiramate in 61 obese individuals with BED, the objective of the present study is (i) to develop a quantitative disease-drug-trial framework to inform future BED clinical trial designs, and (ii) to determine the optimal topiramate dose to achieve therapeutic efficacy.

A Quantitative Justification of Similarity in Placebo Response Between Adults and Adolescents With Acute Exacerbation of Schizophrenia in Clinical Trials.

Early-onset schizophrenia, or "adolescent schizophrenia," has a global incidence ranging up to 4% of all schizophrenia cases. Clinical data from antipsychotic programs were collected from new drug applications submitted to the US Food and Drug administration from 1993 to 2015. A placebo response-dropout model was developed to describe the time course of total positive and negative syndrome scale (PANSS) scores in adults and adolescents.

Development and validation of a HPLC-UV assay for quantification of levetiracetam concentrations in critically ill patients undergoing continuous renal replacement therapy.

Limited clinical data exists on the effects of continuous renal replacement therapy (CRRT) on drug pharmacokinetics. A high-performance liquid chromatography with ultraviolet detection method was developed and validated to determine levetiracetam concentrations in human plasma and CRRT effluent samples. Five hundred microliters of human plasma and 250 μL effluent samples were used to quantify levetiracetam.

Lacosamide Pharmacokinetics in a Critically Ill Patient Receiving Continuous Venovenous Hemofiltration.

Lacosamide is a new-generation antiepileptic drug (AED) that is eliminated by both hepatic and renal mechanisms. Lacosamide elimination by continuous renal replacement therapy (CRRT) has never been studied. The objective of this case report was to describe lacosamide pharmacokinetics in the setting of CRRT.