Optimal Sampling Times in Bioequivalence Studies Using a Simulated Annealing Algorithm

In pharmacokinetic (PK) studies, blood samples are taken over time on subjects after the administration of a drug to measure the time-course of the plasma drug concentrations. In bioequivalence studies, the trapezoidal rule on the sampled time points is often used to estimate the area under the plasma concentration-time curve, a quantity of principle interest. This manuscript investigates the choice of sampling time points to estimate the area under the curve. In particular, we explore the relative merits of several objective functions, those functions which are minimized with respect to the sampling times to obtain an optimal study design. We propose an objective function which overcomes some of the deficits of existing choices. We also present a simulated annealing algorithm to perform the minimization. The main benefits of the simulated annealing algorithm are the ease in which it can handle constraints on the sampling schedules and its ability to accommodate a variety of models and objective functions. The manuscript presents optimal sampling times for some key examples of true underlying models

A SURVEY OF THE LIKELIHOOD APPROACH TO BIOEQUIVALENCE TRIALS

Bioequivalence trials are abbreviated clinical trials whereby a generic drug or new formulation is evaluated to determine if it is equivalent to a corresponding previously approved brand-name drug or formulation. In this manuscript, we survey the process of testing bioequivalence and advocate the likelihood paradigm for representing the resulting data as evidence. We emphasize the unique conflicts between hypothesis testing and confidence intervals in this area - which we believe are indicative of the existence of the systemic defects in the frequentist approach - that the likelihood paradigm avoids. We suggest the direct use of profile likelihoods for evaluating bioequivalence and examine the main properties of profile likelihoods and estimated likelihoods under simulation. This simulation study shows that profile likelihoods are a reasonable alternative to the (unknown) true likelihood for a range of parameters commensurate with bioequivalence research. Our study also shows that the standard methods in the current practice of bioequivalence trials offers only weak evidence from the evidential point of view

A Mechanistic Latent Variable Model for Estimating Drug Concentrations in the Male Genital Tract

The purpose of this study is to develop statistical methodology to facilitate indirect estimation of the concentration of antiretroviral drugs and viral loads in the prostate gland and the seminal vesicle. The differences in antiretroviral drug concentrations in these organs may lead to suboptimal concentrations in one gland compared to the other. Suboptimal levels of the antiretroviral drugs will not be able to fully suppress the virus in that gland, lead to a source of sexually transmissible virus and increase the chance of selecting for drug resistant virus. This information may be useful selecting antiretroviral drug regimen that will achieve optimal concentrations in most of male genital tract glands. Using fractionally collected semen ejaculates, Lundquist (1949) measured levels of surrogate markers in each fraction that are uniquely produced by specific male accessory glands. To determine the original glandular concentrations of the surrogate markers, Lundquist solved a simultaneous series of linear equations. This method has several limitations. In particular, it does not yield a unique solution, it does not address measurement error, and it disregards inter-subject variability in the parameters. To cope with these limitations, we developed a mechanistic latent variable model based on the physiology of the male genital tract and surrogate markers. We employ a Bayesian approach and perform a sensitivity analysis with regard to the distributional assumptions on the random effects and priors. The model and Bayesian approach is validated on experimental data where the concentration of a drug should be (biologically) differentially distributed between the two glands. In this example, the Bayesian model-based conclusions are found to be robust to model specification and this hierarchical approach leads to more scientifically valid conclusions than the original methodology. In particular, unlike existing methods, the proposed model based approach was not affected by a common form of outliers

Combined exercise training reduces blood pressure, arterial stiffness, and insulin resistance in obese prehypertensive adolescent girls

Childhood obesity is strongly linked to pathological processes for cardiovascular diseases in later adulthood. Obese adolescent girls with high blood pressure (BP) are reported to have increased arterial stiffness, which is associated with the development of hypertension and atherosclerosis. The present study sought to examine the impact of combined resistance and aerobic exercise (CRAE) training on BP, brachial-ankle pulse wave velocity (baPWV), insulin resistance (IR), and body composition in obese prehypertensive girls. Forty girls (age, 15 ± 1 years; systolic BP, 132 ± 2 mmHg, diastolic BP, 80 ± 5 mmHg) were randomly assigned to either a combined exercise (EX, n = 20) or no exercise group (CON, n = 20). The EX group performed CRAE for 12 weeks, 3 times per week. BP, baPWV, blood nitrite/nitrate, endothelin-1 (ET-1), homeostasis model assessment for insulin resistance (HOMA-IR), and body composition were measured before and after the exercise intervention. BP (∆-7.3 ± 2.67 mmHg), baPWV (∆-1.23 ± 0.49 m/s), ET-1 (∆-14.35 ± 1.76 μmol/mL), nitrite/nitrate (∆0.5 ± 0.09 μM), HOMA-IR (∆-1.4 ± 0.07), percent body fat (∆-1.35 ± 0.9%), and waist circumference were significantly improved (P \u3c 0.05) in the EX group after 12 weeks of training versus the CON group. These findings indicate that 12 weeks of CRAE improves BP, HOMA-IR, and arterial stiffness and reduces central adiposity in obese adolescent girls with prehypertension. Thus, this study provides evidence that CRAE can be a useful therapeutic treatment for high BP, IR, and central adiposity, thereby reducing the likelihood of pathological development for cardiovascular diseases in later adulthood

Combined resistance and aerobic exercise training reduces insulin resistance and central adiposity in adolescent girls who are obese: randomized clinical trial

Introduction Exercise training is recommended for improving health and protecting against the development of metabolic and cardiovascular pathologies. Combined resistance and aerobic exercise training (CRAE) has been shown to provide unique benefits in older adults with cardiovascular diseases. Purpose We sought to determine the beneficial effects of CRAE in adolescent girls who are obese and hyperinsulinemic. Methods Forty adolescent girls who are obese (age 14.7 ± 1 years; BMI 30 ± 2) were randomly assigned to a “no exercise” (CON n = 20) or combined exercise group (EX n = 20). The EX group performed resistance and aerobic exercise for 12 weeks, 5 times per week. Exercise intensity was increased gradually, from 40 to 70% of heart rate reserve (HRR), every 4 weeks. The brachial-ankle pulse wave velocity (BaPWV), blood pressure (BP), heart rate (HR), blood leptin, adiponectin levels, and body composition were measured before and after the 12-week intervention. Results We observed that CRAE effectively reduced the body fat percentage, body weight, and waist circumference in the EX group (p \u3c 0.05). After 12 weeks of training, subjects in the CRAE group maintained appropriate leptin and adiponectin levels and showed positive improvements of blood insulin, glucose, and insulin resistance parameters relative to baseline and to the CON group (p \u3c 0.05). Conclusion CRAE is a useful therapeutic method to alleviate metabolic risk factors in adolescent girls who are obese and hyperinsulinemic

Parental Understanding of Infant Health Information: Health Literacy, Numeracy, and the Parental Health Literacy Activities Test (PHLAT)

To assess parental health literacy and numeracy skills in understanding instructions for caring for young children, and to develop and validate a new parental health literacy scale, the Parental Health Literacy Activities Test (PHLAT)

Specialty pharmacist integration into an outpatient neurology clinic improves pimavanserin access

Introduction: Access to pimavanserin, the only Parkinson disease–related psychosis treatment approved by the FDA, is restricted by insurance requirements, a limited distribution network, and high costs. Following initiation, patients require monitoring for safety and effectiveness. The primary objective of this study was to evaluate impact of specialty pharmacist (SP) integration on time to insurance approval. Additionally, we describe a pharmacist-led monitoring program. Methods: This was a single-center, retrospective study of adults prescribed pimavanserin by the neurology clinic from June 2016 to June 2018. Patients receiving pimavanserin externally or through clinical trials were excluded. Pre- (June 2016 to December 2016) and post-SP integration (January 2017 to June 2018) periods were assessed. Proportional odds logistic regression was performed to test association of approval time with patient characteristics (age, gender, insurance type) postintegration. Interventions were categorized as clinical care, care coordination, management of adverse event, or adherence. Results: We included 94 patients (32 preintegration, 62 postintegration), 80% male (n=75) and 96% white (n=90) with a mean age of 73 years. Median time to approval was 22 days preintegration and 3 days postintegration. Higher rates of approval (81% vs 95%) and initiation (78% vs 94%) were observed postintegration. Proportional odds logistic regression suggested patients with commercial insurance were likely to have longer time to approval compared with patients with Medicare/Medicaid (odds ratio 7.1; 95% confidence interval: 1.9, 26.7; P=.004). Most interventions were clinical (51%, n=47) or care coordination (42%, n=39). Conclusion: Median time to approval decreased postintegration. The SP performed valuable monitoring and interventions