Prescription Medication Use Among Older Adults in the US.

This survey study describes changes in the use of prescription medications in individuals aged 65 years or older from 1999 through March 2020.

Demographic Diversity of Clinical Trials for Therapeutic Drug Products: A Systematic Review of Recently Published Articles, 2017-2022.

The US Food and Drug Administration (FDA) encourages the use of enrollment practices that will lead to clinical trials that reflect the population most likely to use the therapeutic product (drug or biologic), if approved. In doing so, the benefit-risk profile of the product may be assessed more completely and offer patients and their health care providers a better understanding of the drug profile and greater confidence in clinical trial results. The objective of this systematic review was to assess recent literature on the demographic diversity of clinical trial participants, describe the methods used in defining clinical trial diversity, and address knowledge gaps to enhance clinical trial diversity. Our literature search initially yielded 246 articles. After applying our eligibility criteria, we conducted a full-text review and analyzed the contents of the 28 remaining articles in our systematic review. Eleven (39%) of the 28 articles used a reference standard to compare the participation of populations in clinical trials to assess diversity. The majority of the 28 articles reported on adult participants; only 5 included pediatric populations. Most articles found that women and minority populations were underrepresented in clinical trials. Some articles proposed solutions to improve clinical trial diversity; however, several did not comment on clinical trial diversity. Despite a growing emphasis on demographic diversity in research, certain populations continue to be underrepresented in clinical trials. There is a need to standardize the definition of diversity in clinical trials. Future research into effective enrollment approaches and appropriate reference standards could improve demographic diversity.

Quantification of sertraline maternal/fetal ratio and amniotic fluid concentration using a pregnancy physiologically based pharmacokinetic model.

AIMS: Selective serotonin reuptake inhibitors (SSRIs) are indicated for a variety of psychiatric conditions which may require treatment during pregnancy. Knowledge of appropriate SSRI dosages that maintain maternal therapeutic benefit and minimize fetal risk are needed. Assessment of fetal exposure to drugs is challenging since sampling is often limited to a single concentration from the umbilical cord at delivery. Physiologically based pharmacokinetic (PBPK) modelling provides a non-invasive approach to quantify exposure in pregnancy. METHODS: We incorporated sertraline clearances mediated by passive diffusion, placental efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) into our previously published pregnancy PBPK model for sertraline. Simulations were performed for various sertraline doses (25-200 mg) at 40 weeks gestational age to predict the minimum (Cmin ), maximum (Cmax ) and average (Cavg ) sertraline maternal and fetal plasma concentrations and evaluated them against observed maternal and cord concentrations obtained at delivery from five clinical studies. RESULTS: The accuracy of the PBPK predictions as indicated by the average fold error (AFE) value for Cmax , Cmin and Cavg for maternal plasma sertraline concentrations at delivery was 1.7, 1.2 and 1.4, respectively. The AFE for the Cmax , Cmin and Cavg for cord blood sertraline concentration at delivery was 1.2, 1 and 1.1, respectively. The AFE for cord-maternal sertraline concentration ratio at delivery for Cmax , Cmin and Cavg was 0.7, 0.9 and 0.8, respectively. CONCLUSIONS: The PBPK model we developed may serve as a guide for maternal sertraline dose adjustment during pregnancy considering changes in exposures for both mother and fetus.

Heterogeneity in treatment effects across diverse populations.

Differences in patient characteristics, including age, sex, and race influence the safety and effectiveness of drugs, biologic products, and medical devices. Here we provide a summary of the topics discussed during the opening panel at the 2018 Johns Hopkins Center for Excellence in Regulatory Science and Innovation symposium on Assessing and Communicating Heterogeneity of Treatment Effects for Patient Subpopulations: Challenges and Opportunities. The goal of this session was to provide a brief overview of FDA-regulated therapeutics, including drugs, biologics and medical devices, and some of the major sources of heterogeneity of treatment effects (HTE) related to patient demographics, such as age, sex and race. The panel discussed the US Food and Drug Administration's role in reviewing and regulating drugs, devices, and biologic products and the challenges associated with ensuring that diverse patient populations benefit from these therapeutics. Ultimately, ensuring diverse demographic inclusion in clinical trials, and designing basic and clinical research studies to account for the intended patient population's age, sex, race, and genetic factors among other characteristics, will lead to better, safer therapies for diverse patient populations.

Applying the Noninferiority Paradigm to Assess Exposure-Response Similarity and Dose Between Pediatric and Adult Patients.

The use of extrapolation of efficacy in pediatric drug development programs is possible when disease progression and treatment response are similar in adult and pediatric populations. Historically, the exposure-response (E-R) similarity was assessed by visual inspection of 2 E-R curves to support pediatric extrapolation. The aim of this study was to develop a quantitative framework to describe the E-R relationship and the difference in E-R between pediatric and adult patients based on accumulated experience in pediatric drug development programs. Using clinical data for 8 drugs with either a linear or nonlinear E-R relationship, we adapted the methodology used in noninferiority testing to assess the E-R similarity between adult and pediatric patients at the targeted drug exposure. We implemented bootstrap-based and Bayesian-based methodologies to estimate the probability of concluding noninferiority of the E-R relationship. This approach provides objective criteria that can be applied to an assessment of E-R noninferiority in 2 populations to support extrapolation of efficacy in drug development programs from adults to pediatric populations.

Application of physiologically based pharmacokinetic modeling for sertraline dosing recommendations in pregnancy.

Pregnancy is a period of significant change that impacts physiological and metabolic status leading to alterations in the disposition of drugs. Uncertainty in drug dosing in pregnancy can lead to suboptimal therapy, which can contribute to disease exacerbation. A few studies show there are increased dosing requirements for antidepressants in late pregnancy; however, the quantitative data to guide dose adjustments are sparse. We aimed to develop a physiologically based pharmacokinetic (PBPK) model that allows gestational-age dependent prediction of sertraline dosing in pregnancy. A minimal physiological model with defined gut, liver, plasma, and lumped placental-fetal compartments was constructed using the ordinary differential equation solver package, 'mrgsolve', in R. We extracted data from the literature to parameterize the model, including sertraline physicochemical properties, in vitro metabolism studies, disposition in nonpregnant women, and physiological changes during pregnancy. The model predicted the pharmacokinetic parameters from a clinical study with eight subjects for the second trimester and six subjects for the third trimester. Based on the model, gestational-dependent changes in physiology and metabolism account for increased clearance of sertraline (up to 143% at 40 weeks gestational age), potentially leading to under-dosing of pregnant women when nonpregnancy doses are used. The PBPK model was converted to a prototype web-based interactive dosing tool to demonstrate how the output of a PBPK model may translate into optimal sertraline dosing in pregnancy. Quantitative prediction of drug exposure using PBPK modeling in pregnancy will support clinically appropriate dosing and increase the therapeutic benefit for pregnant women.

Utilizing shared internal control arms and historical information in small-sized platform clinical trials.

Recruitment of patients in concurrent control arms can be very challenging for clinical trials for pediatric and rare diseases. Innovative approaches, such as platform trial designs, including shared internal control arm(s), can potentially reduce the needed sample size, improving the efficiency and speed of the drug development program. Furthermore, historical borrowing, which involves leveraging information from control arms in previous relevant clinical trials, may further enhance a clinical trial's efficiency. In this paper, we discuss platform trials highlighting their advantages and limitations. We then compare various strategies that borrow historical data or information, such as pooling data from different studies, analyzing data from studies separately, test-then-pool, dynamic pooling, and Bayesian hierarchical modeling, which focuses on the meta-analytic-predictive (MAP) prior. We further propose a procedure to illustrate the feasibility of utilizing historical controls under a platform setting and describe the statistical performance of our method via simulations.

Assessing CYP2C19 Ontogeny in Neonates and Infants Using Physiologically Based Pharmacokinetic Models: Impact of Enzyme Maturation Versus Inhibition.

The objective of this study was to develop pediatric physiologically based pharmacokinetic (PBPK) models for pantoprazole and esomeprazole. Pediatric PBPK models were developed by Simcyp version 15 by incorporating cytochrome P450 (CYP)2C19 maturation and auto-inhibition. The predicted-to-observed pantoprazole clearance (CL) ratio ranged from 0.96-1.35 in children 1-17 years of age and 0.43-0.70 in term infants. The predicted-to-observed esomeprazole CL ratio ranged from 1.08-1.50 for children 6-17 years of age, and 0.15-0.33 for infants. The prediction was markedly improved by assuming no auto-inhibition of esomeprazole in infants in the PBPK model. Our results suggested that the CYP2C19 auto-inhibition model was appropriate for esomeprazole in adults and older children but could not be directly extended to infants. A better understanding of the complex interplay of enzyme maturation, inhibition, and compensatory mechanisms for CYP2C19 is necessary for PBPK modeling in infants.

Comparison of exosomal microRNAs secreted by 786-O clear cell renal carcinoma cells and HK-2 proximal tubule-derived cells in culture identifies microRNA-205 as a potential biomarker of clear cell renal carcinoma.

Previous reports have indicated that the abundance of specific microRNAs (miRNA) contained within the exosome/microvesicle compartment of patient biofluids may be useful in diagnosing specific types of cancer. In the present study, the 786-O cell line, which is derived from a clear cell renal cell carcinoma (ccRCC), was used as an in vitro ccRCC tumor model and the human renal proximal tubule cell line HK-2 was used as its normal renal tissue control to investigate the similarities of exosomal content of selected ccRCC miRNA biomarkers in the supernatant with the content of those markers in the cells themselves. A PCR array identified miRNA biomarkers of solid RCC tumors (miR-210, MiR-34a, miR-155-5p and miR-150-5p) that were increased by 2-8 fold in 786-O exosomes compared with the control. These were subsequently chosen for further investigation using TaqMan RT-qPCR in addition to miR-15a and miR-205, which were selected based on prior interest as RCC biomarkers. MiR-15a, -34a, -210 and -155 levels were significantly lower in exosomes when compared with that in whole cells but did not differ between the HK-2 and 786-O cells in either the cytoplasmic, exosome or exosome-free supernatant fractions. By contrast, cytoplasmic miR-150 and miR-205 exhibited significant differences in concentration between the two cell lines. In addition, the cytoplasmic content of miR-150 and miR-205 was mirrored in the exosomal content of these miRNAs. Furthermore, the difference in exosomal miR-205 content was statistically significant. The present study indicated that measurements of the exosomal content of miR-205 and possibly miR-150, but not those of the other examined miRNAs, are proportional to their respective contents in the cells that secreted them. These findings suggest that in vitro RCC systems may be useful in identifying miRNAs with sufficiently high levels of exportation into exosomes; and with sufficiently different expression levels between tumor and normal cells to serve as ccRCC biomarkers in vivo.

Quantitative drug benefit-risk assessment: utility of modeling and simulation to optimize drug safety in older adults.

BACKGROUND: More than 50 % of individuals affected by adverse drug events (ADEs) are older adults. Establishing a drug dosing regimen that balances benefit and risk, and minimizes ADEs in older populations can be challenging. OBJECTIVE: The aim of this study is to evaluate the use of modeling, simulation, and risk-benefit acceptability methods to establish a drug dosing regimen that balances benefit and risk. METHODS: The study population comprised nondiabetic patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) ≥50 years old, who had been on oral olanzapine for ≥2 weeks. We used mixed-effects modeling based on a preexisting pharmacokinetic model to derive clearance estimates, which were then used to determine the olanzapine area under the concentration-time curve (AUC). Subsequently, with multivariate regression and Monte Carlo simulation, we estimated the olanzapine dose corresponding to the benefit-risk AUC breakpoint. RESULTS: The study population (n = 34) was predominantly male (82.3%) and white (67.6%), with a mean age of 54.4 years and treatment duration of 361.8 days. The mean AUC was 747.6 ng h/mL (95% CI = 524.5, 970.7) for the benefit group (n = 16) and 754.1 (95% CI = 505.9, 1002.4) for the risk group (n = 15). The benefit-risk AUC breakpoint was 524.5 ng h/mL and the corresponding oral olanzapine dose that optimizes benefit-risk balance was 17.8 mg/d. CONCLUSIONS: Our study introduces a real-world approach for finding the safe drug dosing regimen without extensive exposure of a vulnerable and older population to drugs. Further studies into the use of modeling, simulation, and risk-benefit acceptability methods to enhance geriatric drug safety are needed.

A systematic comparison of cockcroft-gault and modification of diet in renal disease equations for classification of kidney dysfunction and dosage adjustment.

BACKGROUND: The dosing of drugs in patients with kidney dysfunction is often based on the estimates of kidney function. OBJECTIVE: To systematically compare the performance of the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) equations for dosage adjustment. METHODS: We assessed agreement (concordance, kappa statistics [κ,κ(ω)]) between CG and MDRD using a Food and Drug Administration database to evaluate the effect of renal function on the pharmacokinetics of 36 approved drugs. Across the approved drugs, we compared the correlation between these 2 equations for renal drug clearance (Cl(ren)) and area under the concentration-time curve. For 26 approved drugs that require renal dose adjustment, we also compared dosing regimens and expected exposure using these equations. Sensitivity analyses were performed by adjusting the MDRD estimates for individualized body surface area and/or range of serum creatinine assay calibration errors. RESULTS: In the pharmacokinetic database with 973 subjects (age 18-95 years, weight 35-153 kg, female 33%), we found that the CG and the MDRD classification of renal function generally agreed (64.2%, κ = 0.54, κ(ω) = 0.73). Among the subjects studied for drugs requiring renal dose adjustment, dosages in 12% were changed to a higher or lower dosing category by the MDRD compared to the CG equation. In particular, using MDRD in place of CG for dosage modification yielded higher dosing recommendations for subjects with a combination of age >80 years, weight <55 kg, and serum creatinine >0.7 and ≤1.5 mg/dL; the coefficient of determination was also higher by CG than MDRD in trials that enrolled these or similar patients. CONCLUSIONS: For patients with advanced age, low weight, and modestly elevated serum creatinine, further work is needed before the MDRD equations can replace the CG equation for dose adjustment in the labeling.

The influence of body size descriptors on the estimation of kidney function in normal weight, overweight, obese, and morbidly obese adults.

BACKGROUND: Dosing adjustments for patients with impaired kidney function are often based on estimated creatinine clearance (eCrCl) because measuring kidney function is not always possible for dose adjustment. However, there is no consensus on the body size descriptor that should be used in the estimation equations. OBJECTIVE: To compare the use of alternative body size descriptors (ABSDs) on the performance of kidney function estimation equations compared with measured CrCl (mCrCl). METHODS: We combined 2 DATA SOURCES: a Food and Drug Administration clinical trial database that includes subjects with body mass index (BMI) less than 40 kg/m(2) and published data from those 40 kg/m(2) or more. The 3 parent equations (Cockcroft-Gault [CG], Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease-Epidemiology Collaboration [CKDEPI]), and 14 ABSD-modified equations were compared with mCrCl for accuracy, bias, agreement, goodness of fit (R(2)), and prediction error. These equations were also compared across mCrCl and BMI strata. RESULTS: Subjects (n = 590) were aged 19-80 years; 33.9% were female and BMI ranged from 17.2 to 95.6 kg/m(2). Compared with mCrCl, the use of total weight in the CG equation yielded low accuracy (12.5%) and significant bias (-107 mL/min) in the morbidly obese group. In contrast, the use of lean body weights (BMI ≥40 kg/m(2)) and total ± adjusted weights (BMI <40 kg/m(2)) with the CG equation yielded higher accuracy, greater than or equal to 60.7% across all BMI strata, and was unbiased. Transforming the MDRD or CKDEPI equations with body surface area improved accuracy only at mCrCl of 30-80 mL/min and increased the overall prediction error. CONCLUSIONS: No kidney function equation was consistently accurate and unbiased across weight, mCrCl, and estimate ranges. The accuracy and overestimation bias of the CG equation in obese subjects was improved through the selective use of total, adjusted, and lean body weight by BMI strata.

A pharmacoepidemiologic study of community-dwelling, disabled older women: Factors associated with medication use.

BACKGROUND: Although disabled older adults may be among the subpopulation of adults with the highest risk for adverse drug events (ADEs), reliable data on their use of medications are limited. OBJECTIVES: The aims of this study were to describe the extent and patterns of medication use in community-dwelling, disabled older women, and to identify factors associated with medication use in this population. METHODS: Cross-sectional analyses of baseline data on medication use from the Women's Health and Aging Study I (WHAS I) were performed. WHAS I was an observational study of 1002 community-dwelling women aged >or=65 years who self-reported difficulty in at least 2 of 4 domains of physical functioning (ie, upper-extremity functions, mobility, self-care, and higher functioning tasks needed for independent living in the community). After descriptive analyses of their prescription and over-the-counter (OTC) drugs, associations between participants' characteristics and medication utilization were determined, using generalized linear models. RESULTS: Of the 975 participants, 580 (59.5%) used >or=5 medications and 115 (11.8%) used >or=10 medications (prescriptions and OTCs). The mean number of medications used was 3.9 for prescription drugs and 1.9 for OTC drugs. Cardiovascular drugs and analgesics were the most frequently used prescription and OTC drugs, respectively. Participants with complete outcome and covariate data (n = 803) were included in the multivariate analyses. Cancer was associated with a 13% increase in total medication use (95% CI, 1.00-1.27). Multimorbidity (1.08; 95% CI, 1.02-1.15), frailty (1.13; 95% CI, 1.02-1.26), high Mini-Mental State Examination score (1.03; 95% CI, 1.01-1.05), congestive heart failure (CHF) (1.39; 95% CI, 1.23-1.58), angina (1.27; 95% CI, 1.12-1.44), chronic obstructive pulmonary disease (COPD) (1.20; 95% CI, 1.05-1.37), diabetes mellitus (DM) (1.24; 95% CI, 1.07-1.43), difficulty with shopping for personal items such as medicines and toiletries (1.20; 95% CI, 1.06-1.35), and possession of health insurance (1.21; 95% CI, 1.04-1.40) or a prescription plan (1.16; 95% CI, 1.05-1.29) were independently associated with increased use of prescription drugs. A diagnosis of osteoarthritis of the hands (1.29; 95% CI, 1.121.49) and having a spouse (1.19; 95% CI, 1.01-1.40) were associated with increased use of OTC drugs. Participants with DM (0.78; 95% CI, 0.65-0.94), African Americans (0.70; 95% CI, 0.60-0.82), and those who had difficulty shopping (0.85; 95% CI, 0.72-0.99) used fewer OTCs than did participants without these characteristics. CONCLUSIONS: Most of the disabled older women in this study took >=5 medications at baseline, potentially putting them at high risk for ADEs. Those with multimorbidity, frailty, CHF, angina, DM, COPD, cancer, and difficulty with instrumental activities of daily living are target subpopulations for polypharmacy intervention.

Mechanistic contribution of carnitine deficiency to geriatric frailty.

Frailty is a geriatric syndrome characterized by muscle weakness, sarcopenia, and fatigue, and is associated with several adverse health outcomes, including disability. Design of therapeutic interventions for geriatric frailty has been challenging and may be because of inadequate understanding of its biological underpinnings. Carnitine is important for energy production in skeletal muscles and there seems to be a negative correlation between advancing age and muscle carnitine levels. Carnitine deficiency may therefore contribute to geriatric frailty. Age-associated carnitine deficiency from a variety of etiologies, including organic cation transporter (OCTN2) mutation and carnitine palmitoyltransferase II (CPT) deficiency, may potentially explain the relationship between carnitine-associated mitochondrial dysfunction and geriatric frailty. Development of therapeutic agents capable of prevention or reversal of carnitine deficiency in older adults may minimize the occurrence of frailty in geriatric populations.

Will corticosteroids and other anti-inflammatory agents be effective for diarrhea-predominant irritable bowel syndrome?

Irritable bowel syndrome (IBS) is one of several functional gastrointestinal disorders commonly encountered in both the clinical setting and the general population. The biopsychosocial model is currently believed to be a more complete explanatory mechanism of IBS symptom genesis and propagation. Gut inflammation and immune activation is one of the biological mechanisms for which evidence is emerging. Experimental parasitic infection of mice bowel resulted in elevated substance P levels and increased expression of cyclooxygenase 2 (COX 2) enzyme, prostaglandin E2, IL-4, IL-5, and IL-13. In IBS patients, increased cellularity and proximity of the inflammatory or immune cells to the nerve trunks of the bowel, elevated interleukin-1beta mRNA expression in mucosal biopsies, and increased inducible nitric oxide synthase and nitrotyrosine elaboration (indicative of lymphocyte activation) were observed. Corticosteroids given after the elimination of an experimentally applied parasite from the bowel of mice resulted in the reversal of persistent gut muscle dysfunction. Selective COX-2 inhibitors attenuated the increased bowel smooth muscle contractility resulting from parasite infection of mice gut. In humans, it has been observed that the relative risk of developing IBS in asthma patients was reduced by 60% by the use of oral steroids. Despite such preclinical and human evidence for the role of inflammation and immune activation in IBS, the efficacy of anti-inflammatory and immunomodulatory agents has not been adequately investigated. Budesonide, a corticosteroid with a high mucosal activity and a low bioavailability, is an anti-inflammatory agent that may be worth investigating for its utility in diarrhea-predominant IBS.

The pharmacogenomics of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder mostly affecting geriatric patients worldwide. The high emotional and economic impact of AD on patients, families, and the society has made AD one of the paramount geriatric syndromes. Efforts to find disease-modifying therapy have not yet been rewarding. Despite our increasing appreciation of the role of genetics in AD pathogenesis, pharmacogenomic approaches to uncover drug targets have not been extensively explored. The current knowledge of the genetics of both familial and non-familial (sporadic) AD, and the emerging data on the effect of Apolipoprotein E (ApoE) alleles on the response to AD therapeutic agents, is evidence that the potential utility of pharmacogenomics may not be limited to the familial AD (FAD) but provide answers for AD as a whole. The apparent inability of presently available drugs to alter the course of AD could be a signal that it is time to change the way we think about AD therapeutics.