Inclusion of Subjects who are Obese in Drug Development: Current Status and Opportunities.

The prevalence of obesity has grown tremendously in recent years and this population has an increased risk of disease comorbidities. The presence of disease comorbidities requires treatment interventions and proper dosing guidelines. However, drug development programs often do not have adequate representation of individuals who are obese in clinical trials, leaving gaps in the understanding of treatment response leading to a lack of adequate individualization options. Based on a recent survey of approved drug product package inserts, very few approved products included specific dosing based on obesity, in both adults and pediatrics. Reasons for the limited information on patients who are obese may include the under-reporting of information regarding such patients and a lack of clinical trial diversity in enrolling patient groups in whom obesity or obesity-related comorbidities are more prevalent. An inadvertent impact of the practice of exclusion of subsets of patients with some comorbidities in clinical trials may play a role in the reduced enrollment of individuals who are obese. Recently, regulatory authorities have taken specific initiatives to promote clinical trial diversity, including engaging with stakeholders and publishing regulatory guidance. These guidance documents highlight the need to enroll diverse clinical trial populations and provide recommendations on concepts related to drug development for obese populations. Such efforts will help to address the gap in information regarding drug response and dosing in patients who are obese.

Need for Representation of Pediatric Patients with Obesity in Clinical Trials.

Clinical trials are an integral aspect of drug development. Tremendous progress has been made in ensuring drug products are effective and safe for use in the intended pediatric population, but there remains a paucity of information to guide drug dosages in pediatric patients with obesity. This is concerning because obesity may influence the disposition of drug products. When pediatric patients with obesity are not enrolled in clinical trials, dosing options for use in this subpopulation may be suboptimal. Reliance on physiological-based dosing strategies that are not informed by evaluation of the pharmacokinetics of the drug product could lead to under- or over-dosing with ensuing therapeutic failure or toxicity consequences. Thus, representation of pediatric patients with obesity in clinical trials is crucial to understand the benefit-risk profile of drug products in this subpopulation. It is important to acknowledge that this is a challenging endeavor, but not one that is insurmountable. Collective efforts from multiple stakeholders including drug developers and regulators to enhance diversity in clinical trials can help fill critical gaps in knowledge related to the influence of obesity on drug disposition.

Predicting Food Effects on Oral Extended-Release Drug Products: A Retrospective Evaluation.

Theoretically, the risk of food effects for extended-release (ER) products compared to IR products may be less because: (1) postprandial physiological changes are usually transient and last for 2-3 h only; and (2) the percentage of drug release from an ER product within the first 2-3 h post dose is usually small under both fasted and fed states. The major postprandial physiological changes that can affect oral absorption of ER drugs are delayed gastric emptying and prolonged intestinal transit. Oral absorption of ER drugs under fasted state mainly occurs in large intestine (colon and rectum) while the absorption of ER drugs under fed state occurs in both small and large intestines. We hypothesized that food effects for ER products are mainly caused by intestinal region-dependent absorption and food intake is more likely to increase rather than decrease the exposure of ER products due to a longer transit time and improved absorption in small intestine. For drugs with good absorption from large intestine, food effects on the area under the curve (AUC) of ER products are usually not expected. Our survey of oral drugs approved by the US FDA between 1998-2021 identified 136 oral ER drug products. Among the 136 ER drug products, 31, 6 and 99 products exhibited increased, decreased, and unchanged AUC under fed conditions, respectively. In general, when an ER product exhibits a fasted bioavailability (BA) relative to its corresponding immediate-release (IR) product between 80-125%, regardless the solubility or permeability of drug substances, substantial food effects on the AUC of ER product are generally not expected. If the fasted relative BA data are not available, a high in vitro permeability (i.e., Caco-2 or MDCK cell permeability comparable or higher than that of metoprolol) may inform no food effect on the AUC of an ER product of high-solubility (BCS class I and III) drug.

Leveraging Clinical Pharmacology Data to Assess Biosimilarity and Interchangeability of Insulin Products.

There is over a hundred years of clinical experience with insulin for the treatment of diabetes. The US Food and Drug Administration (FDA) approved the first insulin biosimilar interchangeable product in 2021 for improving glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Several recombinant insulin products are available in the United States, including the recently approved biosimilar insulins. The approval of the biosimilar insulin products was based on comparative analytical characterizations and comparative pharmacokinetic (PK) and pharmacodynamic (PD) data. The primary objective of this review is to discuss the scientific considerations in the demonstration of biosimilarity of a proposed insulin biosimilar to a reference product and the role of clinical pharmacology studies in the determination of biosimilarity and interchangeability. Euglycemic clamp studies are considered a "gold standard" for insulin PK and PD characterization and have been widely used to determine the time-action profiles of rapid-acting, intermediate-acting, and long-acting insulin products. Clinical pharmacology aspects of study design, including selection of appropriate dose, study population, PK, and PD end points, are presented. Finally, the role of clinical pharmacology studies in the interchangeability assessment of insulin and the regulatory pathways used for insulin and the experience with follow-on insulins and the two recently approved biosimilar insulin products is discussed.

Pediatric Drug Development Studies for Familial Hypercholesterolemia Submitted to the US Food and Drug Administration Between 2007 and 2020.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism that leads to an increased risk of developing atherosclerosis and coronary artery disease. Hypercholesterolemia in pediatric patients is typically due to FH. Treatment of pediatric FH is achieved through lifestyle modifications, lipid-modifying pharmacotherapy, and/or apheresis. The primary objective of this review is to describe the characteristics of clinical trials conducted in pediatric patients with FH with data submitted to the US Food and Drug Administration from 2007 to 2020. Of 10 trials with 8 products in pediatric FH submitted to the Food and Drug Administration, 1 product was studied in both the heterozygous and the homozygous phenotypes, 5 were studied for heterozygous hypercholesterolemia only, and 2 were studied for homozygous familial hypercholesterolemia only. Most of the trials included pediatric patients ≥10 years of age and older. Clinical trial characteristics including the primary efficacy end points between pediatric and adult trials were mostly identical. Many lipid-lowering drugs with novel mechanisms of action have been recently approved or are currently being studied. In summary, the drug treatment of hypercholesterolemia in pediatric patients is expanding beyond the use of statins, and now involves multiple mechanisms of action involving cholesterol metabolism. As younger pediatric patients are diagnosed and treated for heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia, optimizing the doses of these agents and safety studies specific to younger pediatric patients will be necessary.

Impact of the US FDA "Biopharmaceutics Classification System" (BCS) Guidance on Global Drug Development.

The FDA guidance on application of the biopharmaceutics classification system (BCS) for waiver of in vivo bioequivalence (BE) studies was issued in August 2000. Since then, this guidance has created worldwide interest among biopharmaceutical scientists in regulatory agencies, academia, and industry toward its implementation and further expansion. This article describes how the review implementation of this guidance was undertaken at the FDA and results of these efforts over last dozen years or so across the new, and the generic, drug domains are provided. Results show that greater than 160 applications were approved, or tentatively approved, based on the BCS approach across multiple therapeutic areas; an additional significant finding was that at least 50% of these approvals were in the central nervous system (CNS) area. These findings indicate a robust utilization of the BCS approach toward reducing unnecessary in vivo BE studies and speeding up availability of high quality pharmaceutical products. The article concludes with a look at the adoption of this framework by regulatory and health policy organizations across the globe, and FDA's current thinking on areas of improvement of this guidance.

Comparing Various In Vitro Prediction Criteria to Assess the Potential of a New Molecular Entity to Inhibit Organic Anion Transporting Polypeptide 1B1.

Evaluation of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an integral part of drug development and is recommended by regulatory agencies. In this study we compared various prediction methods and cutoff criteria based on in vitro inhibition data to assess the potential of a new molecular entity to inhibit OATP1B1 in vivo. In vitro (eg, IC50 , fu,p ) and in vivo (eg, dose, Cmax , change in area under the curve [AUC]) data for 11 substrates and 61 inhibitors for OATP1B1 were obtained from literature and Drugs@FDA, which include 107 clinical (in vivo) DDI studies. Substrate dependency and variability of IC50 values were noted. In addition to the ratio of unbound or total systemic concentration (Imax,u and Imax ) to IC50 , maximum unbound inhibitor concentration at the inlet to the liver (Iu,in,max ) was used for the estimation of "R value" where R = 1 + Iu,in,max /IC50 . Based on our analyses, Imax /Ki ≥ 0.1, R ≥ 1.04, or R ≥ 1.1 seem to be appropriate for reducing the false-negative (FN) predictions. However, as compared with R ≥ 1.1, Imax /Ki ≥ 0.1 and R ≥ 1.04 resulted in higher false positives (FPs) and lower true negatives (TNs). R ≥ 1.1, Imax,u /Ki ≥ 0.02, and R ≥ 1.25 alone, or combined criterion of Imax /Ki ≥ 0.1 and R ≥ 1.25, were reasonable to determine the need to perform clinical DDI studies with OATP1B1 substrates with similar positive and negative predictive values. Possible reasons of FP or FN from different decision criteria should be considered when interpreting prediction results, and the variability in IC50 determination needs to be understood and minimized.

Kidney function changes with aging in adults: comparison between cross-sectional and longitudinal data analyses in renal function assessment.

The study evaluated whether the renal function decline rate per year with age in adults varies based on two primary statistical analyses: cross-section (CS), using one observation per subject, and longitudinal (LT), using multiple observations per subject over time. A total of 16628 records (3946 subjects; age range 30-92 years) of creatinine clearance and relevant demographic data were used. On average, four samples per subject were collected for up to 2364 days (mean: 793 days). A simple linear regression and random coefficient models were selected for CS and LT analyses, respectively. The renal function decline rates per year were 1.33 and 0.95 ml/min/year for CS and LT analyses, respectively, and were slower when the repeated individual measurements were considered. The study confirms that rates are different based on statistical analyses, and that a statistically robust longitudinal model with a proper sampling design provides reliable individual as well as population estimates of the renal function decline rates per year with age in adults. In conclusion, our findings indicated that one should be cautious in interpreting the renal function decline rate with aging information because its estimation was highly dependent on the statistical analyses. From our analyses, a population longitudinal analysis (e.g. random coefficient model) is recommended if individualization is critical, such as a dose adjustment based on renal function during a chronic therapy.

Canagliflozin use in patients with renal impairment-Utility of quantitative clinical pharmacology analyses in dose optimization.

Canagliflozin (INVOKANA™) is approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). Canagliflozin inhibits renal sodium-glucose co-transporter 2 (SGLT2), thereby, reducing reabsorption of filtered glucose and increasing urinary glucose excretion. Given the mechanism of action of SGLT2 inhibitors, we assessed the interplay between renal function, efficacy (HbA1c reduction), and safety (renal adverse reactions). The focus of this article is to highlight the FDA's quantitative clinical pharmacology analyses that were conducted to support the regulatory decision on dosing in patients with renal impairment (RI). The metrics for assessment of efficacy for T2DM drugs is standard; however, there is no standard method for evaluation of renal effects for diabetes drugs. Therefore, several analyses were conducted to assess the impact of canagliflozin on renal function (as measured by eGFR) based on available data. These analyses provided support for approval of canagliflozin in T2DM patients with baseline eGFR ≥ 45 mL/min/1.73 m(2) , highlighting a data-driven approach to dose optimization. The availability of a relatively rich safety dataset (ie, frequent and early measurements of laboratory markers) in the canagliflozin clinical development program enabled adequate assessment of benefit-risk balance in various patient subgroups based on renal function.

Type 2 diabetes in pediatrics and adults: thoughts from a clinical pharmacology perspective.

Type 2 diabetes results when insulin secretion is unable to keep the plasma glucose levels as per acceptable range. This leads to chronic hyperglycemia and its associated microvascular complications such as renal impairment (diabetic nephropathy), retinal abnormalities (diabetic retinopathy), and autonomic, sensory, and motor neuropathies (diabetic neuropathy) and macrovascular disease. Historically, type 2 diabetes is well known as an adult-onset disease; however, lately, the incidence of the disease is reported to be increasing in children. Despite the wealth of information concerning type 2 diabetes in adults, data unique to the pediatric age group regarding the pathophysiology and therapy for type 2 diabetes are limited. For treatment in pediatric type 2 diabetes, metformin and insulin are the only antidiabetic agents approved currently. There are data of use of other oral antidiabetic drugs including glimepiride, rosiglitazone, and glyburide (in combination with metformin) in pediatric patients; however, formal clinical trials to establish the safety and efficacy have not been conducted. This review will compare the clinical pharmacology aspects of the oral type 2 diabetic drugs in pediatric and adult populations in order to determine any differences between the two patient groups.