Retrospective analysis of the biopharmaceutics characteristics of solid oral Modified-Release drug products in approved US FDA NDAs designated as Extended-Release or Delayed-Release formulations.

BACKGROUND: Modified Release (MR) orally administered drugs products [Extended-Release (ER) and Delayed-Release (DR)] differ from Immediate-Release (IR) drug products in their drug release site and/or rate to offer therapeutic advantages. It is important to understand the biopharmaceutics factors that determine how a drug works in the gastrointestinal tract and the various pharmacokinetic properties that determine a drug's rate of absorption and release in the human body. To better understand the biopharmaceutics characteristics of ER and DR drug products, this study retrospectively analyzed submissions approved by the US Food and Drug Administration (FDA), from 2001 to 2021, and their corresponding review documents. This review work is expected to enhance the readers' understanding regarding the biopharmaceutics properties that supported approval of these products' ER claims, as per 21 CFR 320.25(f), and DR claims. METHODS: A comprehensive search was conducted using the FDA's internal New Drug Application (NDA) database for ER and DR oral drug products approved between 2001 and 2021. The search yielded 87 ER applications (23 ER capsules and 64 ER tablets) and 21 DR applications (10 DR capsules, 11 DR tablets) for which electronic records were accessible. These products were analyzed for overall drug product design, dosing frequency compared to the reference (if applicable), degree of fluctuation, dissolution method, and alcohol dose-dumping. RESULTS: Out of 87 total applications for ER drug products that were assessed, 62% of the ER tablets contained a polymer matrix formulation, and hypromellose (HPMC) was used in 50% of these products. 52% of the ER capsules consisted of polymer beads while about half of the DR drug products contained a non-bead formulation with a combination of polymers. The majority of ER drug products were found to have a reduction in dosing frequency and a decrease in the degree of fluctuation when compared to the IR reference product. The 13 ER drug products that exhibited an increase in degree of fluctuation exhibited general and pharmacodynamic benefits, such as reduced dosing frequency and reduced pill burden. The majority of DR formulations were developed to prevent drug degradation in the stomach, followed by to decrease potential stomach irritation, and lastly for localized release in the colon. The majority of ER drug products had 1:1 ratios of dissolution duration compared to dosing frequency (i.e., the majority of ER drug products had a dissolution duration of 24 h and were dosed every 24 h while those with a dissolution duration of 12 h were dosed every 12 h). The majority of ER applications had single-stage dissolution methods while most DR drug products used biphasic dissolution methods. All of the DR dissolution methods incorporated an acid stage of 2 h and a buffer stage with various timeframes. 53% the DR drug products had a ratio of dissolution duration to dosing frequency of 1:4 (e.g. a dissolution duration of 2 h to a dosing frequency of 8 h) or 1:8 (e.g. a dissolution duration of 2 h to a dosing frequency of 16 h). Of the ER tablets and DR drug products, 72% exhibited no alcohol dose-dumping under in vitro testing conditions. ER capsules, however, did not yield similar results-most of which exhibited alcohol induced dose-dumping. Alcohol dose dumping was mitigated by either in vivo studies or warnings on the drug product label. CONCLUSION: The results of this study help the reader understand the design, characteristics, and pharmacological advantages of the ER and DR drug products for patient benefit; as well as the regulations governing the FDA's assessment of ER claims.

Drug Dissolution in Oral Drug Absorption: Workshop Report.

The in-person workshop "Drug Dissolution in Oral Drug Absorption" was held on May 23-24, 2023, in Baltimore, MD, USA. The workshop was organized into lectures and breakout sessions. Three common topics that were re-visited by various lecturers were amorphous solid dispersions (ASDs), dissolution/permeation interplay, and in vitro methods to predict in vivo biopharmaceutics performance and risk. Topics that repeatedly surfaced across breakout sessions were the following: (1) meaning and assessment of "dissolved drug," particularly of poorly water soluble drug in colloidal environments (e.g., fed conditions, ASDs); (2) potential limitations of a test that employs sink conditions for a poorly water soluble drug; (3) non-compendial methods (e.g., two-stage or multi-stage method, dissolution/permeation methods); (4) non-compendial conditions (e.g., apex vessels, non-sink conditions); and (5) potential benefit of having both a quality control method for batch release and a biopredictive/biorelevant method for biowaiver or bridging scenarios. An identified obstacle to non-compendial methods is the uncertainty of global regulatory acceptance of such methods.

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.

Regulatory utility of physiologically-based pharmacokinetic modeling to support alternative bioequivalence approaches and risk assessment: A workshop summary report.

This report summarizes the proceedings for day 2 sessions 1 and 3 of the 2-day public workshop entitled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches," a jointly sponsored workshop by the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG). The aims of this workshop were: (1) to discuss how mechanistic modeling, including physiologically-based pharmacokinetic (PBPK) modeling and simulation, can support product development, and regulatory submissions; (2) to share the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (3) to establish a consensus on best practices for using PBPK modeling for BE assessment to help drive further investment by the generic drug industry into mechanistic modeling and simulation; and (4) to introduce the concept of a Model Master File to improve model-sharing. The theme of day 2 covered PBPK absorption model for oral products as an alternative BE approach and a tool for supporting risk assessment and biowaiver (session 1), oral PBPK for evaluating the impact of food on BE (session 2), successful cases, and challenges for oral PBPK (session 3). This report summarizes the topics of the presentations of day 2 sessions 1 and session 3 from FDA, academia, and pharmaceutical industry, including the current status of oral PBPK, case examples as well as the challenges and opportunities in this area. In addition, panel discussions on the utility of oral PBPK in both new drugs and generic drugs from regulatory and industry perspective are also summarized.

Application of Solubility and Dissolution Profile Comparison for Prediction of Gastric pH-Mediated Drug-Drug Interactions.

The objective of this study was to assess how solubility and dissolution profile comparisons under different pH conditions can be used to predict gastric pH-mediated drug-drug interaction (DDI) potential. We collected information for new molecular entities (NMEs) approved from 2003 to 2019 by the U.S. Food and Drug Administration (FDA) that had dedicated clinical DDI studies with acid-reducing agents (ARAs). Among these, 67 NMEs with solubility under different pHs and dissolution profiles generated in pH 1.2, 4.5, and 6.8 aqueous media were included for analysis. Similarity factor (f2) was used to compare dissolution profiles at different pHs for pH-mediated DDI prediction (e.g., f2<50 predicts positive DDI). Prediction accuracy was calculated based on the outcome comparison between predicted and observed DDIs. Based on dissolution profile comparisons and observed DDI data, weak base drugs (WBDs) (n = 49) showed 72.5% prediction accuracy under the fasted conditions, and 66.7% prediction accuracy under fed conditions. While using solubility and clinical dose for prediction, the prediction accuracy was 80% under fasted conditions and 66.7% under fed conditions, respectively. Comparison of dissolution profiles generated at pH 1.2, 4.5, and 6.8 can be used to predict gastric pH-mediated DDI potential for WBDs. It demonstrated comparable prediction accuracy under both fasted and fed conditions when compared to the prediction using solubility and clinical dose. Furthermore, dissolution profile comparison could add an additional understanding of possible impact of pH change on the release behavior of the drug product. Graphical abstract.

Understanding In Vivo Dissolution of Immediate Release (IR) Solid Oral Drug Products Containing Weak Acid BCS Class 2 (BCS Class 2a) Drugs.

In vivo drug dissolution kinetics of BCS Class 2a IR solid oral drug products remains largely unknown. An understanding to what extent the solubility influences in vivo dissolution is needed to design appropriate in vitro dissolution methods. In this study, nonsteroidal anti-inflammatory drugs (NSAIDs) are used to investigate the in vivo dissolution of BCS Class 2a drugs based on numerical deconvolution analyses. The PK data were obtained from published literature or drug applications submitted to the FDA. It has been hypothesized that the in vivo drug dissolution rate would likely correlate to the solubility of NSAIDs in the media at gastrointestinal pH. Our findings show a short lag time of absorption (Tlag), comparable to the liquid gastric emptying time and independent of the solubility and formulation. In Vivo drug dissolution of NSAIDs was generally rapid and complete within the regular drug residence time in the small intestine while multi-phase absorption was observed in some subjects for all the NSAIDs. The comparisons of in vivo drug dissolution rate, which was characterized by in vivo dissolution half-life (Thalf), indicate that solubility has a minimal impact on in vivo drug dissolution rate for NSAIDs. Gastric emptying regulated by migrating motor complex (MMC) under fasted state most likely governs drug dissolution and absorption of NSAIDs. For BCS Class 2a IR solid oral drug products, large variability of gastric emptying and MMC as well as the strong driving force of intestinal absorption probably outweigh the impact of solubility on drug in vivo dissolution.

Biopharmaceutics Applications of Physiologically Based Pharmacokinetic Absorption Modeling and Simulation in Regulatory Submissions to the U.S. Food and Drug Administration for New Drugs.

Physiologically based pharmacokinetic (PBPK) absorption modeling and simulation is increasingly used as a tool in drug product development, not only in support of clinical pharmacology applications (e.g., drug-drug interaction, dose selection) but also from quality perspective, enhancing drug product understanding. This report provides a summary of the status and the application of PBPK absorption modeling and simulation in new drug application (NDA) submissions to the U.S. Food and Drug Administration to support drug product quality (e.g., clinically relevant dissolution specifications, active pharmaceutical ingredient (API) particle size distribution specifications). During the 10 years from 2008 to 2018, a total of 24 NDA submissions included the use of PBPK absorption modeling and simulations for biopharmaceutics-related assessment. In these submissions, PBPK absorption modeling and simulation served as an impactful tool in establishing the relationship of critical quality attributes (CQAs) including formulation variables, specifically in vitro dissolution, to the in vivo performance. This article also summarizes common practices in PBPK approaches and proposes future directions for the use of PBPK absorption modeling and simulation in drug product quality assessment.Graphical abstract.

Best Practices in the Development and Validation of Physiologically Based Biopharmaceutics Modeling. A Workshop Summary Report.

This workshop report summarizes the proceedings of Day 2 of a three-day workshop on "Current State and Future Expectations of Translational Modeling Strategies toSupportDrug Product Development, Manufacturing Changes and Controls". From a drug product quality perspective, physiologically based biopharmaceutics modeling (PBBM) is a tool to link variations in the drug product quality attributes to in vivo outcomes enabling the establishment of clinically relevant drug product specifications (CRDPS). Day 2 of the workshop focused on best practices in developing, verifying and validating PBBM. This manuscript gives an overview of podium presentations and summarizes breakout (BO) session discussions related to (1) challenges and opportunities for using PBBM to assess the clinical impact of formulation and manufacturing changes on the in vivo performance of a drug product, (2) best practices to account for parameter uncertainty and variability during model development, (3) best practices in the development, verification and validation of PBBM and (4) opportunities and knowledge gaps related to leveraging PBBM for virtual bioequivalence simulations.

Applications of Physiologically Based Biopharmaceutics Modeling (PBBM) to Support Drug Product Quality: A Workshop Summary Report.

This report summarizes the proceedings for Day 3 of the workshop titled "Current State and Future Expectations of Translational Modeling Strategies toSupportDrug Product Development, Manufacturing Changes and Controls". From a drug product quality perspective, patient-centric product development necessitates the development of clinically relevant drug product specifications (CRDPS). In this regard, Physiologically Based Biopharmaceutics modeling (PBBM) is a viable tool to establish links between in-vitro to in-vivo data, and support with establishing CRDPS. The theme of day 3 was practical applications of PBBM to support drug product quality. In this manuscript, case studies from US FDA, EMA and pharmaceutical industry on applications of PBBM in drug product quality are summarized which include 1) regulatory agency's perspectives on establishing the safe space and achieving study waivers, 2) model-informed risk assessment on the effects of acid reducing agents, bridging of dissolution methods, food effect, and formulation selection, and 3) understanding clinical formulation performance. Breakout session discussions focused on four topics - 1) terminologies related to physiologically based modeling in support of drug product quality, 2) regulatory harmonization on evidentiary standards, 3) CRDPS approaches and 4) bridging between biorelevant and quality control (QC) dissolution methods.

Using a Physiologically Based Pharmacokinetic Absorption Model to Establish Dissolution Bioequivalence Safe Space for Oseltamivir in Adult and Pediatric Populations.

Bioequivalence (BE) studies support the approval and clinical use of both new drug and generic drug products. Virtual BE studies have been conducted using physiologically based pharmacokinetic absorption models (PBPK AMs) to aid the evaluations of generic drug products. The aim of the current study is to determine the dissolution boundary for maintaining BE between the test and reference oseltamivir phosphate (OP) drug products using the PBPK AM-based virtual BE studies in adults and pediatrics. The adult PBPK AM for OP and its metabolite oseltamivir carboxylate (OC) are developed and verified/validated using intravenous and oral data from multiple generic OP products. The pediatric PBPK AM is extrapolated from the adult PBPK AM. The virtual BE analysis is conducted using simulated PK profiles from the reference products and the generic products with theoretical dissolution profiles as inputs. Results indicate that the generic products with 10% slower dissolution profile than the pivotal reference bio-batch could still maintain BE to the reference in adults. In contrast, a stringent trend of dissolution boundary is observed for pediatrics (6% slower for adolescents, 4% slower for 0-2-month neonates) to maintain BE. This study addresses the important applications of PBPK AM in evaluating BE in different age populations, mitigating risk of formulation/batch changes, and providing a quantitative basis for setting clinically relevant dissolution specifications for OP and OC in both adults and pediatrics.

Dissolution Testing in Drug Product Development: Workshop Summary Report.

This publication summarizes the proceedings and key outcomes of the first day ("Day 1") of the 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." The overall aims of the workshop were to foster a productive dialog between industry and regulatory agencies and to discuss current strategies toward the development and implementation of clinically relevant dissolution specifications as an integral part of enhanced drug product understanding and effective drug product life-cycle management. The Day 1 podium presentations covered existing challenges and concerns for implementing highly valuable, yet often unique and novel experimental dissolution setups as quality control tools. In addition, several podium presentations highlighted opportunities to replace conventional dissolution testing with surrogate test methods to enable robust drug product and process understanding within the context of quality by design (QbD), new manufacturing technologies, and real-time release testing (RTRT). The topics covered on Day 1 laid the foundation for subsequent discussions which focused on the challenges related to establishing an in vitro-in vivo link and approaches for establishing clinically relevant drug product specifications which are becoming an expectation in regulatory submissions. Clarification of dissolution-related terminology used inconsistently among the scientific community, and the purpose of various testing approaches were key discussion topics of the Day 1 breakout sessions. The outcome of these discussions along with creative ways to overcome challenges related to bridging "exploratory dissolution approaches" with methods suitable for end-product control testing are captured within this report.

Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report.

This publication summarizes the proceedings of day 3 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.

Making Dreams, Not Babies: The Power of Hope in a Teen Family Planning Clinic.

Teenage pregnancy is a signifi cant social issue in the United States, resulting in increased levels of poverty. Most public health family planning efforts have traditionally focused on teaching teens the how-to of contraception, with little focus on teaching the why-to. During my time as a nurse practitioner in a public health department family planning clinic, I developed a method to open discussions with patients about the possibilities of a future that includes delayed childbearing. My experience with this strategy taught me that hope may indeed be the most powerful contraceptive of all.

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.

The Effect of Chlorhexidine Bathing on Rates of Nosocomial Infections Among the Critically Ill Population: An Analysis of Current Clinical Research and Recommendations for Practice.

BACKGROUND: This literature review examined the current research of evidence-based standards to evaluate the effectiveness of daily bathing with 2% chlorhexidine gluconate (CHG; manufactured by Sage Products Inc) compared with traditional non-antimicrobial bathing on reducing the incidence of nosocomial infections in the critically ill population. OBJECTIVE/AIM: The objective of this article is 3-fold: first, to provide a background on the increased susceptibility to pathogens that have become endemic in many intensive care units; second, to challenge health care providers to question current practice and consider additional ways to ensure safety and better outcomes in the critically ill population; and third, to provide health care providers with clinical evidence to avoid infection control failures. METHOD: To determine whether published standards for daily patient bathing exist, a search was conducted of bibliographic databases for articles published within the last 5 years (2010-2015). Ultimately, 3 large multicenter cluster randomized controlled studies were chosen to compare the outcomes of daily bathing with 2% CHG cloths with those of daily bathing with non-antimicrobial cloths. RESULTS: The side-by-side comparison of the studies revealed similar outcomes, but with variations in study design. Climo et al (2013) and Milestone et al (2013) recommended the implementation of daily bathing with 2% CHG washcloths as a strategy to decrease nosocomial infections in the critically ill population. Huang et al (2013) recommended universal decolonization as the most effective method to decrease nosocomial infections. DISCUSSION: The analysis of the 3 primary studies revealed similar findings that support the recommendation for the implementation of daily bathing with 2% CHG in the critically ill population. Further research will inform clinicians on the susceptibility of bacteria to CHG and the probability of creating microbial resistance.

Common deficiencies with bioequivalence submissions in abbreviated new drug applications assessed by FDA.

PURPOSE: A generic product must meet the standards established by the Food and Drug Administration (FDA) to be approved for marketing in the USA. FDA approves a generic product for marketing if it is proved to be therapeutically equivalent to the reference product. Bioequivalence (BE) between a proposed generic product and its corresponding reference product is one of the major components of therapeutic equivalence. These approvals may be delayed if the BE portion of the submission is determined to be deficient. Many of these BE deficiencies recur commonly and can be avoided. METHOD: We conducted a survey of the BE submissions to abbreviated new drug applications (ANDAs) over years 2001 to 2008 to identify the most commonly occurring BE deficiencies. RESULTS: Recurring deficiencies are found in a majority of the ANDAs reviewed by FDA's Division of Bioequivalence. The most common deficiencies were the two deficiencies related to dissolution (method and specifications) found in 23.3% of the applications and analytical method validation and/or report found in 16.5% of the applications. The approval of generic drugs would be greatly accelerated if these deficiencies could be avoided.

Using the "write" resources: nursing student evaluation of an interdisciplinary collaboration using a professional writing assignment.

Nursing students need the necessary resources to successfully complete a professional paper writing assignment. The purpose of this article is to describe resource support and evaluation strategies used in a professional paper writing assignment in a baccalaureate nursing program. The impetus for the study is to address the need for nursing faculty to move students toward writing proficiency while improving their information management skills. Students need resources to successfully complete professional papers due to the need for mining relevant professional sources, assistance with editing, and refinement of paper gained through peer feedback. Methods include evaluation of the interdisciplinary resource collaboration with campus librarians (information literacy), campus writing center tutorial oversight, and peer reviewer support and feedback. Student evaluation of the teaching strategy found the resources helpful for completion of the writing assignment and the collaborative learning with campus colleagues and writing experts beneficial.

Headed in the "write" direction: nursing student publication and health promotion in the community.

Effective writing is vital to nursing practice. As educators, we sought to incorporate a meaningful writing assignment as part of a junior-level professional development course. We used innovative methods that support the missions of higher education in general and nursing education in particular while promoting healthful living and establishing the community-as-client. In addition to fostering health education and health promotion, this writing assignment served to enhance students' writing skills and provide them with an opportunity to have their work published. The venue for publication was The Auburn Villager, a weekly local newspaper with a circulation of 6,000 within the local community in East Alabama. The writing assignment was a tremendous success on many levels. Foremost among the positive outcomes was student pride in experiencing publication of their creative work. In addition, students reported a feeling of satisfaction that the assignment had both practical and educational utility.

Making dreams, not babies: the power of hope in a teen family planning clinic.

Teenage pregnancy is a significant social issue in the United States, resulting in increased levels of poverty. Most public health family planning efforts have traditionally focused on teaching teens the how-to of contraception, with little focus on teaching the why-to. During my time as a nurse practitioner in a public health department family planning clinic, I developed a method to open discussions with patients about the possibilities of a future that includes delayed childbearing. My experience with this strategy taught me that hope may indeed be the most powerful contraceptive of all.

Nitric oxide cell signaling: S-nitrosation of Ras superfamily GTPases.

The Ras superfamily of small GTPases cycle between inactive GDP-bound and active GTP-bound states to modulate a diverse array of processes involved in cellular growth control. While the basic mechanisms by which GTPase regulatory proteins regulate GTPase substrates have been revealed through numerous studies, detailed studies into the mechanism(s) of free radical-mediated GTPase regulation have only more recently been tackled. This article reviews the mechanism of free radical-mediated GTPase regulation and shows nitric oxide can serve as important regulator of small GTPase proteins (i.e. Ras and RhoA) through protein modifications such as S-nitrosation.