Ramana S. Uppoor

Improving Pediatric Dosing Through Pediatric Initiatives: What We Have Learned

OBJECTIVE. The goal was to review the impact of pediatric drug studies, as measured by the improvement in pediatric dosing and other pertinent information captured in the drug labeling. METHODS. We reviewed the pediatric studies for 108 products submitted (July 1998 through October 2005) in response to a Food and Drug Administration written request for pediatric studies, and the subsequent labeling changes. We analyzed the dosing modifications and focused on drug clearance as an important parameter influencing pediatric dosing. RESULTS. The first 108 drugs with new or revised pediatric labeling changes had dosing changes or pharmacokinetic information (n = 23), new safety information (n = 34), information concerning lack of efficacy (n = 19), new pediatric formulations (n = 12), and extended age limits (n = 77). A product might have had ≥1 labeling change. We selected specific examples (n = 16) that illustrate significant differences in pediatric pharmacokinetics. CONCLUSIONS. Critical changes in drug labeling for pediatric patients illustrate that unique pediatric dosing often is necessary, reflecting growth and maturational stages of pediatric patients. These changes provide evidence that pediatric dosing should not be determined by simply applying weight-based calculations to the adult dose. Drug clearance is highly variable in the pediatric population and is not readily predictable on the basis of adult information.

Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications.

The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.

Development and internal validation of an in vitro-in vivo correlation for a hydrophilic metoprolol tartrate extended release tablet formulation

AbstractPurpose. To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a hydrophilic matrix extended release metoprolol tablet. Methods. In vitro dissolution of the metoprolol tablets was examined using the following methods: Apparatus II, pH 1.2 & 6.8 at 50 rpm and Apparatus I, pH 6.8, at 100 and 150 rpm. Seven healthy subjects received three metoprolol formulations (100 mg): slow, moderate, fast releasing and an oral solution (50 mg). Serial blood samples were collected over 48 hours and analyzed by a validated HPLC assay using fluorescence detection. The f2 metric (similarity factor) was used to analyze the dissolution data. Correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted metoprolol concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for Cmax and AUC to determine the validity of the correlation. Results. Apparatus I operated at 150 rpm, and pH of 6.8 was found to be the most discriminating dissolution method. There was a significant linear relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for Cmax and AUC for all formulations of less than 10% was found for all IVIVC models. Conclusions. The relatively low prediction errors for Cmax and AUC observed strongly suggest that the metoprolol IVIVC models are valid. The average percent prediction error of less than 10% indicates that the correlation is predictive and allows the associated dissolution data to be used as a surrogate for bioavailability studies.

Effect of Ethanol on Opioid Drug Permeability Through Caco-2 Cell Monolayers

Several articles have shown that alcohol can alter the pharmacokinetics and bioavailability of drugs through changes in gastric emptying, gastrointestinal motility, drug metabolism and solubility, and hepatic clearance (1–5). Acute and chronic ethanol exposure cause functional and morphological damage to the gastrointestinal mucosal surface through mucosal injury, epithelial membrane integrity, and disruption of the tight junction barrier (6–8). Co-ingestion of alcoholic beverages with certain extended-release drug product formulations may accelerate drug release and affect the rate of its gastrointestinal absorption (9). Also, ethanol may enhance the adverse effects of opioids (10). When Opana® (oxymorphone) tablets were co-ingested with 4–40% ethanol, there were variable effects on the area under the concentration–time curve (AUC) and maximal plasma concentration (Cmax) (11). The increase in Cmax due to ethanol was seen with another extended release oxymorphone product with no effect on AUC (12). Elevated Cmax was seen with 14% and 40% ethanol when taken with oxycodone multiparticulate capsules (13). A minimal effect on overall exposure was seen with a controlled release OROS® hydromorphone formulation with 4–40% ethanol with an increase in Cmax (9). The objective of this project was to determine whether the presence of ethanol alters the in vitro permeability of model opioid drugs. Oxycodone and hydromorphone have moderate intestinal permeabilities with a bioavailability of 60–87% and 62%, respectively, whereas oxymorphone has a low bioavailability of 10% (11,14,15). Atenolol and metoprolol experiments were carried out to evaluate alcohol effects on low and high permeability drugs, respectively (16).

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 FDAs current thinking on areas of improvement of this guidance.

Biowaiver and Biopharmaceutics Classification System

Biowaiver is defined as FDA waiving the requirement for the in vivo bioavailability/bioequivalence studies. This chapter discusses the following biowaivers: (a) For drug products where bioavailability is self-evident e.g., solutions, (b) Biowaivers in situations where one can rely on in vitro methods instead of in vivo for assessing bioavailability, and (c) Biowaivers based on Biopharmaceutics classification system.

Chapter 14 – Bioavailability and Bioequivalence*

Bioavailability (BA) and bioequivalence (BE) studies are essential in oral dosage form development. This chapter provides readers an overview of general concept of BA and BE. Details on typical BA/BE study designs, study conducts, bioassays, and data analyses are discussed, with a primary focus on orally administered drugs. Special topics on BE for narrow therapeutic drugs and highly variable drugs, together with application of partial areas under the curve for BE testing are also presented. In addition, issues related to biowaiver are discussed in details.

Partial Area Under the Curve: An Additional Pharmacokinetic Metric for Bioavailability and Bioequivalence Assessments

To facilitate specific product development, AUCs obtained over time intervals of interest, known as partial AUC, can be used for bioavailability and bioequivalence assessment. Partial AUC, which describes shapes of pharmacokinetic profiles, is most useful in products with complicated release mechanisms where traditional bioequivalence variables such as C max and AUC0–∞ are not sufficient to distinguish performance of products and ensure therapeutic equivalence. In this chapter, the utility of partial AUC in formulations with same release mechanism, formulations with multimodal release mechanisms, and formulations with different release mechanisms are discussed in detail.