Shrikant V. Dighe

Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: Increasing the power of bioavailability tests

A new methodology for comparative bioavailability testing is described in which each drug formulation is compared with a stable isotope-labeled variant of the drug that is consumed orally in solution at the same time the tested formulation is ingested. The methodology is used to determine the comparative bioavailabilities of two commercially available brands of imipramine hydrochloride. The power of the new methodology to detect differences between drug formulations, when, in fact, such differences exist, is shown to be superior to that of conventional bioavailability tests.

Bioequivalence of racemic drugs

Although pharmacokinetic and pharmacodynamic differences between the enantiomers of a chiral drug have been known or suspected for many years, racemate drugs have frequently been developed and approved without clinical pharmacologic consideration of their chiral components. In the late 1970s, the technology to isolate, manufacture, and detect pure enantiomers of racemate drugs became generally available. This availability has created new demands on both pharmaceutical firms and regulatory agencies. To prepare for this new technology, the Center for Drug Evaluation and Research at the Food and Drug Administration is formulating a policy statement to guide evaluation of new chiral drugs. At this time, it appears that whatever new policies are developed will not necessarily be applied retroactively to previously approved racemate drugs. Additional policies to guide the development and approval of generic and OTC chiral drugs may be required. In the Office of Generic Drugs in the Center, abbreviated new drug or antibiotic applications are approved on the basis of adequate chemistry, manufacturing, and control procedures and comparative pharmacokinetics (bioequivalence). The generic drug must be a racemate or single enantiomer if the corresponding innovator drug is a race‐mate or single enantiomer respectively. Whether a generic firm will be required to provide bioequivalence information on enantiomers of a racemate is determined on a case‐by‐case basis. Although it might be claimed that a generic drug product should be required only to undergo the same general kind of pharmaceutical evaluation as did the innovator, there may be instances when the approval of a generic drug or antibiotic will require measurement of specific enantiomers of a chiral drug.

Bioequivalence of Topical Dermatological Products

Topical products include a broad array of preparations that are designed to deliver drugs externally to prevent or treat disease and/or to alleviate symptomatology. General categories include ophthalmic and otic preparations, mouth, throat, and anorectal preparations, spermicides and vaginal preparations, irrigating solutions, antiseptics and germicides, and dermatological products.1 This chapter will consider only the last of these categories, topical dermatological products, and will focus on issues concerning the documentation of bioequivalence between topical dermatological formulations containing the same active agent. Documentation of bioequivalence is required by the U.S. Food and Drug Administration (FDA) to approve generic versions of products that have been approved as “new drugs,” that is, for products which have been approved through the submission, review, and approval of data in a New Drug Application (NDA). Bioequivalence is generally not required for over-the-counter products, nor is it necessarily a concern for drugs or products that do not now come under regulatory scrutiny. This chapter will not address bioavailability/bioequivalence of products that are applied topically but are designed to administer drugs into the systemic circulation. Bioavailability/bioequivalence of these transdermal formulations is considered in Chapter 22 of this volume.

Subject Selection and Management in Bioequtvalence Studies

AbstractThis article summarizes the criteria for selection of subjects to participate in bioequivalence studies and the management of these subjects while the study is in progress. Factors such as gender, age, body size, nutritional status, tobacco use, disease states, concurrent drug use, and substance abuse must be considered to identify a suitable subject population in which the product formulations, and not intersubject variations, will be the only significant determinants of bioequivalence. Fluid and food intake, physical activity, and consumption of certain dietary products must be carefully restricted during the study course so that these factors will not influence drug absorption or elimination.

Current Bioavailability and Bioequivalence Requirements and Regulations

AbstractThe 1977 Bioavailability/Bioequivalence Regulations formalized the position and thinking of the Food and Drug Administration with regard to bioavailability of drug products marketed in the United States. The regulations defined the terminology involved, set forth criteria for waiver of in vivo bioavailability studies and listed the drugs that would require bioavailability/bioequivalence studies. The regulations also delineated the general approaches for determining bioavailability, laid down guidelines for conducting in vivo bioavailability studies for conventional dosage forms, combination drug products, and controlled release drug products; set forth criteria and evidence to establish a bioequivalence requirement and described the types of bioequivalence requirements. Over the last few years, a number of presentations have been made by the officials of the Agency to describe and explain the regulations at various forums. I am sure that most of you are quite familiar with the various aspects of t...

Bioavailability and Bioequivalence of Transdermal Drug Delivery Systems

Administration of a drug topically results in direct application of drug at the site of action to cure or ameliorate a dermatological disorder. In contrast, administration of a drug across the skin to the vasculature is designed to achieve systemic effects and is thus, in essence, no different from administration of a drug via oral, inhalation, buccal, nasal, or other routes that lead to entry of drug into the systemic circulation. Although applied topically, drug molecules in a transdermal system undergo percutaneous penetration/absorption and are taken up by the microcirculation in the dermal papillary layer for transport to target tissue via the systemic circulation. Transdermal drug delivery has become increasingly popular over the last several years for many reasons, including (1) availability of sophisticated formulation technology to create reliable, pharmaceutically elegant transdermal drug delivery systems; (2) the development of a biopharma-ceutical, pharmacokinetic, and pharmacodynamic science base to allow definition and study of important safety and efficacy issues that are associated with transdermal drug delivery systems; (3) the opportunities afforded by transdermal drug delivery systems for better patient compliance and more consistent and reliable drug concentrations over protracted dosing periods; (4) a high degree of acceptance by both patients and health care professionals with consequent improved compliance and dosimetry; and (5) development or extension of market exclusivity for off-patent drugs or drugs that are losing patent or exclusivity protection.