Characterization of the iDDPs

A question that may arise about the proposed EbD approach is whether there are in vitro markers or biomarkers available for characterization of iDDPs. Literature information indicates that the in vivo drug delivery pathways may not be well documented for most pharmaceutical products, presumably because of the paucity of methodology for study in this area. Nonetheless, some of the research tools may have been applied for these purposes during drug discovery and development.

One example is the application of in vitro dissolution or release testing for predicting drug release in vivo. In vitro dissolution and release testing has been routinely used to guide drug development as well as predict bioequivalence between products before and after changes in formulation or manufacturing. The key issue is whether these methods adequately emulate critical in vivo release or dissolution processes. As dictated in US regulations, in vitro dissolution or release testing can be used as an indicator for bioequivalence if it is correlated with and predictive of human in vivo bioavailability data (2, 10). Indeed, a major problem with many of the current in vitro dissolution and/or release methods lies in the lack of correlation between in vitro and in vivo data.

Potential factors affecting iDDPs

Several pharmaceutical factors are known to influence the course of drug delivery and release in vivo, which may include formulation, excipient, dosage form, product design, and manufacturing process. In addition, biopharmaceutical considerations ought to be given with respect to the potential effects of certain excipients on drug bioavailability and possible drug/formulation interactions with intrinsic or extrinsic factors. Although most excipients on the market are devoid of pharmacologic action, some common excipients (e.g., sorbitol and polysorbate 80) have been shown to exert unintended influence on iDDPs and in turn, bioavailability and bioequivalence (16). Similarly, the impact of various intrinsic and extrinsic factors on iDDPs and drug absorption may have been underestimated.

The ICH E5 document has provided several good examples of intrinsic and extrinsic factors that may influence pharmacokinetic and pharmacodynamic responses of many drugs (17). As illustrated, important intrinsic factors may include genetic, physiological, and pathological conditions of the patient. On the other hand, relevant extrinsic factors may be related to the environment (e.g., climate, sunlight, and pollution), food intake (e.g., beverage and diet), lifestyle (e.g., smoking and exercise), and concomitant medications.

The potential interplay between pharmaceutical characteristics such as formulation and intrinsic factors such as gender has also been studied and reported in the literature (18). In this case, bioequivalence studies were conducted on two extended-release products containing the same drug substance. Higher plasma concentrations were obtained in females (compared with males) from Product A, yet no gender difference was found for Product B. Investigation with in vitro dissolution testing at various pH values also showed dissimilar dissolution profiles between the two formulations. In the case of Product A, a lower fraction of the drug dissolved at pH 4.5 and a higher fraction dissolved at pH 6.8, possibly reflecting more drugs in the ileum and perhaps in the colon. For Product B, however, most of the drug dissolved at pH 4.5, suggesting a rapid release at the duodenum and jejunum. Literature information revealed that women tend to have longer gastric emptying time and longer intestinal transit time. With all the data collected, therefore, the pharmacokinetic differences observed in this study have been attributed to the potential interaction between formulation and gender, as evidenced by the different drug release profiles from the two formulations and differing GI transit time in men and women.

Apart from intrinsic factors, the impact of extrinsic factors on iDDPs may be exemplified by the market withdrawal of Palladone (hydromorphone HCl extended-release, Purdue Pharma, Cranbury, NJ) capsules in 2005. As a derivative of morphine, hydromorphone is known to be a potent centrally acting analgesic drug. Palladone was withdrawn because this extended-release product consisted of a matrix system that was found to be prone to dose dumping when taken with alcohol. A similar problem occurred with fentanyl transdermal delivery systems. It was suspected that an increased rate and extent of drug permeation through the skin might have occurred after some of the fentanyl patches were exposed to heat.

Overall, the potential interplay between pharmaceutical attributes and intrinsic/extrinsic factors may be investigated during the course of drug development. These interactions may be proactively explored through in vitro, in silico, or in vivo methods that allow for the study of iDDPs before drug absorption.

Conclusion

Theoretical considerations prescribe that bioequivalence may be assessed by focusing comparisons on the in vivo drug delivery profiles (iDDPs) between formulations. The rationale for this approach rests on the premises that absorption process is the key determinant for bioequivalence, given constant clearance within each individual across formulations. Because drug absorption is chiefly controlled by when, where, and how the drug is released from the formulation, it follows that bioequivalence assessment may be made by means of the comparison of iDDPs between products. Similarly, to achieve bioequivalence of advanced pharmaceutical dosage forms or delivery systems, one can first determine the critical characteristics of the reference iDDP and then use this information as the target profile for design and manufacturing of the test product. It is surmised that in vitro markers or biomarkers are available or can be developed to characterize the pivotal stage(s) of an IDDP. In analogy to the QbD paradigm for pharmaceutical development, this equivalence-by-design (EbD) approach can be applied to devise the test product by mapping the target iDDP through the use of in vitro markers or biomarkers. Ultimately, successful design of an equivalent product can be accomplished with a better understanding of all the relevant factors that may have potential impact on the iDDPs of the products in comparison.

Mei-Ling Chen, PhD, is associate director at the Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave., Building 51, Rm. 4108, Silver Spring, MD 20993-0002, tel. 301.796.1658, fax 301.796.9997, meiling.chen@fda.hhs.gov