April 15, 2010 (Vol. 30, No. 8)

14C Dosing Combined with Accelerator Mass Spec Is Being Used to Replace Traditional Methodology

When the majority of new drug candidates are developed for oral or some other extravascular dose route, it is easy to understand why pharmaceutical companies may seek to avoid or delay the generation of intravenous pharmacokinetic data during early development.

There is no clear regulatory requirement that specifies it as necessary, the exception is Australia where the authorities do request to see data on absolute bioavailability. Although the data generated is extremely useful in understanding drug performance, the costs and time involved in developing a suitable formulation, generating the safety information, and conducting the clinical studies are a heavy burden to overcome unless there is a strong rationale indicated from pharmacokinetic and bioavailability data generated in early clinical studies.

Quotient Bioresearch’s ivMicrotracer™ allows companies to make informed decisions regarding the development of candidate drugs. The data generated can identify issues earlier in development, enabling project activities to be prioritized appropriately, which can inform the design of subsequent clinical studies.

ivMicrotracer studies can be conducted without the need for additional preclinical testing to support IV dosing. With this approach, an intravenous dose of 14C radiolabelled drug is concomitantly administered with the extravascular dose.

In recent years, generating intravenous pharmacokinetic and absolute bioavailability data for orally administered drugs has been made significantly simpler with the advent of intravenous 14C microtracer dosing and accelerator mass spectrometry (AMS) analysis. A key requirement for the success of this approach is the ability to link the clinical testing process to a manufacturing capability that can rapidly develop, test, and release a suitable intravenous dose for clinical use.

Despite the absence of a clear regulatory requirement for the data (except in Australia), the value of intravenous pharmacokinetic data in understanding the characteristics of a new orally administered drug product cannot be understated.  It is particularly useful where the relative bioavailability by the extravascular route is apparently low or has considerable variability.

Information can also be obtained on fundamental pharmacokinetic parameters such as volume of distribution and clearance. Ascertaining the potential for biliary excretion and systemic metabolism is also possible. All of this data will better inform the overall development strategy for the drug candidate and potentially any back-up compounds with similar structures.

Intravenous pharmacokinetic data can also be used in conjunction with data generated following oral administration by solid or liquid doses in modeling exercises to understand in vivo absorption and dissolution rates. Such information generates a platform from which the in vitro/in vivo correlation can be understood. This provides a key piece of information in understanding the potential for modified delivery of the drug during formulation development.

All of this information helps researchers understand the drug’s absorption, distribution, and systemic clearance from the body, and can, therefore, be vital in avoiding the discovery of problems late in drug development when the implications for the life-cycle of the drug product can be significant.

Generation of this intravenous data can now be enhanced by incorporating the intravenous 14C microtracer dose as part of a conventional Phase I study (Figure). An intravenous microtracer dose can be added to a single or multiple ascending-dose study or to a gender, food effect, or a drug-drug interaction study in such a way that the incremental costs are limited to the manufacture of the radiotracer and intravenous formulation for clinical use, additional clinical activities in the study protocol, and AMS analysis.

The incorporation of an ivMicrotracer into a standard single ascending dose protocol

Iain Shaw ([email protected]) is director of 14C
enabled drug development, and Lloyd Stevens is senior research fellow
at Quotient Bioresearch.

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