The identification and development of successful drug candidates is an increasingly complex and expensive process and pharmaceutical companies are constantly looking for new technologies to improve compound selection. ivMicrotracer technology from Quotient Clinical, couples tracer intravenous dosing with accelerator mass spectrometry (AMS) to give clinical pharmacologists access to comprehensive human pharmacokinetic data early in drug development.1,2
ivMicrotracer studies allow researchers to evaluate the intravenous (IV) pharmacokinetics of drugs in healthy human volunteers in early clinical studies. This approach provides a powerful way of defining the pharmacokinetic characteristics and absolute bioavailability of lead compounds. Generating this information early in development gives an improved understanding of clinical pharmacokinetic data, potential delivery and formulation options and potentially a reduction in late-stage attrition.
Benefits of Carbon-14 ivMicrotracer Studies
Intravenous pharmacokinetics and absolute bioavailability data may be requested by regulatory authorities to address issues associated with poor and variable bioavailability. Traditionally this meant developing a suitable intravenous formulation and its associated specific preclinical and clinical evaluation prior to conducting an oral/IV crossover study. This approach can take up to one year and cost well over $1.5 million. Carbon-14 ivMicrotracer studies are an alternative approach and can be incorporated into an early clinical development program with minimal impact on overall costs and timings.
ivMicrotracer studies allow development teams to make better informed decisions regarding candidate drugs. The pharmacokinetic data generated can identify issues earlier in development, enabling project activities to be prioritized appropriately and the design of clinical studies to be adjusted as necessary. Because ivMicrotracer studies can be conducted without additional pre-clinical testing to support IV dosing, pharmacokinetic data can be generated in less than five months and for less than $500,000.
ivMicrotracer studies can be performed on drugs intended for any extravascular route of administration. Understanding the pharmacokinetics of drugs intended for oral or other extravascular dose routes is greatly enhanced if the clearance, distribution volumes, and absolute bioavailability are determined by an ivMicrotracer study. An intravenous carbon-14 microdose, usually between a hundredth and a thousandth of the extravascular dose is administered at the time of maximum concentration (Tmax) of the extravascular (or non-IV) dose. Plasma samples for the IV dose are analyzed by LC-AMS and for the oral dose by LC-MS/MS. Administering the IV dose at the Tmax for the extravascular dose ensures that the body handles the tracer IV dose in exactly the same manner as and simultaneously with the extravascular therapeutic dose.3, 4, 5 (Figure 1)
ivMicrotracer studies can be conducted more quickly and cheaply than traditional IV/PK studies. The flexibility of the carbon-14 ivMicrotracer approach allows it to be added directly to an otherwise standard early development clinical protocol. The additional information that is generated can greatly benefit the design of the subsequent clinical program resulting in better study outcomes. Data generated can add considerable value to understanding drug pharmacokinetics, bioavailability, formulation performance and in conjunction with appropriate modelling and simulation tools can support formulation design through to in vitro-in vivo correlation.
At a Glance
Company: Quotient Clinical
Date Introduced: 2008
Product Description: Quotient Clinical ivMicrotracer studies are used in Phase I to obtain lead compound IV PK and absolute bioavailability data. These studies involve concomitant (piggy-back) IV administration of a carbon-14-drug tracer dose at the Tmax of an oral, or other extravascular, therapeutic dose.
About the Author
Iain Shaw is director of 14-C Enabled Drug Development at Quotient Clinical. Prior to this, he was programme manager for Covance Laboratories and has almost 15 years experience in the pharmaceutical industry. Iain has a BSc in Agricultural Chemistry from the University of Glasgow.
1. Vogel JS, Turteltaub KW. Accelerator Mass Spectrometry as a bioanalytical tool for nutritional research. Adv Exp Med Biol. 1998 445; 397-410
2. Lappin G, et al. Use of microdosing to predict pharmacokinetics at the therapeutic dose: Experience with 5 drugs. Clin Pharmacol Ther. 2006 80; 203-215
3. Sarapa, et al; J Clin P’col. 2005: 45 p 1198-1205
4. Stevens LA, et al; Microdose and microtracer intravenous pharmacokinetics of RDEA 806 in healthy subjects. Poster presented at the ASCPT meeting March, 2009, National Harbour, MD
5. Stevens LA, et al; A Microdosing study to assess the oral absorption of 14C_EM-1321 in healthy male subjects. Poster presented at the 2006 AAPS Annual Meeting and Exposition.
Filed Under: Drug Discovery