Microdosing Cuts Drug-Development Time

However, there has been concern that a microdose may not predict the behavior of clinical doses, since nonlinearities may be induced when binding, metabolizing, or eliminating systems become saturated. To address this concern, an industry-sponsored trial was undertaken using several drugs with known human PK characteristics at pharmacologic dose levels. Each was administered at a microdose level and at a therapeutic dose level to subjects in an appropriate cross-over design. The trial was intended to be a rigorous test using compounds expected to strongly challenge the microdosing concept.

Of the five drugs studied, the microdose PK data reflected the pharmacologic dose for three and gave important metabolism data for one. One compound was a no-test. "The results will represent a surprise for some in the pharmaceutical community as the concept works in circumstances that were cited as being unlikely for microdosing to succeed,” observed Dr. Graham Lappin, head of R&D at Xceleron (Heslington, UK; www.xceleron.co.uk), who announced the trial's results at the annual meeting of the American Society for Clinical Pharmacology and Therapeutics in Orlando (FL, USA) in March 2005.

Microdosing can be used to assist in the compound candidate selection process, determine the first dose for the subsequent phase I study, select the best animal species for long-term toxicologic studies, and calculate the likely cost of goods when the drug goes into production. Currently, as many as one in three drugs fail in phase I testing despite extensive screening of candidates. A high proportion of these failures are due to sub-optimal pharmacokinetics.




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