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The Application of Accelerator Mass Spectrometry to Absolute Bioavailability Studies in Humans: Simultaneous Administration of an Intravenous Microdose of ¹⁴C-Nelfinavir Mesylate Solution and Oral Nelfinavir to Healthy Volunteers

From Clinical Pharmacology, Pfizer Global Research & Development, San Diego, California (Dr Sarapa, Dr Hsyu); and Xceleron Ltd, York, United Kingdom (Dr Lappin, Dr Garner). Dr Sarapa's current affiliation is Daiichi Medical Research, Park Ridge, New Jersey.

The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of ¹⁴C-nelfinavir mesylate on day 1 and at steady state. Nelfinavir oral bioavailability decreased from 0.88 to 0.47 over the 11-day study period. The moderate bioavailability of nelfinavir was due to significant first-pass metabolism rather than low absorption, limiting the potential of formulation improvement to decrease pill burden. Human absolute bioavailability studies with accelerator mass spectrometry microdosing, in which an intravenous microdose is given along with a conventional oral dose of the same drug, can differentiate between gastrointestinal absorption and the first-pass metabolism of new drug candidates. Accelerator mass spectrometry allowed a several thousand-fold dose reduction of ¹⁴C-nelfinavir relative to that required for liquid scintillation counting. Accelerator mass spectrometry microdosing reduces potential safety issues around dosing radioactivity to humans and prevents the need to formulate high intravenous doses.

Key Words: Absolute bioavailability • AMS • nelfinavir • human microdosing

Address for reprints: Nenad Sarapa, MD, Daiichi Medical Research, 1 Maynard Drive, Park Ridge, NJ 07656; e-mail: nenadsarapa{at}dmr.daiichius.com.

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