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The Application of Accelerator Mass Spectrometry to Absolute Bioavailability Studies in Humans: Simultaneous Administration of an Intravenous Microdose of 14 C‐Nelfinavir Mesylate Solution and Oral Nelfinavir to Healthy Volunteers
Author(s) -
Sarapa Nenad,
Hsyu PoeHirr,
Lappin Graham,
Garner Ronald Colin
Publication year - 2005
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270005280051
Subject(s) - nelfinavir , bioavailability , microdose , accelerator mass spectrometry , pharmacology , pharmacokinetics , medicine , chemistry , chromatography , mass spectrometry , family medicine , human immunodeficiency virus (hiv) , viral load , antiretroviral therapy
The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of 14 C‐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 14 C‐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.