Graham Lappin1, Lloyd Stevens. 1. Xceleron Ltd, The Biocentre, Innovation Way, York, YO10 5NY, UK. graham.lappin@xceleron.com
Abstract
BACKGROUND: Accelerator mass spectrometry (AMS) is a sensitive isotope ratio technique used in drug development that allows for small levels of 14C-drug to be administered to humans, thereby removing regulatory hurdles associated with radiotracer studies. AMS uses innovative study designs to obtain pharmacokinetic and metabolism data. OBJECTIVE: This review addresses the metabolism and pharmacokinetics relevant to cases where therapeutic drug concentrations are achieved in humans. METHODS: The review focuses on two study designs: i) administration of tracer 14C-drug intravenously with a simultaneous non-labelled extravascular therapeutic dose to obtain the pharmacokinetic parameters of clearance, volume of distribution and absolute bioavailability without extensive intravenous toxicology safety studies or formulation development; and ii) use of low levels of 14C-drug during Phase I studies to investigate the quantitative metabolism of the drug in humans early in drug development, as required by the new FDA guideline issued in February 2008. RESULTS/ CONCLUSIONS: Early knowledge about a drug's clearance, volume of distribution, absolute bioavailability and metabolism can affect the development of a new drug candidate.
BACKGROUND: Accelerator mass spectrometry (AMS) is a sensitive isotope ratio technique used in drug development that allows for small levels of 14C-drug to be administered to humans, thereby removing regulatory hurdles associated with radiotracer studies. AMS uses innovative study designs to obtain pharmacokinetic and metabolism data. OBJECTIVE: This review addresses the metabolism and pharmacokinetics relevant to cases where therapeutic drug concentrations are achieved in humans. METHODS: The review focuses on two study designs: i) administration of tracer 14C-drug intravenously with a simultaneous non-labelled extravascular therapeutic dose to obtain the pharmacokinetic parameters of clearance, volume of distribution and absolute bioavailability without extensive intravenous toxicology safety studies or formulation development; and ii) use of low levels of 14C-drug during Phase I studies to investigate the quantitative metabolism of the drug in humans early in drug development, as required by the new FDA guideline issued in February 2008. RESULTS/ CONCLUSIONS: Early knowledge about a drug's clearance, volume of distribution, absolute bioavailability and metabolism can affect the development of a new drug candidate.
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Authors: Claudia C Wagner; Marie Simpson; Markus Zeitlinger; Martin Bauer; Rudolf Karch; Aiman Abrahim; Thomas Feurstein; Matthias Schütz; Kurt Kletter; Markus Müller; Graham Lappin; Oliver Langer Journal: Clin Pharmacokinet Date: 2011-02 Impact factor: 6.447