A rat pharmacokinetic/pharmacodynamic model for assessment of lipopolysaccharide-induced tumor necrosis factor-alpha production

IntroductionTumor necrosis factor-alpha (TNFα) participates in many inflammatory processes. TNFα modulators show beneficial effects for the treatment of many diseases including rheumatoid arthritis. The purpose of this study was to validate a rat pharmacokinetic/pharmacodynamic (PK/PD) model for rapid assessment of drug candidates that intended to interrupt TNFα synthesis or release.MethodsRats received intravenous (IV) or oral administrations of test article or dose vehicle, followed by LPS challenge. Plasma levels of test article and TNFα were determined. The areas under the concentration–time curves (AUCdrug and AUCTNFα) were calculated. The overall percentage of inhibition on TNFα release in vivo was calculated by comparing AUCTNFα of the test article treated group against that for the vehicle control group.ResultsThe dosing vehicles tested in this study did not increase plasma TNFα level. At IV dose of up to 100 μg/kg, LPS did not alter the pharmacokinetics of the compound tested. Using a selective TNFα converting enzyme (TACE) inhibitor as model compound, this PK/PD model demonstrated its ability to correlate plasma test article concentration with its biological activity of lowering the LPS-induced TNFα plasma levels in vivo.DiscussionA rat PK/PD model for evaluation of the effect of drug candidates on LPS-induced TNFα synthesis and/or release has been investigated. This model provides integrated information on pharmacokinetics and in vivo potency of the test articles.