PURPOSE: The aim of this study was to explore the possibility of achieving a practical dosing regimen for 2,4,6-triiodophenol (AM-24), a new leukotriene B4 (LTB4) synthesis inhibitor. First, a model capable of dealing with the nonlinearity in its pharmacokinetic profile was built, and then it was combined with a pharmacodynamic model previously established with data from earlier phase I trials. METHODS: One week after the first 240-, 350-, or 500-mg oral dose of AM-24, six additional doses were given to 24 healthy volunteers once daily. A total of 33 blood samples were obtained from each individual. Different models, including enzyme turnover models, were fitted to the data by using the software NONMEM. RESULTS: Drug absorption was modeled with a first-order process. Drug disposition was described with a one-compartment model, and elimination with an (auto)inhibited and a noninhibited clearance. AM-24 inhibited the enzyme production rate to a maximum of 98%. Relative bioavailability was independent of the decrease in the amount of enzyme. The estimate of the enzyme turnover half-life was 8.5 h. CONCLUSIONS: Simulations have shown that steady-state conditions eliciting 90% of maximal LTB4 synthesis inhibition can be reached after 3 weeks during an oral treatment with AM-24 administered at the dosage of 500 mg once daily.
PURPOSE: The aim of this study was to explore the possibility of achieving a practical dosing regimen for 2,4,6-triiodophenol (AM-24), a new leukotriene B4 (LTB4) synthesis inhibitor. First, a model capable of dealing with the nonlinearity in its pharmacokinetic profile was built, and then it was combined with a pharmacodynamic model previously established with data from earlier phase I trials. METHODS: One week after the first 240-, 350-, or 500-mg oral dose of AM-24, six additional doses were given to 24 healthy volunteers once daily. A total of 33 blood samples were obtained from each individual. Different models, including enzyme turnover models, were fitted to the data by using the software NONMEM. RESULTS: Drug absorption was modeled with a first-order process. Drug disposition was described with a one-compartment model, and elimination with an (auto)inhibited and a noninhibited clearance. AM-24 inhibited the enzyme production rate to a maximum of 98%. Relative bioavailability was independent of the decrease in the amount of enzyme. The estimate of the enzyme turnover half-life was 8.5 h. CONCLUSIONS: Simulations have shown that steady-state conditions eliciting 90% of maximal LTB4 synthesis inhibition can be reached after 3 weeks during an oral treatment with AM-24 administered at the dosage of 500 mg once daily.
Authors: M Hassan; U S Svensson; P Ljungman; B Björkstrand; H Olsson; M Bielenstein; M Abdel-Rehim; C Nilsson; M Johansson; M O Karlsson Journal: Br J Clin Pharmacol Date: 1999-11 Impact factor: 4.335
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