Dealing with time-dependent pharmacokinetics during the early clinical development of a new leukotriene B4 synthesis inhibitor.
OBJECTIVE
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.
Trocóniz
Iñaki F
IF
Departmento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Navarra, Pamplona, Spain.
Zsolt
Ilonka
I
Garrido
María J
MJ
Valle
Marta
M
Antonijoan
Rosa M
RM
Barbanoj
Manel J
MJ
D000284:Administration, Oral; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001682:Biological Availability; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010636:Phenols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic
D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D010636:Phenols; D007975:Leukotriene B4; C066859:2,4,6-triiodophenol; D001094:Arachidonate 5-Lipoxygenase