Kayode Ogungbenro and Leon Aarons
Centre for Applied Pharmacokinetic Research, The University of Manchester, Manchester, M13 9PT, United Kingdom
Objectives: Methotrexate is an antimetabolite and antifolate drug used in the treatment of cancer and autoimmune disorders [1]. Its volume of distribution is equal to the volume of body water and it is about 30-40% bound in plasma. Elimination of methotrexate is renal (70-80%), biliary (25-15%) and metabolic (5%). Renal elimination is mainly by filtration, and active secretion and reabsorption also play significant roles. Oral methotrexate is rapidly absorbed and bioavailability is highly variable (50-90%) [2]. The aim of this work was to develop a physiologically based pharmacokinetic model for low dose methotrexate following intravenous and oral dosing in human.
Methods: A physiologically based pharmacokinetic model with separate compartments for plasma, red blood cells, liver, gut tissue, enterocyte, stomach, gut lumen, kidney, skin, bone marrow, spleen, thymus muscle and rest of the body was developed using plasma and intracellular red blood cell concentrations. Nonlinear tissue binding and enterohepatic recirculation were incorporated. A kidney model with compartments for kidney vascular, kidney tissue, glomerulus and proximal tubule was incorporated to account for filtration, secretion and active reabsorption. System parameters such as blood flows and organ volumes were obtained from the literature. Some drug parameters were obtained from the literature and the rest were optimised.
Results: The model adequately predicts plasma concentration following intravenous and oral dosing in humans. Simulations suggest that the nonlinearity in the observed profile is as a result of saturable active reabsorption and nonlinear distribution into the red blood cells. At low doses active reabsorption is very important.
Conclusions: A physiologically based pharmacokinetic model that can predict concentrations in different tissues has been developed and this can be used for dose optimisation.
References:
[1] Bannwarth B, Pehourcq F, Schaeverbeke T, Dehais J (1996) Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet 30: 194-210.
[2] Schmiegelow K (2009) Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol 146: 489-503
Reference: PAGE 22 (2013) Abstr 2695 [www.page-meeting.org/?abstract=2695]
Poster: Absorption and Physiology-Based PK