Objective: To compare the bioavailability of oral and subcutaneous methotrexate (MTX) in children with juvenile idiopathic arthritis (JIA).
Methods: Seventeen JIA patients were administered oral (6.1-22.5 mg/m(2)) or subcutaneous (8.8-28.6 mg/m(2)) MTX. Blood samples were drawn pre-dose, and at 1, 2, and 4 hours after administration. Plasma MTX was determined by high-performance liquid chromatography. Non-compartmental pharmacokinetic analysis included the maximum concentration of plasma MTX (C(max)) and the area under the plasma concentration-time curve in the interval of 0-4h (AUC(0-4h)).
Results: The slopes of the regression lines of the dose-corrected parameters Cmax and AUC(0-4h) plotted against the dose were negative for oral administration indicating non-linearity in pharmacokinetics, while they did not differ from zero for subcutaneous MTX. In two groups dosed orally with < or = 10 or >10 mg/m(2) (the average doses: 7.8 vs. 13.8 mg/m(2), p<0.002), the C(max) and AUC(0-4h) were comparable (p > or = 0.32). In four patients switched from oral to subcutaneous administration of the same dose, the bioavailability of oral MTX tended to be 11-15% lower when compared to subcutaneous route.
Conclusion: The differences in the pharmacokinetic measures of early systemic exposure between oral and subcutaneous routes support the view that lower and saturable intestinal absorption of oral MTX limits its bioavailability and efficacy within the range of standard doses used to treat children with JIA. In light of this evidence it can be recommended to use parenteral route of administration when MTX dose around and above 10-15 mg/m(2) is needed to achieve sufficient response.