Impact of Individual and Cassette Administration on Pharmacokinetics of Prednisolone, Diclofenac, and Methotrexate in a Rodent Model of Rheumatoid Arthritis.

INTRODUCTION

To find out how arthritic diseases affect the pharmacokinetics of prednisolone, diclofenac, and methotrexate when given individually and as a cassette in male Sprague-Dawley rats, the study's main goal was to look into drug-drug interactions (DDI). For the treatment of moderate to severe arthritis, doctors commonly prescribe all three drugs alone or in combination.

METHODOLOGY: Pharmacokinetics (PK) was evaluated using individual and cassette dosing in male Sprague-Dawley rats in a fasting state. Respective experimental groups were administered orally with prednisolone (5.0 mg/kg), diclofenac (10.0 mg/kg), and methotrexate (0.5 mg/kg) during either discrete or cassette dosing, at a dose volume of 5 mL/kg. Blood samples were collected through the jugular vein and analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetics parameters were calculated using Phoenix software version 8.1.

RESULTS

Prednisolone significantly decreased the AUC0-last in both the arthritic group and the cassette group when compared to the standalone normal animal group. Neither cassette dosing in the normal group nor discrete dosing in the arthritic group affected the pharmacokinetics (PK) of diclofenac. However, the AUC0-last value for diclofenac significantly decreased during cassette dosing in the arthritic group. Individual administration of methotrexate in the arthritic group resulted in a significant decrease in AUC0-last, while the healthy group experienced a substantial increase when administered as a cassette.

DISCUSSION: Poly-pharmacy is quite commonly practiced in arthritic patients. Co-administration of multiple drugs together may alter the systemic exposure due to disease condition and drug-drug interaction which ultimately may lead to off target toxicity or sub-therapeutic exposure. The suboptimal therapeutic response may lead to prolonged medication therapy for desired benefit. However, This study has a potential limitation that, diseased induced model may not accurately reflect the human auto-immune disease pathophysiology and further the pharmacokinetics and drug-drug interaction may further vary according to the stage in rheumatoid arthritis patients.

CONCLUSION

Along with the pharmacological DDI, this study looked at how disease affected the PK of prednisolone, diclofenac, and methotrexate when these drugs were given in both discrete and cassette doses. Significant differences in AUC0-t and Cmax of prednisolone and methotrexate pharmacokinetics when dosed as a cassette or individually in arthritic groups were noticed. The serum concentration of methotrexate increased when it was combined with diclofenac. Further, the metabolism of methotrexate increased when combined with prednisolone.