This study will evaluate how methotrexate is processed in the body when given with low doses of rifampicin or cyclosporine. These drugs may affect how methotrexate is absorbed and cleared, which could change its safety and effectiveness. Healthy volunteers will receive methotrexate with either rifampicin or cyclosporine, and blood samples will be collected to measure drug levels. The findings may help identify possible drug interactions and improve the safe use of methotrexate.
Unexpected or unrecognized drug-drug interactions can reduce efficacy, cause toxicity, or even lead to fatal outcomes. Inhibition or induction of drug transporters involved in hepatic or renal uptake/efflux may alter drug exposure, affecting safety and efficacy. The FDA requires clinically significant interactions to be assessed prior to approval. OATPs (primarily hepatic uptake) and BCRP (hepatic and renal efflux) share many substrates, but their combined inhibition has not been well studied in humans. Methotrexate, a substrate of both OATP and BCRP, is widely used at varying doses for cancer, psoriasis, and rheumatoid arthritis, often in combination with other drugs such as NSAIDs, which may result in interactions requiring close monitoring. Rifampicin, an antibiotic, inhibits OATP1B1/1B3 in a dose-dependent manner, while cyclosporine, an immunosuppressant, inhibits OATP and BCRP. In our previous study (IRB No. B-2110-715-001), the investigators quantitatively demonstrated that rifampicin reduces 7-OH-methotrexate formation via OATP inhibition. However, dose-dependent inhibition by rifampicin and the impact of cyclosporine on methotrexate pharmacokinetics remain unclear. This study aims to evaluate the pharmacokinetics of methotrexate following co-administration with low-dose rifampicin (150 or 300 mg) and cyclosporine in healthy volunteers. The investigators will also explore the role of methotrexate metabolites as potential biomarkers to assess OATP-mediated interactions.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
12
Methotrexate Tab. 2.5 mg (Korea United Pharm)
Rifampin Cap. 150 mg (Yuhan Corporation)
Cypol-N Cap. 100 mg (Chong Kun Dang)
Seoul National University Bundang Hospital
Seongnam-si, Gyeonggi-do, South Korea
MTX Cmax
Peack plasma concentration (Cmax) of methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
MTX AUClast
Area under the concentration-time curve to last measurable concentration (AUClast) of methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
MTX AUCinf
Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of Methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
MTX Tmax
Time to maximum plasma concentration (Tmax) of methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
MTX t1/2
Terminal elimination half-life (t1/2) of methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
MTX CL/F
Apparent clearance (CL/F) of methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
MTX Vz/F
Apparent volume of distribution (Vz/F) of methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
MTX fe
Fraction of dose excreted unchanged in urine (fe) of methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
MTX CLR
Renal clearance (CLR) of methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX Cmax
Maximum plasma concentration (Cmax) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX AUClast
Area under the plasma concentration-time curve from time zero to the last measurable concentration (AUClast) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX AUCinf
Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX Tmax
Time to maximum plasma concentration (Tmax) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX t1/2
Terminal elimination half-life (t1/2) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX CL/F
Apparent clearance (CL/F) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX Vz/F
Apparent volume of distribution (Vz/F) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX fe
Fraction of dose excreted unchanged in urine (fe) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX CLR
Renal clearance (CLR) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
7-OH MTX MR
Metabolic ratio (MR) of 7-hydroxy methotrexate
Time frame: pre-dose (0 hours), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours post-dose for each period (11 time points per period)
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