Background/Purpose: ASP015K is an oral Janus kinase (JAK) inhibitor with selectivity for JAK1/3 in development for treatment of rheumatoid arthritis (RA) and other autoimmune diseases. Methotrexate (MTX) is the most common non-biologic DMARD therapy and recommended as first-line therapy in RA treatment guidelines. In humans, MTX is primarily excreted unchanged into urine. Transporter-mediated renal tubular secretion of MTX is thought to be a major mechanism of PK interaction with other drugs. In vitro experiments were performed to evaluate the effects of ASP015K on renal transporters. A clinical drug-drug interaction study was also conducted to evaluate the effect of multiple-dose of ASP015K on MTX PK, and the short-term safety and tolerability of coadministration in RA patients.

Methods: In vitro experiments were conducted to assess the inhibitory potency of ASP015K on human multidrug resistance-associated protein 2/4 (MRP2/4) and organic anion transporter 1/3 (OAT1/3). A phase 1, open-label, single-sequence study was conducted to confirm the in vivo effect of ASP015K on the PK of MTX, a substrate of MRP2/4 and OAT1/3. Fifteen subjects diagnosed with RA for ≥6 months and had been treated with MTX (15 to 25 mg weekly) for ≥28 days were enrolled. Subjects received their usual prescribed dose of MTX on day 1. They then received ASP015K 100 mg BID for 6.5 days (day 3 through the morning of day 9), and a second prescribed dose of MTX in combination with ASP015K on day 8. Serial blood samples were collected for MTX concentration assay after dosing on day 1 (MTX alone) and 8 (MTX+ASP), and for ASP015K concentration assay after dosing on day 7 (ASP alone) and 8 (MTX+ASP). Predose concentrations (C_tough) of ASP015K were measured on days 3, 4, 5, 6, 7 and 8. Urinary excretion of MTX was also assessed.

Results: ASP015K demonstrated no in vitro inhibitory effect on MRP2/4 or OAT1 (IC₅₀ > 100 µM); it inhibited OAT3 with an IC₅₀ of 5 µM. Fourteen subjects completed the phase 1 study for PK evaluation. Results showed that MTX exposure was not affected by coadministration of ASP015K; AUC_inf ratio (MTX+ASP / MTX alone) was 103% [90% confidence interval (CI) 93, 113]; C_max ratio was 92% [90% CI 83, 103]. Analysis of C_trough indicated ASP015K levels reached steady state on day 5. ASP015K AUC_12,ss was not affected by coadministration of MTX with a ratio (MTX+ASP / ASP alone) of 98% [90% CI, 91, 106]. ASP015K C_max decreased by 8% with a ratio (MTX+ASP / ASP alone) of 92% [90% CI, 78, 108], which was considered not to be clinically significant. The unbound C_max of ASP015K at 100 mg BID was estimated to be <1/10^th of the IC₅₀for OAT3 in vitro suggesting that ASP015K would not affect MTX PK. ASP015K was well tolerated when coadministed with MTX. One subject experienced an SAE (urinary tract infection) before receiving study drug and subsequently a second SAE (gastroenteritis) after receiving MTX on day 1 but before receiving ASP015K. This subject was discontinued from the study.

Conclusion: Coadministration of ASP015K and MTX was well tolerated in this short-term study exhibiting no clinically significant effect on the PK profile of either drug. Efficacy and safety of ASP015K/MTX combination therapy is being assessed in ongoing phase 2 trials in RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/coadministration-of-asp015k-a-novel-janus-kinase-inhibitor-with-methotrexate-demonstrates-tolerability-and-lack-of-pharmacokinetic-interactions-in-patients-with-rheumatoid-arthritis/