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AB0363 Coadministration of asp015k, a novel janus kinase inhibitor, with methotrexate demonstrates tolerability and lack of pharmacokinetic interactions in patients with rheumatoid arthritis
  1. T. Zhu1,
  2. K. Oda2,
  3. U. Valluri1,
  4. B. Moore1,
  5. Y. Cao1,
  6. V. Chindalore3,
  7. B. Akinlade1
  1. 1Astellas Pharma Global Development, Inc., Northbrook, United States
  2. 2Astellas Pharma Inc., Osaka, Japan
  3. 3Pinnacle Research Group/Anniston Medical Clinic, Anniston, United States

Abstract

Background 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 nonbiologic DMARD therapy and is recommended as first-line therapy in RA treatment guidelines. In humans, MTX is primarily excreted unchanged in urine. Transporter-mediated renal tubular secretion of MTX is thought to be a major mechanism of pharmacokinetic (PK) drug-drug interactions.

Objectives In vitro experiments were performed to evaluate the effects of ASP015K on renal transporters. A clinical drug-drug interaction study in RA patients evaluated the effects of multiple-dose ASP015K on MTX PK and the short-term safety and tolerability of coadministration.

Methods In vitro experiments assessed 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. 15 patients diagnosed with RA for ≥6 months who had been treated with MTX (15–25 mg weekly) for ≥28 d were enrolled. Patients received their usual prescribed dose of MTX on day 1. They then received ASP015K 100 mg BID for 6.5 d (days 3–9 [morning]) and a second prescribed dose of MTX in combination with ASP015K on day 8. Serial blood samples were collected for MTX concentrations after dosing on day 1 (MTX alone) and 8 (MTX+ASP), and for ASP015K concentrations after dosing on day 7 (ASP alone) and 8 (MTX+ASP). Predose ASP015K concentrations (Ctrough) were measured on days 3–8. Urinary excretion of MTX and ASP015K was 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. 14 patients completed the phase 1 study for PK evaluation. Results showed that MTX exposure was not affected by coadministration of ASP015K; AUCinf ratio (MTX+ASP/MTX alone) was 103% [90% CI, 93–113]; Cmax ratio was 92% [90% CI, 83–103]. Analysis of Ctrough indicated ASP015K levels reached steady state on day 5. ASP015K AUC12,ss was not affected by coadministration of MTX with a ratio (MTX+ASP/ASP alone) of 98% [90% CI, 91–106]. ASP015K Cmax 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 Cmax of ASP015K at 100 mg BID was estimated to be <1/10th of the IC50 for OAT3 in vitro, suggesting that ASP015K would not affect MTX PK. ASP015K was well tolerated when coadministered with MTX. One patient experienced a 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 patient was withdrawn.

Conclusions 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.

Disclosure of Interest T. Zhu Employee of: Astellas Pharma Global Development, Inc., K. Oda Employee of: Astellas Pharma Inc., U. Valluri Employee of: Astellas Pharma Global Development, Inc., B. Moore Employee of: Astellas Pharma Global Development, Inc., Y. Cao Employee of: Astellas Pharma Global Development, Inc., V. Chindalore: None Declared, B. Akinlade Employee of: Astellas Pharma Global Development, Inc.

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