Background/Purpose: GLPG0634 is an orally-available, selective Janus kinase 1 (JAK1) inhibitor. Selective inhibition of JAK1 may combine improved safety and clinical efficacy profiles with a rapid onset of action. GLPG0634 showed encouraging safety and efficacy results in early clinical studies treating RA patients for 4 weeks. As RA patients can be on multiple medications, an understanding of the potential for drug-drug interaction was of interest.The exploration of potential drug-drug interactions in vitro and in humans is presented here.

Methods: Inhibition or induction of drug-metabolizing enzymes [CYP450, uridine glucuronyltransferases (UGT)] and key drug transporters (Pgp, BCRP, BSEP, OATs, OCTs, OATP1B1 and OATP1B3) were studied using human microsomes, cell systems or recombinant enzymes with reference substrates as suitable. An open-label study in healthy subjects was conducted to confirm the in vitro conclusion on interaction potential with CYP3A4 by evaluating the effects of GLPG0634 co-administration on a sensitive CYP3A4 substrate, midazolam. The oral pharmacokinetics of midazolam was assessed following a single dose of 2 mg prior to and after once daily dosing of 200 mg GLPG0634 for 7 days. Furthermore, the potential interaction with methotrexate, a drug commonly administered to RA patients and shown in vitro to be partially eliminated in urine by OCTs transporters was investigated during a clinical study in RA patients treated with up to 300 mg daily dose GLPG0634 for 4 weeks.  

Results: In vitro studies showed that the GLPG0634 metabolism is not CYP450 dependent and is mediated by carboxylesterases (CES)with 70% of the metabolite produced by CES2. In vitro, GLPG0634 and its main metabolite do not induce CYP1A2, CYP2B6 and CYP3A4 at concentrations at least two-fold of the peak concentration (C_max) in patients administered a 200 mg daily dose of GLPG0634. The IC₅₀ for inhibition of each of the CYPs tested and UGT1A1 and UGT2B7 is at least 7-fold above the C_max for GLPG0634 and its main metabolite. Drug transporters are not inhibited by GLPG0634 and its metabolite, except minor effects on OCT2. The IC₅₀ for OCT2 inhibition are 2.6- and 6.2-fold over the C_max values of GLPG0634 and its metabolite, respectively, after a daily dose of 200 mg, while. In healthy subjects, there was no difference in the plasma midazolam pharmacokinetic profile with and without GLPG0634. Adjusted geometric ratios for midazolam plus GLPG0634 were 99.3% [87.6-112.5%] and 105.4% [94.8-117.3%] for C_max and AUC, respectively, well within the no effect boundary guidelines (80-125%). In RA patients, neither the C_max, nor AUC of methotrexate in plasma was influenced by the co-administration of GLPG0634, with mean values of 156-172 ng/mL and 568-680 ng.h/mL for C_max and AUC, respectively. GLPG0634 was safe and well tolerated.

Conclusion: The clinical data show a lack of relevant drug interactions by GLPG0634 with CYP3A4 substrates, either through inhibition or induction of CYP3A4 activity in humans, as well as with OCTs transporters via methotrexate elimination. All together the in vitro data on CYP450s, UGTs and key drug transporters, support that GLPG0634 can be co-administered with drugs usually administered to RA patients without dose adjustment.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-1-and-phase-2-data-confirm-that-glpg0634-a-selective-jak1-inhibitor-has-a-low-potential-for-drug-drug-interactions/