Filgotinib is an oral, small molecule, selective Janus kinase 1 (JAK1) inhibitor, currently in late stage clinical trials with excellent early response and sustained clinical efficacy in rheumatoid arthritis and Crohn’s disease. Filgotinib has encouraging safety profile compared to other JAK1 inhibitors in clinical trials. With a half-maximal inhibitory concentration (ICso) value of 629 nM. filgotinib is 30 times more selective for JAK1 than JAK2. Additionally, filgotinib has a major metabolite with similar JAK1 selectivity yet reduced potency. Selectively inhibiting JAK1 modulates a subset of proinflammatory cytokines within the JAK-signal transducer and activator of transcription (STAT) pathway, which may improve the benefit-risk profile compared with the non-selective JAK inhibitors.
With a peak age of onset around 50 years, rheumatoid arthritis is a chronic, progressive systematic inflammatory disease often requiring lifelong disease-modifying therapy. Characterization of the potential effect of age on filgotinib pharmacokinetics will inform whether dose adjustments are necessary in the older adults. Various physiological changes that can impact drug disposition are associated with aging, such as reduced mass and total body water, and increased body fat. The most significant organ changes in the older adults occur in the kidneys, with a decline in estimated glomerular filtration rate (eGFR) from 0.40 ml min–1 1.73 m–2 to 1.02 ml min–1 1.73 m–2 per year. Filgotinib and its metabolites are predominantly eliminated via renal excretion in urine (>80%). Although the metabolism of filgotinib is not mediated by cytochrome P450 (CYP450) at the hepatic level, but rather by intestinal carboxylesterase isoform 2 (CES2), there is limited information available on the potential impact of aging on these enzymes.
In a recent research paper, published in the British Journal of Clinical Pharmacology, Dr. Florence Namour at Galapagos SASU (France) with Drs. Liesbeth Fagard, Annegret Van der Aa, Pille Harrison, and Chantal Tasset at Galapagos NV (Belgium), and also in collaboration with Dr. Yan Xin at Gilead Sciences Inc (United State), sought to characterize the effect of aging and renal impairment on the pharmacokinetics of filgotinib and its major metabolite, to gain information on optimal dosing. The study was carried out by using two groups of 10 healthy subjects (65-74 and ≥ 75 years of age) and a control group of 10 younger healthy subjects (40-50 years of age). The impact of non-acute kidney injury was investigated in three groups of renally impaired subjects (mild [eGFR: 60–89 ml min–1 1.73 m–2], moderate [eGFR: 30–59 ml min–1 1.73 m–2], and severe [eGFR: 15–29 ml min–1 1.73 m–2]) and a control group with normal renal function. The pharmacokinetics of filgotinib and its metabolite were evaluated following filgotinib 100mg once daily dosing for 10 days.
The authors observed that after repeated daily oral administration, regardless of the age group and the degree of renal impairment, filgotinib was rapidly absorbed with steady state concentrations in plasma reached by the second dosing day. It was also shown that there were no or minimal differences between age groups of all pharmacokinetic parameters for filgotinib and its main metabolite, including the percentage excreted unchanged in urine which was not affected by age. In all renal function groups, the between-subject variability, as reflected was moderate to high after multiple dosing (CV%s up to 60%).
Florence Namour and colleagues were able to show that age and mild to moderate renal injury had a limited impact on the pharmacokinetics of filgotinib. In subjects with severe renal injury, the exposure to the major metabolite was elevated, consistent with its renal elimination pathway. Currently, filgotinib dosed at 100-200 mg once daily is being evaluated in pivotal phase III studies in patients across several indications including rheumatoid arthritis, Crohn’s disease and ulcerative colitis. Results from these studies should further support the safety profile of filgotinib and are relevant to its use in settings of rheumatoid arthritis and non-acute kidney disease.
Namour, F., Fagard, L., Aa, A., Harrison, P., Xin, Y., Tasset, C. Influence of age and renal impairment on the steady state pharmacokinetics of filgotinib, a selective JAK1 inhibitor Br J Clin Pharmacol. 2018 Dec; 84(12): 2779–2789 doi: 10.1111/bcp.13726Go To Br J Clin Pharmacol. 2018