Filgotinib, a JAK1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects

Anderson, Kacey; Yan, Xin; Zheng, Hao; Yun, Chohee; Kwan, Ellen; Qin, Ann; Namour, Florence; Kearney, Brian P.; Mathias, Anita

doi:10.1002/cpdd.755

Cited by 8 publications

(12 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…17 The effects of the drug on patients with end-stage renal disease [CrCl <15 mL/min] and severe hepatic impairment [Child-Pugh C] have not been studied, while both filgotinib and its metabolite have not been associated with prolongation of the corrected QT interval. 17 , 20 Regarding the interactions between filgotinib and other molecules, it should be emphasized that filgotinib does not significantly inhibit or induce cytochrome P450 [CYP] enzymes or UDP-glucuronosyltransferases, which are generally involved in drug interactions, suggesting a low risk of interaction with other drugs. 21–24 …”

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

Positioning Filgotinib in the Treatment Algorithm of Moderate to Severe Ulcerative Colitis

D’Amico

Magro

Peyrin–Biroulet

et al. 2021

Journal of Crohn's and Colitis

View full text Add to dashboard Cite

Background and aims Filgotinib is a small molecule that selectively inhibits Janus kinase (JAK) type 1. It is already approved for the treatment of rheumatoid arthritis and is being evaluated for the management of patients with moderate to severe ulcerative colitis (UC). The purpose of this review is to provide an overview of the currently available data on filgotinib and to define how to position this new drug in the treatment algorithm of patients with ulcerative colitis. Methods Pubmed, Embase, and Scopus databases were searched up to June 25, 2021 in order to identify studies reporting efficacy and safety data of filgotinib in patients with UC. Results Data from a phase III study enrolling UC patients with moderate to severe disease show that filgotinib is effective with a reassuring safety profile. Filgotinib treatment is not associated with a greater risk of thrombosis and herpes zoster infections compared to other JAK inhibitors. However, animal studies reported impaired spermatogenesis and histopathological effects on male reproductive organs, making it necessary to deepen this aspect in dedicated human studies. Conclusions Filgotinib is an effective and safe drug for treatment of both biologic-naive and biologic experienced patients with moderate to severe UC and may soon be available.

show abstract

Section: Pharmacokinetics and Pharmacodynamicsmentioning

confidence: 99%

Positioning Filgotinib in the Treatment Algorithm of Moderate to Severe Ulcerative Colitis

D’Amico

Magro

Peyrin–Biroulet

et al. 2021

Journal of Crohn's and Colitis

View full text Add to dashboard Cite

show abstract

“…Systemic exposures of FIL and MET were within the expected range based on historical data, 21 indicating lack of an effect of a single dose of OC on the PK of FIL. Overall, the combination of FIL with a representative hormonal OC medication was generally well tolerated.…”

Section: Discussionmentioning

confidence: 73%

“…Corresponding FIL plasma PK parameters are presented in Table 5. The exposures of FIL and MET were within the range of clinically observed exposures 9,10,21 …”

Section: Resultsmentioning

confidence: 83%

“…A sample size of 24 subjects (12 per sequence) was projected to achieve at least 90% power, such that the 90% confidence intervals (CIs) for the geometric least‐squares means (GLSM) ratio of LEVO and EE AUC and C max in test versus reference treatments would be within (70%, 143%), if the true GLSM ratio was 1.0. An analysis of variance using a mixed‐effects model, with treatment, sequence, and period as fixed effects and subject within sequence as a random effect, 20 was fitted to the natural logarithmic transformation of PK parameters for each analyte. Two‐sided 90%CIs) were calculated for the ratio of GLSM) of primary PK parameters (AUC inf , AUC last , and C max ) between test (FIL and OC) vs reference (OC alone) treatments for each analyte.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Lack of Drug‐Drug Interaction Between Filgotinib, a Selective JAK1 Inhibitor, and Oral Hormonal Contraceptives Levonorgestrel/Ethinyl Estradiol in Healthy Volunteers

Begley

Anderson

Watkins

et al. 2020

Clinical Pharm in Drug Dev

Self Cite

View full text Add to dashboard Cite

Filgotinib (FIL) is a potent and selective JAK1 inhibitor in clinical development for treatment of severe inflammatory diseases. A drug‐drug interaction study to evaluate the potential effect of FIL on the pharmacokinetics (PK) of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted. This was a phase 1, open‐label, randomized, crossover study in healthy female subjects (N = 24). Subjects received a single dose of LEVO (150 μg)/EE (30 μg) alone (reference), or in combination with multiple‐dose FIL (200 mg once daily for 15 days; test). Intensive PK sampling was conducted, and safety was assessed throughout the study. PK interactions were evaluated using 90% confidence intervals of the geometric least squares mean ratios of the test versus reference treatments. All 24 subjects enrolled completed study treatments. Coadministration of FIL with the oral contraceptive did not alter the PK of LEVO and EE; the 90% confidence intervals of the geometric least squares mean ratios were contained within bioequivalence bounds (80%‐125%). Exposures of FIL were consistent with observed clinical exposure data. Study treatments were generally well tolerated. All adverse events were mild. Coadministration with FIL did not alter the PK of LEVO/EE, and hormonal contraceptives can serve as an effective contraception method for subjects on FIL treatment.

show abstract

“…There are a number of small-molecule JAK family inhibitors that have been approved and/or are in the late stage of clinical development: tofacitinib (a JAK1 and JAK3 selective inhibitor), 24 ruxolitinib (a JAK1 and JAK2 selective inhibitor), 25 filgotinib (a JAK1 selective inhibitor), 26 baricitinib (a JAK1 and JAK3 selective inhibitor), 27,28 and upadacitinib (a JAK1 selective inhibitor). 29 They have differential selectivity for different subtypes of the JAK family, and all of them have reported negative QTc results.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Clinical Cardiac Safety of Itacitinib, a JAK1 Inhibitor, in Healthy Participants

Gong

Darpö²,

Xue³

et al. 2019

Clinical Pharm in Drug Dev

View full text Add to dashboard Cite

Itacitinib is a JAK1-selective inhibitor in phase 3 development in graft-versus-host disease. A post hoc electrocardiogram (ECG) analysis and a plasma concentration-QTc (C-QTc) analysis were performed to assess cardiac safety using data from the first-inhuman itacitinib study. The study included 2 cohorts of 12 healthy participants each in an interleaving dosing design with single doses of 10-300 mg or placebo; 500 and 1000 mg doses were subsequently added with 12 participants randomized to itacitinib or placebo. Continuous Holter recordings were collected from 1 hour predose to 8 hours postdose on each dosing day, and ECG intervals were blindly extracted to match timed pharmacokinetic samples. Data showed no hysteresis, and a prespecified linear mixed-effects C-QTc model was used with change-frombaseline QTcF (QT interval corrected for heart rate by Fridericia's method) as the dependent variable, plasma itacitinib concentrations and centered baseline QTcF as continuous covariates, treatment and time as categorical factors, and a random intercept per participant. The estimated slope of the C-QTc relationship was not significantly different from zero: 0.0002 milliseconds per nM (90%CI,-0.00019 to 0.00054 milliseconds). No clinically meaningful effects on cardiac conduction (PR and QRS intervals) or any categorical PR or QRS outliers were observed. A QTc effect exceeding the threshold of concern (10 milliseconds) can be excluded for itacitinib plasma concentrations up to ß13 000 nM (ß7200 ng/mL), which is well above the maximum concentration expected with the highest proposed therapeutic dose of itacitinib either with concomitant use of cytochrome P450 3A4 inhibitors or in patients with impaired hepatic function.

show abstract

Filgotinib, a JAK1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects

Cited by 8 publications

References 16 publications

Positioning Filgotinib in the Treatment Algorithm of Moderate to Severe Ulcerative Colitis

Positioning Filgotinib in the Treatment Algorithm of Moderate to Severe Ulcerative Colitis

Lack of Drug‐Drug Interaction Between Filgotinib, a Selective JAK1 Inhibitor, and Oral Hormonal Contraceptives Levonorgestrel/Ethinyl Estradiol in Healthy Volunteers

Evaluation of Clinical Cardiac Safety of Itacitinib, a JAK1 Inhibitor, in Healthy Participants

Contact Info

Product

Resources

About