Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis

Mohamed, Mohamed‐Eslam F.; Camp, Heidi S.; Jiang, Ping; Padley, Robert J.; Asatryan, Armen; Othman, Ahmed A.

doi:10.1007/s40262-016-0419-y

Cited by 95 publications

(151 citation statements)

References 20 publications

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“…10 The lower limit of quantitation for upadacitinib in plasma was 0.05 ng/mL. 10 The lower limit of quantitation for upadacitinib in plasma was 0.05 ng/mL.…”

Section: Pharmacokinetic Samplingmentioning

confidence: 98%

“…10 Following administration of the upadacitinib IR formulation, the maximum upadacitinib plasma concentration was achieved within 2 hours of dosing, followed by a biexponential decline in plasma levels. 10 Following administration of the upadacitinib IR formulation, the maximum upadacitinib plasma concentration was achieved within 2 hours of dosing, followed by a biexponential decline in plasma levels.…”

mentioning

confidence: 99%

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Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended‐Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials

Mohamed

Zeng

Marroum

et al. 2018

Clinical Pharm in Drug Dev

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Upadacitinib is a Janus kinase 1 inhibitor under development for the treatment of several inflammatory disorders including rheumatoid arthritis (RA). Upadacitinib was administered in the phase 2 RA trials primarily as twice-daily regimens of an immediate-release (IR) formulation. The upadacitinib extended-release (ER) formulation was developed to enable once-daily dosing. In the present study, upadacitinib pharmacokinetics were characterized after the administration of single and multiple once-daily doses of the ER formulation in healthy subjects relative to single and multiple twice-daily doses of the IR formulation. Increase in upadacitinib exposure was dose-proportional over the evaluated 15- to 30-mg ER dose range. Single 15- and 30-mg ER doses provided equivalent AUC compared with single 12- and 24-mg IR doses, respectively. A high-fat breakfast increased upadacitinib ER C and AUC by only 20% and 17%, respectively, relative to fasting conditions. The median time to peak plasma concentrations was 2 to 4 hours for the ER formulation, and steady state was achieved by day 4 of once-daily dosing. Doses of 15 and 30 mg once daily using the ER formulation provided equivalent AUC , comparable C and C , and a fluctuation index over a 24-hour period at steady state similar to 6 and 12 mg twice daily, respectively, using the IR formulation. These results supported the use of upadacitinib 15- and 30-mg doses of the ER formulation in the phase 3 trials in RA.

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“…10 The lower limit of quantitation for upadacitinib in plasma was 0.05 ng/mL. 10 The lower limit of quantitation for upadacitinib in plasma was 0.05 ng/mL.…”

Section: Pharmacokinetic Samplingmentioning

confidence: 98%

mentioning

confidence: 99%

Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended‐Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials

Mohamed

Zeng

Marroum

et al. 2018

Clinical Pharm in Drug Dev

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“…JAK1 selectivity (ABT-494 and filgotinib) may be associated with an improved safety profile compared with non-selective JAK inhibitors 71. TD-1473 is a novel pan-JAK inhibitor designed to inhibit JAK in the GI tract upon oral dosing.…”

Section: Tofacitinib and Other Jak Inhibitorsmentioning

confidence: 99%

Next generation of small molecules in inflammatory bowel disease

Olivera

Danese

Peyrin–Biroulet

2016

Gut

128

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“…Upadacitinib is being developed for the treatment of rheumatoid arthritis (RA) as well as for other immune‐mediated inflammatory diseases. In subjects with moderate to severe RA, upadacitinib demonstrated favorable efficacy and acceptable safety profiles, including in 2 phase 2 studies and in 5 phase 3 studies . Additionally, upadacitinib recently demonstrated favorable efficacy in subjects with ulcerative colitis, Crohn disease, and atopic dermatitis in phase 2 studies .…”

mentioning

confidence: 99%

“…Upadacitinib potently inhibits JAK1 but is less potent against the other isoforms, JAK2, JAK3, and tyrosine kinase 2 . The enhanced selectivity of upadacitinib against JAK1 may offer an improved benefit‐risk profile in patients with inflammatory disease, including limiting the adverse effects on immune function and erythropoietin signaling . Upadacitinib is being developed for the treatment of rheumatoid arthritis (RA) as well as for other immune‐mediated inflammatory diseases.…”

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confidence: 99%

Characterization of the Effect of Renal Impairment on Upadacitinib Pharmacokinetics

Mohamed

Trueman

Tian

et al. 2019

The Journal of Clinical Pharma

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Upadacitinib is a novel selective Janus kinase 1 inhibitor developed for treatment of rheumatoid arthritis and other autoimmune diseases. The objective of this study was to assess the pharmacokinetics and safety of a single upadacitinib dose in subjects with normal renal function and in subjects with renal impairment. A total of 24 subjects between the ages of 18 and 75 years were assigned to 1 of 4 renal function groups based on estimated glomerular filtration rate (normal, mild, moderate, severe; N = 6/group). A single 15‐mg dose of upadacitinib extended‐release formulation was administered under fasting conditions. Serial plasma and urine samples were assayed to evaluate the effect of renal impairment on upadacitinib exposure through regression analysis and analysis of covariance. The primary analysis was the regression analysis of upadacitinib exposures versus estimated glomerular filtration rate. The point estimates for upadacitinib plasma exposure ratios (90% confidence interval [CI]) in subjects with mild, moderate, and severe renal impairment were 1.18 (90%CI, 1.06–1.32), 1.33 (90%CI, 1.11–1.59), and 1.44 (90%CI, 1.14–1.82) for area under the plasma concentration–time curve and 1.06 (90%CI, 0.92–1.23), 1.11 (90%CI, 0.88–1.40), and 1.14 (90%CI, 0.84–1.56) for maximum observed plasma concentration, respectively, relative to subjects with normal renal function based on the regression analysis. The analysis of covariance categorical analysis provided consistent results. Upadacitinib was well tolerated by all subjects, and no safety issues were identified in subjects with renal impairment. Renal impairment has a limited effect on upadacitinib pharmacokinetics. This is in agreement with the known limited role of urinary excretion in upadacitinib elimination. Based on the limited impact on exposure, no dose adjustment is necessary for upadacitinib in subjects with impaired renal function.

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Pharmacokinetics, Safety and Tolerability of ABT-494, a Novel Selective JAK 1 Inhibitor, in Healthy Volunteers and Subjects with Rheumatoid Arthritis

Abstract: ClinicalTrials.gov ( https://clinicaltrials.gov/ ) identifier: NCT01741493.

Cited by 95 publications

References 20 publications

Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended‐Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials

Pharmacokinetics of Upadacitinib With the Clinical Regimens of the Extended‐Release Formulation Utilized in Rheumatoid Arthritis Phase 3 Trials

Next generation of small molecules in inflammatory bowel disease

Characterization of the Effect of Renal Impairment on Upadacitinib Pharmacokinetics

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