Population Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects with Rheumatoid Arthritis: Analyses of Phase I and II Clinical Trials

The Journal of Clinical Pharma

Tian

et al. 2019

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Upadacitinib is a selective Janus kinase 1 inhibitor being developed for the treatment of several inflammatory autoimmune diseases, including rheumatoid arthritis. Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A enzymes. This open‐label, single‐dose, multicenter study assessed the pharmacokinetics of upadacitinib following oral administration of a single 15‐mg dose of the upadacitinib extended‐release formulation in subjects with mild (n = 6) and moderate (n = 6) hepatic impairment relative to demographically matched healthy subjects (n = 6). Subjects were assigned to 1 of the 3 groups according to the Child‐Pugh classification. Relative to subjects with normal hepatic function, the ratios (90% confidence intervals) of upadacitinib area under the plasma concentration‐versus‐time profile from time 0 to infinity (AUCinf) for subjects with mild and moderate hepatic impairment were 1.28 (0.91‐1.79) and 1.24 (0.87‐1.76), respectively. The central ratios of upadacitinib maximum observed concentration (Cmax) were 1.04 (0.77‐1.39) and 1.43 (1.05‐1.95) in subjects with mild and moderate hepatic impairment, respectively, compared with subjects with normal hepatic function. No clinically significant changes in vital signs or hematology measurements were observed, and no new safety events were identified in this study. These results indicate that mild and moderate hepatic impairment has no clinically relevant effect on upadacitinib pharmacokinetics.

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confidence: 80%

Characterization of the Effect of Hepatic Impairment on Upadacitinib Pharmacokinetics

Trueman

The Journal of Clinical Pharma

Tian

et al. 2019

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“…However, given that renal elimination plays a minor role in upadacitinib elimination, hemodialysis is not expected to have a clinically relevant effect on upadacitinib plasma exposures . In subjects with RA, upadacitinib CL/F for the immediate‐release formulation is estimated to be 30.2 L/h (503 mL/min) . Based on a percentage of upadacitinib immediate‐release dose eliminated in the urine of approximately 20%, upadacitinib nonrenal clearance is estimated to be approximately 400 mL/min (assuming 100% bioavailability for the immediate‐release formulation).…”

Section: Discussionmentioning

confidence: 99%

“…Upadacitinib pharmacokinetics were characterized in healthy subjects following the administration of a range of immediate‐release (1 mg to 48 mg) and extended‐release (7.5 mg to 45 mg [including data on file, AbbVie]) doses . Upadacitinib plasma exposures were approximately dose‐proportional over the range of immediate‐release or extended‐release doses evaluated in clinical studies . Approximately 20% of upadacitinib immediate‐release dose is eliminated in urine as unchanged upadacitinib .…”

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confidence: 99%

Characterization of the Effect of Renal Impairment on Upadacitinib Pharmacokinetics

The Journal of Clinical Pharma

Trueman

Tian

et al. 2019

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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.

“…There was no significant accumulation of upadacitinib in plasma with twice-daily dosing of the IR formulation, and approximately 20% of the upadacitinib dose was eliminated unchanged in urine. 12 Intersubject variability in healthy subjects and subjects with rheumatoid arthritis (RA) was estimated to be 16% and 26%, respectively, for apparent upadacitinib oral clearance and 14% and 27%, respectively, for upadacitinib apparent central volume of distribution. Administration of the strong CYP3A inhibitor ketoconazole resulted in a 75% increase in upadacitinib AUC, whereas the CYP inducer rifampin decreased upadacitinib AUC by 60%.…”

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confidence: 99%

“…10 Upadacitinib is a nonsensitive substrate for cytochrome P450 (CYP) 3A with a minor contribution of CYP2D6 in vitro. 12 Two dose-ranging phase 2 studies evaluated the efficacy and safety of upadacitinib in subjects with RA who had inadequate response to methotrexate or anti-tumor necrosis factor therapy. 11 In a population pharmacokinetic analysis of phase 1 and 2 studies, the CYP2D6 metabolic phenotype showed no effect on the apparent upadacitinib oral clearance; mild and moderate renal impairment was estimated to result in 16% and 32% higher upadacitinib AUC compared with subjects with normal renal function.…”

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confidence: 99%

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

Clinical Pharm in Drug Dev

Zeng

Marroum

et al. 2018

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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.