Chemical formula: C₁₇H₁₉F₃N₆O Molecular mass: 380.375 g/mol
Upadacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Upadacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.
JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In a cell-free isolated enzyme assay, upadacitinib had greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2. In human leukocyte cellular assays, upadacitinib inhibited cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1/JAK3 more potently than JAK2/JAK2 mediated STAT phosphorylation. However, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.
In healthy volunteers, the administration of upadacitinib (immediate release formulation) resulted in a dose- and concentration-dependent inhibition of IL-6 (JAK1/JAK2)-induced STAT3 and IL-7 (JAK1/JAK3)-induced STAT5 phosphorylation in whole blood. The maximal inhibition was observed 1 hour after dosing which returned to near baseline by the end of dosing interval.
Treatment with upadacitinib was associated with a small, transient increase in mean ALC from baseline up to Week 36 which gradually returned to, at or near baseline levels with continued treatment.
In the controlled period, small decreases from baseline in mean IgG and IgM levels were observed with upadacitinib treatment; however, the mean values at baseline and at all visits were within the normal reference range.
At 6 times the mean maximum exposure of the 15 mg once daily dose, there was no clinically relevant effect on the QTc interval.
Upadacitinib plasma exposures are proportional to dose over the therapeutic dose range. Steady-state plasma concentrations are achieved within 4 days with minimal accumulation after multiple once-daily administrations.
Following oral administration of upadacitinib extended-release formulation, upadacitinib is absorbed with a median Tmax of 2 to 4 hours.
Coadministration of upadacitinib with a high-fat/ high-calorie meal had no clinically relevant effect on upadacitinib exposures (increased AUCinf by 29% and Cmax by 39%). In clinical trials, upadacitinib was administered without regard to meals.
Upadacitinib is 52% bound to plasma proteins. Upadacitinib partitions similarly between plasma and blood cellular components with a blood to plasma ratio of 1.0.
Upadacitinib metabolism is mediated by mainly CYP3A4 with a potential minor contribution from CYP2D6. The pharmacologic activity of upadacitinib is attributed to the parent molecule. In a human radiolabeled study, unchanged upadacitinib accounted for 79% of the total radioactivity in plasma while the main metabolite detected (product of monooxidation followed by glucuronidation) accounted for 13% of the total plasma radioactivity. No active metabolites have been identified for upadacitinib.
Following single dose administration of [14C]-upadacitinib immediate-release solution, upadacitinib was eliminated predominantly as the unchanged parent substance in urine (24%) and feces (38%). Approximately 34% of upadacitinib dose was excreted as metabolites. Upadacitinib mean terminal elimination half-life ranged from 8 to 14 hours.
Body weight, gender, race, ethnicity, and age did not have a clinically meaningful effect on upadacitinib exposure.
Renal impairment has no clinically relevant effect on upadacitinib exposure. Upadacitinib AUCinf was 18%, 33%, and 44% higher in subjects with mild, moderate, and severe renal impairment, respectively, compared to subjects with normal renal function. Upadacitinib Cmax was similar in subjects with normal and impaired renal function.
Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment has no clinically relevant effect on upadacitinib exposure. Upadacitinib AUCinf was 28% and 24% higher in subjects with mild and moderate hepatic impairment, respectively, compared to subjects with normal liver function. Upadacitinib Cmax was unchanged in subjects with mild hepatic impairment and 43% higher in subjects with moderate hepatic impairment compared to subjects with normal liver function. Upadacitinib was not studied in patients with severe hepatic impairment (Child-Pugh C).
Upadacitinib is metabolized in vitro by CYP3A4 with a minor contribution from CYP2D6. The effect of co-administered drugs on upadacitinib plasma exposures is provided in Table 1.
Table 1. Change in Pharmacokinetics of Upadacitinib in the Presence of Co-administered Drugs:
Co-administered Drug | Regimen of Co-administered Drug | Ratio (90% CI)a | |
---|---|---|---|
Cmax | AUC | ||
Methotrexate | 10 to 25 mg/week | 0.97 (0.86-1.09) | 0.99 (0.93-1.06) |
Strong CYP3A4 inhibitor: Ketoconazole | 400 mg once daily x 6 days | 1.70 (1.55-1.89) | 1.75 (1.62-1.88) |
Strong CYP3A4 inducer: Rifampin | 600 mg once daily x 9 days | 0.49 (0.44-0.55) | 0.39 (0.37-0.42) |
OATP1B inhibitor: Rifampin | 600 mg single dose | 1.14 (1.02-1.28) | 1.07 (1.01-1.14) |
CI: Confidence interval
a Ratios for Cmax and AUC compare co-administration of the medication with upadacitinib vs. administration of upadacitinib alone.
pH modifying medications (e.g., antacids or proton pump inhibitors) are not expected to affect upadacitinib plasma exposures based on in vitro assessments and population pharmacokinetic analyses. CYP2D6 metabolic phenotype had no effect on upadacitinib pharmacokinetics (based on population pharmacokinetic analyses), indicating that inhibitors of CYP2D6 have no clinically relevant effect on upadacitinib exposures.
In vitro studies indicate that upadacitinib does not inhibit or induce the activity of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at clinically relevant concentrations. In vitro studies indicate that upadacitinib does not inhibit the transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, and MATE2K at clinically relevant concentrations.
Clinical studies indicate that upadacitinib has no clinically relevant effects on the pharmacokinetics of co-administered drugs. Summary of results from clinical studies which evaluated the effect of upadacitinib on other drugs is provided in Table 2.
Table 2. Change in Pharmacokinetics of Co-administered Drugs or In Vivo Markers of CYP Activity in the Presence of Upadacitinib:
Co-administered Drug or CYP Activity Marker | Multiple-Dose Regimen of Upadacitinib | Ratio (90% CI)a | |
---|---|---|---|
Cmax | AUC | ||
Methotrexate | 6 mg to 24 mg BIDb | 1.03 (0.86-1.23) | 1.14 (0.91-1.43) |
Sensitive CYP1A2 Substrate: Caffeine | 30 mg QDc | 1.13 (1.05-1.22) | 1.22 (1.15-1.29) |
Sensitive CYP3A Substrate: Midazolam | 30 mg QDc | 0.74 (0.68-0.80) | 0.74 (0.68-0.80) |
Sensitive CYP2D6 Substrate: Dextromethorphan | 30 mg QDc | 1.09 (0.98-1.21) | 1.07 (0.95-1.22) |
Sensitive CYP2C9 Substrate: S-Warfarin | 30 mg QDc | 1.07 (1.02-1.11) | 1.11 (1.07-1.15) |
Sensitive CYP2C19 Marker: 5-OH Omeprazole to Omeprazole metabolic ratio | 30 mg QD c | -- | 1.09 (1.00-1.19) |
CYP2B6 Substrate: Bupropion | 30 mg QD c | 0.87 (0.79-0.96) | 0.92 (0.87-0.98) |
Rosuvastatin | 30 mg QDc | 0.77 (0.63-0.94) | 0.67 (0.56-0.82) |
Atorvastatin | 30 mg QDc | 0.88 (0.79-0.97) | 0.77 (0.70-0.85) |
Ethinylestradiol | 30 mg QDc | 0.96 (0.89-1.02) | 1.11 (1.04-1.19) |
Levonorgestrel | 30 mg QDc | 0.96 (0.87-1.06) | 0.96 (0.85-1.07) |
CYP: cytochrome P450; CI: Confidence interval; BID: twice daily; QD: once daily
a Ratios for Cmax and AUC compare co-administration of the medication with upadacitinib vs. administration of medication alone.
b Immediate-release formulation
c Extended-release formulation
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