Tofacitinib
by Douglas Black, Pharm.D.
last updated
2022-11-26 14:53:26.787073-05:00
© Antimicrobial Therapy, Inc.
Usage and Dosing
- Tofacitinib (Xeljanz) is a selective inhibitor of Janus kinase (JAK) 1 and JAK3, with functional selectivity for JAK2. This, plus action on other critical pathways of the inflammatory cascade, may lessen progressive, inflammation-driven lung injury in patients with COVID-19 pneumonia.
- Studied in patients hospitalized for <72 hours with COVID-10 pneumonia not requiring mechanical ventilation or ECMO (N Engl J Med 2021;385:406).
- Randomized placebo-controlled trial of 289 patients showed an approximate 40% reduction in risk of progression to death or respiratory failure for Tofacitinib compared to placebo, 18% vs. 29% (risk ratio, 0.63, p=0.04).
- 79% of patients were receiving supplement oxygen at enrollment and 89% of patients also received glucocorticoid therapy.
- Patients with a history of or current thrombosis, personal or first-degree family history of blood clotting disorders, immunosuppression, active cancer, or those with certain cytopenias were excluded from this trial.
- Randomized placebo-controlled trial of 289 patients showed an approximate 40% reduction in risk of progression to death or respiratory failure for Tofacitinib compared to placebo, 18% vs. 29% (risk ratio, 0.63, p=0.04).
Adult Dose
- COVID-19: 10 mg po q12h (for up to 14 days)
Pediatric Dose
- COVID-19 study patients were 18 years of age and older (N Engl J Med 2021;385:406).
Renal Adjustment
- 5 mg po q12h in patients with eGFR <50 ml/min/1.73m2 (N Engl J Med 2021;385:406).
Hepatic Adjustment
- Mild impairment: no dosage adjustment.
- Moderate impairment: 5 mg po q12h (N Engl J Med 2021;385:406).
- Severe impairment: no data (use of tofacitinib in severe hepatic impairment not recommended by manufacturer).
Adverse Effects
- Serious infections (TB, fungal infections, other opportunistic infections)
- Malignancy and lymphoproliferative disorders
- Thrombosis, including DVT and PE
- Gastrointestinal perforations
- Hypersensitivity reactions
- Neutropenia, lymphopenia, anemia
- AST, ALT elevations
- Lipid elevations (total cholesterol, LDL, HDL)
Pharmacology
Class | Janus kinase inhibitor |
PK/PD Index | No data |
Pharmaceutical Preparation |
Tab (5, 10 mg)
XR tab (11, 22 mg
Oral soln (1 mg/mL)
|
Pregnancy Category |
Insufficient data in humans, toxic in animals |
---|---|
Food Effect1 | Take with or without food |
Oral Absorption2 (%) |
74 |
Tmax (hr) | 0.8 |
Peak Serum Level3 (nanograms/mL) |
84.7 (10 mg po q12h, SS) |
Protein Binding (%) |
40 |
Average Serum Half-life4 (hr) |
3 |
Elimination | Hepatic metabolism, renal |
Biliary Penetration5 (%) | No data |
CSF/Blood Penetration6 (%) |
No data |
Therapeutic Levels in CSF7 | No data |
Volume of Distribution8 (Vd) |
87 L |
AUC9 (nanograms*hr/mL) |
539.6 (10 mg po q12h, 0-24h) |
CYP450, Transporter Interactions |
Substrate for CYP3A4 |
- Notes:
- 1 Adult preparations unless otherwise noted.
- 2 Absorption under optimal conditions.
- 3 Total drug; adjust for protein binding to determine free drug concentration.
- SD = after single dose
- SS = steady state after multiple doses
- 4 Assumes CrCl > 80 mL/min
- 5 Peak concentration in bile/peak concentration in serum x 100
- 6 CSF levels with inflammation
- 7 Judgment based on drug dose & organism susceptibility. CSF concentration ideally ≥10x above MIC.
- 8 Volume of Distribution (Vd):
- V/F = Vd/oral bioavailability
- Vss = Vd at steady state
- Vss/F = Vd at steady state/oral bioavailability
- 9 Area under the plasma concentration versus time curve
Major Drug Interactions
Drug | Effect on concentration | Suggested management |
Strong CYP3A4 inhibitor | ↑ tofacitinib | 5 mg q12h (N Engl J Med 2021;385:406) |
Moderate CYP3A4 inhibitor plus strong CYP2C19 inhibitor | ↑ tofacitinib | 5 mg q12h (N Engl J Med 2021;385:406) |