LITFULO is a kinase inhibitor.
Ritlecitinib irreversibly inhibits Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family by blocking the adenosine triphosphate (ATP) binding site. In cellular settings, ritlecitinib inhibits cytokine induced STAT phosphorylation mediated by JAK3-dependent receptors. Additionally, ritlecitinib inhibits signaling of immune receptors dependent on TEC kinase family members. The relevance of inhibition of specific JAK or TEC family enzymes to therapeutic effectiveness is not currently known.
Lymphocyte Subsets
A dose-dependent early decrease in absolute lymphocyte levels, T lymphocytes (CD3) and T lymphocyte subsets (CD4 and CD8) was associated with LITFULO treatment in patients with alopecia areata. In addition, there was a dose-dependent early decrease in NK cells (CD16/56) which remained stable at the lower level up to Week 48. For the 50 mg QD dose, there was an initial decrease in median lymphocyte levels which remained consistent up to Week 48. There was no change observed in B lymphocytes (CD19) in any treatment group.
Ritlecitinib AUC0-tau and Cmax increase in an approximately dose-proportional manner up to 200 mg. Steady state was reached approximately by Day 4.
Absorption
The ritlecitinib absolute oral bioavailability is approximately 64%. Ritlecitinib peak plasma concentrations were reached within 1 hour following an oral dose.
Effect of Food
Food does not have a clinically significant impact on the systemic exposures of ritlecitinib. The coadministration of a 100 mg ritlecitinib capsule with a high-fat meal reduced the ritlecitinib Cmax by ~32% and AUCinf was increased by 11%. In clinical trials, ritlecitinib was administered without regard to meals [see Dosage and Administration (2.2)].
Elimination
The ritlecitinib mean terminal half-life ranges from 1.3 to 2.3 hours.
Metabolism
The metabolism of ritlecitinib is mediated by multiple pathways with no single route contributing to more than 25% of the total metabolism. These pathways include:
Specific Populations
No clinically relevant differences in the pharmacokinetics of ritlecitinib were observed based on age (12-73 years), body weight, gender, GST genotype, and race.
Patients with Renal Impairment
The AUC24 observed in patients with severe renal impairment (eGFR <30 mL/min) was 55.2% higher compared with the AUC24 in matched participants with normal renal functions. These differences are not considered clinically significant. Ritlecitinib has not been studied in patients with mild (eGFR 60 to <90 mL/min) or moderate (eGFR 30 to <60 mL/min) renal impairment, as a clinically relevant increase in ritlecitinib exposure is not expected in these patients. The eGFR and classification of renal function status of patients was done using the Modification of Diet in Renal Disease (MDRD) formula. Ritlecitinib has not been studied in patients with ESRD or in renal transplant recipients.
Patients with Hepatic Impairment
Patients with moderate (Child Pugh B) hepatic impairment had an 18.5% increase in ritlecitinib AUC24 compared to patients with normal hepatic function. Ritlecitinib has not been studied in patients with mild (Child Pugh A) hepatic impairment, as a clinically relevant increase in ritlecitinib exposure is not expected in these patients.
Ritlecitinib has not been studied in patients with severe (Child Pugh C) hepatic impairment and is not recommended for use in these patients [see Dosage and Administration (2.3) and Use In Specific Populations (8.6)].
Drug Interaction Studies
Clinical Studies
Effect of other drugs on ritlecitinib
The effect of coadministered drugs on the pharmacokinetics of ritlecitinib is presented in Table 5.
Coadministered Drugs | Regimen of Coadministered Drug | Dose of Ritlecitinib | Ratio* (90% Confidence Interval) | |
Cmax | AUCinf | |||
Strong CYP3A inhibitor: Itraconazole† | 200 mg once daily × 5 days | 30 mg | 1.03 (0.83, 1.27) | 1.15 (1.05, 1.27) |
Strong CYP enzyme inducer: Rifampin | 600 mg once daily × 8 days | 50 mg | 0.75 (0.63, 0.89) | 0.56 (0.52, 0.60) |
Effect of ritlecitinib on other drugs
The effect of ritlecitinib on the pharmacokinetics of coadministered drugs is presented in Table 6.
| |||
Coadministered Drugs | Dose Regimen of Ritlecitinib | Ratio* (90% Confidence Interval) | |
Cmax | AUCinf | ||
Oral contraceptive: Ethinyl estradiol (EE) and levonorgestrel (LN)† | 50 mg once daily × 11 days | EE: 0.92 (0.84, 1.01) LN: 0.80 (0.73, 0.88) | EE: 0.98 (0.91, 1.06) LN‡: 0.88 (0.83, 0.93) |
Sensitive CYP3A substrate: Midazolam [see Drug Interactions (7.1)] | 200 mg once daily × 11 days§ | 1.81 (1.48, 2.21) | 2.69 (2.16, 3.36) |
Sensitive CYP1A2 substrate: Caffeine [see Drug Interactions (7.1)] | 200 mg once daily × 9 days§ | 1.10 (1.04, 1.16) | 2.65 (2.34, 3.00) |
Sensitive CYP2B6 substrate: Efavirenz† | 200 mg once daily × 11 days§ | 0.88 (0.77, 1.01) | 1.00¶ (0.95, 1.04) |
Sensitive CYP2C substrate: Tolbutamide† | 200 mg once daily × 10 days§ | 1.03 (0.97, 1.10) | 0.99 (0.92, 1.07) |
Sensitive OATP1B1, BCRP and OAT3 substrate: Rosuvastatin† | 200 mg once daily × 10 days§ | 0.73 (0.63, 0.83) | 0.87 (0.75, 1.01) |
Sensitive OCT1 substrate: Sumatriptan† | 400 mg single dose coadministration# | 0.87 (0.73, 1.03) | 1.30 (1.17, 1.44) |
400 mg single dose 8 hours prior to Sumatriptan# | 1.50 (1.26, 1.78) | 1.50 (1.35, 1.66) | |
In Vitro Studies
CYP Related Pathways: Ritlecitinib is not an inhibitor of CYP2D6.
Other Metabolic Pathways: Ritlecitinib is not an inhibitor of uridine 5’ diphospho glucuronosyltransferases (UGTs) (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7), GSTs or sulfotransferases (SULTs).
Transporter Systems: Ritlecitinib is not an inhibitor of P-glycoprotein (P-gp) or bile salt export pump (BSEP).
LITFULO is a kinase inhibitor.
Ritlecitinib irreversibly inhibits Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family by blocking the adenosine triphosphate (ATP) binding site. In cellular settings, ritlecitinib inhibits cytokine induced STAT phosphorylation mediated by JAK3-dependent receptors. Additionally, ritlecitinib inhibits signaling of immune receptors dependent on TEC kinase family members. The relevance of inhibition of specific JAK or TEC family enzymes to therapeutic effectiveness is not currently known.
Lymphocyte Subsets
A dose-dependent early decrease in absolute lymphocyte levels, T lymphocytes (CD3) and T lymphocyte subsets (CD4 and CD8) was associated with LITFULO treatment in patients with alopecia areata. In addition, there was a dose-dependent early decrease in NK cells (CD16/56) which remained stable at the lower level up to Week 48. For the 50 mg QD dose, there was an initial decrease in median lymphocyte levels which remained consistent up to Week 48. There was no change observed in B lymphocytes (CD19) in any treatment group.
Ritlecitinib AUC0-tau and Cmax increase in an approximately dose-proportional manner up to 200 mg. Steady state was reached approximately by Day 4.
Absorption
The ritlecitinib absolute oral bioavailability is approximately 64%. Ritlecitinib peak plasma concentrations were reached within 1 hour following an oral dose.
Effect of Food
Food does not have a clinically significant impact on the systemic exposures of ritlecitinib. The coadministration of a 100 mg ritlecitinib capsule with a high-fat meal reduced the ritlecitinib Cmax by ~32% and AUCinf was increased by 11%. In clinical trials, ritlecitinib was administered without regard to meals [see Dosage and Administration (2.2)].
Elimination
The ritlecitinib mean terminal half-life ranges from 1.3 to 2.3 hours.
Metabolism
The metabolism of ritlecitinib is mediated by multiple pathways with no single route contributing to more than 25% of the total metabolism. These pathways include:
Specific Populations
No clinically relevant differences in the pharmacokinetics of ritlecitinib were observed based on age (12-73 years), body weight, gender, GST genotype, and race.
Patients with Renal Impairment
The AUC24 observed in patients with severe renal impairment (eGFR <30 mL/min) was 55.2% higher compared with the AUC24 in matched participants with normal renal functions. These differences are not considered clinically significant. Ritlecitinib has not been studied in patients with mild (eGFR 60 to <90 mL/min) or moderate (eGFR 30 to <60 mL/min) renal impairment, as a clinically relevant increase in ritlecitinib exposure is not expected in these patients. The eGFR and classification of renal function status of patients was done using the Modification of Diet in Renal Disease (MDRD) formula. Ritlecitinib has not been studied in patients with ESRD or in renal transplant recipients.
Patients with Hepatic Impairment
Patients with moderate (Child Pugh B) hepatic impairment had an 18.5% increase in ritlecitinib AUC24 compared to patients with normal hepatic function. Ritlecitinib has not been studied in patients with mild (Child Pugh A) hepatic impairment, as a clinically relevant increase in ritlecitinib exposure is not expected in these patients.
Ritlecitinib has not been studied in patients with severe (Child Pugh C) hepatic impairment and is not recommended for use in these patients [see Dosage and Administration (2.3) and Use In Specific Populations (8.6)].
Drug Interaction Studies
Clinical Studies
Effect of other drugs on ritlecitinib
The effect of coadministered drugs on the pharmacokinetics of ritlecitinib is presented in Table 5.
Coadministered Drugs | Regimen of Coadministered Drug | Dose of Ritlecitinib | Ratio* (90% Confidence Interval) | |
Cmax | AUCinf | |||
Strong CYP3A inhibitor: Itraconazole† | 200 mg once daily × 5 days | 30 mg | 1.03 (0.83, 1.27) | 1.15 (1.05, 1.27) |
Strong CYP enzyme inducer: Rifampin | 600 mg once daily × 8 days | 50 mg | 0.75 (0.63, 0.89) | 0.56 (0.52, 0.60) |
Effect of ritlecitinib on other drugs
The effect of ritlecitinib on the pharmacokinetics of coadministered drugs is presented in Table 6.
| |||
Coadministered Drugs | Dose Regimen of Ritlecitinib | Ratio* (90% Confidence Interval) | |
Cmax | AUCinf | ||
Oral contraceptive: Ethinyl estradiol (EE) and levonorgestrel (LN)† | 50 mg once daily × 11 days | EE: 0.92 (0.84, 1.01) LN: 0.80 (0.73, 0.88) | EE: 0.98 (0.91, 1.06) LN‡: 0.88 (0.83, 0.93) |
Sensitive CYP3A substrate: Midazolam [see Drug Interactions (7.1)] | 200 mg once daily × 11 days§ | 1.81 (1.48, 2.21) | 2.69 (2.16, 3.36) |
Sensitive CYP1A2 substrate: Caffeine [see Drug Interactions (7.1)] | 200 mg once daily × 9 days§ | 1.10 (1.04, 1.16) | 2.65 (2.34, 3.00) |
Sensitive CYP2B6 substrate: Efavirenz† | 200 mg once daily × 11 days§ | 0.88 (0.77, 1.01) | 1.00¶ (0.95, 1.04) |
Sensitive CYP2C substrate: Tolbutamide† | 200 mg once daily × 10 days§ | 1.03 (0.97, 1.10) | 0.99 (0.92, 1.07) |
Sensitive OATP1B1, BCRP and OAT3 substrate: Rosuvastatin† | 200 mg once daily × 10 days§ | 0.73 (0.63, 0.83) | 0.87 (0.75, 1.01) |
Sensitive OCT1 substrate: Sumatriptan† | 400 mg single dose coadministration# | 0.87 (0.73, 1.03) | 1.30 (1.17, 1.44) |
400 mg single dose 8 hours prior to Sumatriptan# | 1.50 (1.26, 1.78) | 1.50 (1.35, 1.66) | |
In Vitro Studies
CYP Related Pathways: Ritlecitinib is not an inhibitor of CYP2D6.
Other Metabolic Pathways: Ritlecitinib is not an inhibitor of uridine 5’ diphospho glucuronosyltransferases (UGTs) (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7), GSTs or sulfotransferases (SULTs).
Transporter Systems: Ritlecitinib is not an inhibitor of P-glycoprotein (P-gp) or bile salt export pump (BSEP).
{{section_body_html_patient}}
Chat online with Pfizer Medical Information regarding your inquiry on a Pfizer medicine.
*Speak with a Pfizer Medical Information Professional regarding your medical inquiry. Available 9AM-5PM ET Monday to Friday; excluding holidays.
Submit a medical question for Pfizer prescription products.
Pfizer Safety
To report an adverse event related to the Pfizer-BioNTech COVID-19 Vaccine, and you are not part of a clinical trial* for this product, click the link below to submit your information:
Pfizer Safety Reporting Site*If you are involved in a clinical trial for this product, adverse events should be reported to your coordinating study site.
If you cannot use the above website, or would like to report an adverse event related to a different Pfizer product, please call Pfizer Safety at (800) 438-1985.
FDA Medwatch
You may also contact the U.S. Food and Drug Administration (FDA) directly to report adverse events or product quality concerns either online at www.fda.gov/medwatch or call (800) 822-7967.