12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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.

Cardiac Electrophysiology

At 12 times the mean maximum exposure of the 50 mg once daily dose in patients with alopecia areata, there was no clinically relevant effect on the QTc interval.

12.3 Pharmacokinetics

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)].

Distribution

Approximately 14% of circulating ritlecitinib is bound to plasma proteins.

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:

•: Glutathione S-transferase (GST): cytosolic GST A1/3, M1/3/5, P1, S1, T2, Z1 and microsomal GST 1/2/3
•: CYP enzymes (CYP3A, CYP2C8, CYP1A2, and CYP2C9)

Excretion

Approximately 66% of radiolabeled ritlecitinib dose is excreted in the urine and 20% in the feces. Approximately 4% of the ritlecitinib dose is excreted unchanged drug in urine.

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.

Table 5. Change in Pharmacokinetics of Ritlecitinib in the Presence of Coadministered Drugs
* Ratios for Cmax and AUCinf compare coadministration of ritlecitinib with the drug versus administration of ritlecitinib alone. † Drug interaction with CYP3A inhibitor is not clinically significant.
Coadministered Drugs	Regimen of Coadministered Drug	Dose of Ritlecitinib	Ratio* (90% Confidence Interval)
Coadministered Drugs	Regimen of Coadministered Drug	Dose of Ritlecitinib	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.

Table 6. Change in Pharmacokinetics of Coadministered Drugs in the Presence of Ritlecitinib
* Ratios for Cmax and AUCinf compare coadministration of the drug with ritlecitinib versus administration of the drug alone. † Drug interactions with ritlecitinib for oral contraceptives, CYP2B6 substrates, CYP2C substrates, and substrates of OATP1B1, BCRP, OAT3, and OCT1 transporters are not clinically significant. ‡ AUClast of levonorgestrel was reported in lieu of AUCinf because the terminal phase of levonorgestrel was not well characterized. § Ritlecitinib dosage 4 times the approved recommended dosage. ¶ AUC0-72 of efavirenz was reported # Ritlecitinib dosage 8 times the approved recommended dosage.
Coadministered Drugs	Dose Regimen of Ritlecitinib	Ratio* (90% Confidence Interval)
Coadministered Drugs	Dose Regimen of Ritlecitinib	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)
Sensitive OCT1 substrate: Sumatriptan†	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).