12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
CIBINQO is a Janus kinase (JAK) inhibitor.
Abrocitinib reversibly inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. In a cell-free isolated enzyme assay, abrocitinib was selective for JAK1 over JAK2 (28-fold), JAK3 (>340-fold), and tyrosine kinase (TYK) 2 (43-fold), as well as the broader kinome. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Both the parent compound and the active metabolites inhibit JAK1 activity in vitro with similar levels of selectivity.
Treatment with CIBINQO was associated with dose-dependent reduction in serum markers of inflammation, including high sensitivity C-reactive protein (hsCRP), interleukin-31 (IL-31) and thymus and activation regulated chemokine (TARC). These changes returned to near baseline within 4 weeks of drug discontinuation.
Effect on Platelet Count
Treatment with CIBINQO was also associated with a transient, dose-dependent decrease in platelet count with the nadir occurring at a median of 24 days after continuous administration of abrocitinib 200 mg once daily. The percent change from baseline of the nadir increases with decreasing baseline platelet counts (-41.2%, -33.4%, and -26.5% for baseline platelet counts of 170, 220, and 270× 103/mm3, respectively). Recovery of platelet count (~40% recovery by 12 weeks) occurred without discontinuation of the treatment.
Abrocitinib plasma Cmax and AUC increased dose proportionally up to 200 mg. Steady-state plasma concentrations of abrocitinib are achieved within 48 hours after once daily administration.
Abrocitinib is absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. The peak plasma concentrations of abrocitinib are reached within 1 hour.
Effect of Food
Coadministration of CIBINQO with a high-fat, high-calorie meal (total 916 calories, with approximate distribution of 55% fat, 29% carbohydrates, and 16% protein) had no clinically relevant effect on abrocitinib exposures (AUC and Cmax of abrocitinib increased by approximately 26% and 29%, respectively, and Tmax was prolonged by 2 hours) [see Dosage and Administration (2.7)].
After intravenous administration, the volume of distribution of abrocitinib is approximately 100 L. Approximately 64%, 37% and 29% of circulating abrocitinib and its active metabolites M1 and M2, respectively, are bound to plasma proteins. Abrocitinib and its active metabolites M1 and M2 bind predominantly to albumin and distribute equally between red blood cells and plasma.
Abrocitinib is eliminated primarily by metabolic clearance mechanisms. The mean elimination half-lives of abrocitinib and its two active metabolites, M1 and M2, range 3 to 5 hours.
The metabolism of abrocitinib is mediated by multiple CYP enzymes, CYP2C19 (~53%), CYP2C9 (~30%), CYP3A4 (~11%) and CYP2B6 (~6%). In a human radiolabeled study, abrocitinib was the most prevalent circulating species, with two active polar mono-hydroxylated metabolites identified as M1 (3-hydroxypropyl), and M2 (2-hydroxypropyl). Metabolite M1 is less active than abrocitinib while metabolite M2 is as active as the parent. The pharmacologic activity of abrocitinib is attributable to the unbound exposure of parent molecule (~60%) as well as M1 (~10%) and M2 (~30%) in systemic circulation. The sum of unbound exposures of abrocitinib, M1 and M2, each expressed in molar units and adjusted for relative potencies, is referred to as the combined exposure of abrocitinib and its two active metabolites, M1 and M2.
Body weight, sex, race, and age did not have a clinically meaningful effect on CIBINQO exposure.
Patients with Renal Impairment
In a renal impairment study, subjects with severe (eGFR <30 mL/min as estimated by MDRD equation) and moderate (eGFR 30–59 mL/min, MDRD) renal impairment had approximately 191% and 110% increase in the combined exposure (AUCinf,u) of abrocitinib and its active metabolites, M1 and M2, respectively, compared to subjects with normal renal function (eGFR ≥90 mL/min, MDRD). Based on these results, a clinically significant increase in the combined exposure of abrocitinib and its active metabolites, M1 and M2, is not expected in subjects with mild renal impairment (eGFR 60 –89 mL/min, MDRD) [see Dosage and Administration (2.3) and Use in Specific Population (8.6)].
CIBINQO has not been studied in subjects on renal replacement therapy [see Dosage and Administration (2.3) and Use in Specific Population (8.6)]. In Phase 3 clinical studies, CIBINQO was not evaluated in subjects with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.
Patients with Hepatic Impairment
Subjects with mild hepatic impairment (Child Pugh A) had approximately 4% decrease in the combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2, compared to subjects with normal hepatic function. Subjects with moderate hepatic impairment (Child Pugh B) had approximately 15% increase in the combined exposure (AUCinf,u) of abrocitinib and its two active metabolites, M1 and M2, compared to subjects with normal hepatic function. These changes are not clinically significant. In clinical studies, CIBINQO has not been studied in subjects with severe (Child Pugh C) hepatic impairment, or in subjects screened positive for active hepatitis B or hepatitis C [see Use in Specific Populations (8.7) and Warnings and Precautions (5.1)].
Drug Interaction Studies
The effect of coadministered drugs on the pharmacokinetics of abrocitinib is presented in Table 6.
|Coadministered Drugs||Regimen of Coadministered Drug||Dose of Abrocitinib||Ratio* (90% Confidence Interval)|
|Strong CYP2C19 and moderate CYP3A inhibitor:|
Fluvoxamine [see Drug Interactions (7.1)]
|50 mg once daily × 9 days||100 mg||1.33 (1.00–1.78)||1.91 (1.74–2.10)|
|Strong CYP2C19, moderate CYP2C9 and CYP3A inhibitor:|
Fluconazole [see Drug Interactions (7.1)]
|400 mg on Day 1 and 200 mg on Days 2–7||100 mg||1.23 (1.08–1.42)||2.55† (2.42–2.69)|
|Strong CYP Enzymes Inducers:|
Rifampin [see Drug Interactions (7.1)]
|600 mg once daily × 8 days||200 mg||0.69 (0.50–0.94)||0.44 (0.41–0.47)|
|1,000 mg twice daily × 3 days||200 mg||1.30 (1.04–1.63)||1.66 (1.52–1.80)|
The effect of abrocitinib on the pharmacokinetics of coadministered drugs is presented in Table 7.
|Coadministered Drugs or In Vivo Markers of CYP Activity||Dose Regimen of Abrocitinib||Ratio* (90% Confidence Interval)|
Ethinyl estradiol (EE) and levonorgestrel (LN)
|200 mg once daily × 9 days||EE: 1.07 (0.99, 1.15)|
LN: 0.86 (0.75, 0.97)
|EE: 1.19 (1.12, 1.26)|
LN†: 0.98 (0.87, 1.10)
|Sensitive CYP3A Substrate:|
|200 mg once daily × 7 days||0.93 (0.84, 1.04)||0.92 (0.86, 0.99)|
|Sensitive P-gp substrate:|
|200 mg single dose||1.40 (0.92, 2.13)||1.53 (1.09, 2.15)|
|Sensitive BCRP and OAT3 substrate:|
|200 mg once daily × 3 days||0.99 (0.86, 1.14)||1.02 (0.93, 1.12)|
|Sensitive MATE1/2K substrate:|
|200 mg once daily × 2 days||0.88 (0.81, 0.96)||0.93 (0.85, 1.03)|
Coadministration of dabigatran etexilate (a P-gp substrate), with a single dose of CIBINQO 200 mg increased dabigatran AUCinf and Cmax by approximately 53% and 40%, respectively, compared with administration alone. These increases in dabigatran exposure are not considered clinically significant change. However, appropriate dose titration of P-gp substrate where small concentration changes may lead to serious or life-threatening toxicities (e.g., digoxin) when coadministered with the CIBINQO would be needed.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Abrocitinib and its metabolites M1 and M2 are not inhibitors or inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.
Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Abrocitinib and its metabolites M1 and M2 are not inhibitors or inducers of UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.
Patients who are CYP2C19 poor metabolizers have little to no CYP2C19 enzyme function compared to CYP2C19 normal metabolizers that have fully functional CYP2C19 enzymes.
After single doses of abrocitinib, CYP2C19 poor metabolizers demonstrated dose-normalized AUC of abrocitinib values that were 2.3-fold higher when compared to CYP2C19 normal metabolizers. Approximately 3–5% of Caucasians and Blacks and 15 to 20% of Asians are CYP2C19 poor metabolizers [see Dosage and Administration (2.4) and Use in Specific Populations (8.8)].