Absorption
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)].
Distribution
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.
Elimination
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.
Metabolism
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.
Excretion
After a single radiolabeled abrocitinib dose, less than 1% of the dose was excreted in urine as unchanged drug. The metabolites of abrocitinib, M1 and M2 are excreted predominantly in urine, and are substrates of OAT3 transporter.
Specific Populations
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 patients 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 trials, 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 trials, 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
Clinical Studies
The effect of coadministered drugs on the pharmacokinetics of abrocitinib is presented in Table 6.
Table 6. Change in Pharmacokinetics of the Combined Exposure of Abrocitinib and its Two Active Metabolites (M1 and M2) in the Presence of Coadministered Drugs |
Coadministered Drugs | Regimen of Coadministered Drug | Dose of Abrocitinib | Ratio* (90% Confidence Interval) |
Cmax,u | AUCinf,u |
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) |
OAT3 inhibitor: Probenecid‡ | 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.
Table 7. Change in Pharmacokinetics of Coadministered Drugs in the Presence of Abrocitinib |
Coadministered Drugs or In Vivo Markers of CYP Activity | Dose Regimen of Abrocitinib | Ratio* (90% Confidence Interval) |
Cmax | AUCinf |
Oral contraceptive: 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: Midazolam | 200 mg once daily × 7 days | 0.93 (0.84, 1.04) | 0.92 (0.86, 0.99) |
Sensitive P-gp substrate: Dabigatran | 200 mg single dose | 1.40 (0.92, 2.13) | 1.53 (1.09, 2.15) |
Sensitive BCRP and OAT3 substrate: Rosuvastatin | 200 mg once daily × 3 days | 0.99 (0.86, 1.14) | 1.02 (0.93, 1.12) |
Sensitive MATE1/2K substrate: Metformin | 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.
Transporter Systems: Abrocitinib is an inhibitor of organic cation transporter (OCT)1 but is not an inhibitor of organic anion transporting polypeptide (OATP)1B1/1B3, bile salt export pump (BSEP), OAT1 or OCT2.