CIBINQO 10 Action And Clinical Pharmacology

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10.1 Mechanism of Action

Abrocitinib is a highly selective Janus kinase (JAK)1 inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor‑receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within signaling pathways, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Abrocitinib modulates the signaling pathway at the point of JAK1, preventing the phosphorylation and activation of STATs. 

Abrocitinib reversibly and selectively inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. In a cell-free isolated enzyme assay, abrocitinib has biochemical selectivity for JAK1 over the other 3 JAK isoforms JAK2 (28-fold), JAK3 (>340-fold) and tyrosine kinase (TYK) 2 (43-fold), and even higher selectivity over the broader kinome. In cellular settings, where JAK enzymes transmit signals in pairs (i.e., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2), abrocitinib preferentially inhibits cytokine‑induced STAT phosphorylation mediated by receptors utilizing JAK1 relative to receptors utilizing JAK2 only or JAK2/TYK2 pairs. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Both the parent compound and the active metabolites (M1 and M2) inhibit cytokine signaling with similar levels of selectivity.

10.2 Pharmacodynamics

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.

10.3 Pharmacokinetics

Table 6 - Summary of Abrocitinib and its Active Metabolites Pharmacokinetic Parameters after Single Oral Administration* of Abrocitinib in Healthy Participants**

 

Cmax (ng/mL)a

Tmax (h)b

t½ (h)c

AUC0-∞ (ng·h/mL)a

CL/F (L/h)a

Vz/F (L)a

100 mg

Abrocitinib

420.2

1

4.3

1578

63.41

323.3

M1

49.0

1

4.3

565.6

N/A

N/A

M2

95.8

1

2.9

532.9

N/A

N/A

200 mg

Abrocitinib

756.5

1

5.9

3902

51.24

375.2

M1

210.2

1

4.2

998.5

N/A

N/A

M2

162.1

2

3.9

1197

N/A

N/A

*
Steady-state Cmax of the unbound active moiety (abrocitinib + M1 + M2) was approximately 1.37-fold higher relative to the single-dose.
**
Cmax and AUC values of abrocitinib in AD patients are ~30% higher at steady-state relative to healthy volunteers, based on population PK analysis.  
a
Geometric mean
b
Median
c
Arithmetic mean
 
(M1 and M2 metabolites) 

Absorption

Abrocitinib is well-absorbed with over 91% extent of oral absorption and absolute oral bioavailability of approximately 60%. Both Cmax and AUC of abrocitinib increased dose proportionally over the recommended daily dosage range. Coadministration of CIBINQO with a high-fat meal had no clinically relevant effect on abrocitinib exposures (AUC and Cmax increased by approximately 26% and 29%, respectively, and Tmax was prolonged by 2 hours). In clinical studies, CIBINQO was administered without regard to food.

Distribution

After intravenous administration, the volume of distribution of CIBINQO is about 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 bind predominantly to albumin. Abrocitinib and its active metabolites distribute equally between red blood cells and plasma. 

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 3 polar mono-hydroxylated metabolites identified as M1 (3-hydroxypropyl), M2 (2-hydroxypropyl), and M4 (pyrrolidinone pyrimidine). Of the 3 metabolites in circulation, M1 and M2 have similar JAK inhibitory profiles as abrocitinib, while M4 was pharmacologically inactive. The pharmacologic activity of CIBINQO is attributable to the unbound exposures 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 abrocitinib active moiety. 

Elimination

CIBINQO is eliminated primarily by metabolic clearance mechanisms, with less than 1% of the dose excreted in urine as unchanged drug. The metabolites of abrocitinib, M1, M2 and M4 are excreted predominantly in urine, and are substrates of OAT3 transporter. 

Special Populations and Conditions 

  • Pediatrics: Adolescents (12 to less than 18 years of age):
    Based on population pharmacokinetic analysis, mean CIBINQO steady-state exposure in adolescent patients is estimated to be approximately 30% lower compared to adults of the same weight, with similar range of exposures in adult and adolescent patients. These differences in mean exposures were not considered clinically significant. 

Pediatric (under 12 years of age):
The pharmacokinetics of CIBINQO in pediatric patients under 12 years of age have not yet been established. 

  • Geriatrics: After considering hepatic or renal impairment effects related to increasing age in the elderly, age ≥65 years does not have a clinically significant effect on exposures of abrocitinib or active moiety. 
  • Sex: Body weight, gender, CYP2C19/2C9 genotype, race, and age did not have a clinically meaningful effect on CIBINQO exposure. 
  • Pregnancy and Breast-feeding: Women of reproductive potential should be advised to use effective contraception during treatment and for 1 month following the final dose of CIBINQO. The limited human data on use of CIBINQO in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. 

In a pre- and postnatal development study in pregnant rats, CIBINQO oral administration during gestation and through lactation resulted in lower postnatal survival and lower offspring body weights at exposures equal to or greater than approximately 11 times the unbound human AUC the maximum recommended clinical dose of 200 mg once. CIBINQO should not be used during pregnancy unless clearly necessary.

  • Hepatic Insufficiency: Patients with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had approximately 4% decrease and 15% increase in active moiety AUCinf, respectively, compared to patients with normal hepatic function. These changes are not clinically significant, and no dose adjustment is required in patients with mild or moderate hepatic impairment. In clinical studies, CIBINQO was not evaluated in patients with severe (Child Pugh C) hepatic impairment, or in patients screened positive for active hepatitis B or hepatitis C.
  • Renal Insufficiency: In a renal impairment study, patients with severe (eGFR <30 mL/min) and moderate (eGFR 30 to <60 mL/min) renal impairment had approximately 191% and 110% increase in active moiety AUCinf, respectively, compared to patients with normal renal function (eGFR ≥90 mL/min). Based on these results, a clinically significant increase in abrocitinib active moiety is not expected in patients with mild renal impairment (creatinine clearance 60 to <90 mL/min). The eGFR in individual patients was estimated using Modification of Diet in Renal Disease (MDRD) formula.

CIBINQO has not been studied in patients with ESRD on renal replacement therapy. In Phase 3 clinical studies, CIBINQO was not evaluated in patients with atopic dermatitis with baseline creatinine clearance values less than 40 mL/min.