Additional Biologic Therapeutics: Dupilumab, Omalizumab, Others

Structure

Dupilumab is a recombinant, fully human IgG ₄ κ mAb targeted against the α-subunit of IL-4 receptors (type 1 and type 2) ( Table 31.1 ). It has a molecular mass of 147 kiloDaltons (kDa). Dupilumab is produced in Chinese Hamster Ovary (CHO) cells via recombinant deoxyribonucleic acid (DNA) technology.

Pharmacokinetics

Dupilumab demonstrates nonlinear pharmacokinetic behavior. Systemic exposure to dupilumab increases more than the proportional increase in dose. Dupilumab reaches peak serum concentration at 1 week with steady state achieved by week 16. Absorption of dupilumab is first order; however, the mechanism of absorption is not fully understood. Lymphatic absorption has been proposed for subcutaneously administered mAbs, and was successfully demonstrated with human recombinant interferon α-2a in sheep. Whether or not this can be extrapolated to dupilumab is unknown. The volume of distribution of dupilumab is 4.6 L. Each subcutaneous injection has an approximate bioavailability of 64%.

Q31.3 Clearance of dupilumab has not been well characterized; however, metabolism is thought to mimic endogenous IgG degradation via antibody-complex endocytosis and target-mediated clearance. As such, dupilumab follows both linear and nonlinear elimination pathways. Linear elimination is estimated at 0.13 L/day whereas nonlinear elimination is concentration dependent and occurs at clinically significant dosages, most notably between 75 mg and 300 mg. Population studies of pharmacokinetics demonstrated that maximum target-mediated elimination rates of dupilumab were equal between healthy and atopic individuals, confirming that the IL-4Rα subunit is not directly related in AD pathogenesis, but rather a shared target for the downstream effectors.

Individualized dosing of dupilumab is not required based on sex or weight for adult patients. Although body weight does alter the pharmacokinetics and serum concentration levels of dupilumab, phase III trial data demonstrated similar response rates (Eczema Area and Severity Index [EASI]-75, Investigator Global Assessment [IGA] 0/1) across body weight groups for both every 2-week and every week dosing with 300 mg. Dosing is modified for adolescent patients receiving dupilumab: patients <60 kilograms (kgs) receive an initial dose of 400mg followed by maintenance doses of 200mg every other week, while patients ≥ 60kgs receive the adult dosing regimen.

There are no studies evaluating the effects of dupilumab in renal or hepatic impairment.

Mechanism of Action

Q31.4 Dupilumab directly antagonizes the α-subunit of both type 1 and type 2 IL-4 receptors. Type 1 receptors bind IL-4 alone, whereas type 2 receptors bind both IL-4 and IL-13. By targeting the IL-4Rα subunit, dupilumab inhibits downstream signaling of both IL-4 and IL-13, type 2 cytokines that play a major role in the pathogenesis of AD.

Historically, the immune dysregulation of AD was described as biphasic. T-helper (Th)2 cytokines (IL-4, IL-5, IL-13) were thought to drive acute lesions whereas Th1 cytokines (interferon [IFN]-γ) caused chronic skin lesions. More recently, studies utilizing gene arrays and quantitative real-time polymerase chain reaction reveal that the immune dysfunction in AD is more likely on a continuum than truly biphasic. These genomic expression studies demonstrate notable increases in type 2 cytokines (IL-4, IL-13, IL-31) and small increases in Th1 (IFN-γ) in acute skin lesions with intensification of type 2 cytokines and a dramatic increase in type 1 cytokines in chronic skin lesions.

US Food And Drug Administration-Approved Dermatology Indication ( Box 31.1 )

Dupilumab has been FDA-approved for the treatment of patients ≥ 12 years of age with moderate to severe AD whose disease is inadequately controlled either with topical prescriptions or for whom topical prescriptions are not appropriate. It may be used alone or in combination with topical corticosteroids (CS).

Off-Label Dermatologic Indications

Q31.5 Dupilumab was developed and investigated as a targeted therapy for AD. Clinicians are currently considering dupilumab for a number other dermatologic conditions.

Warnings and Precautions