Pharmacokinetic Modeling of Spesolimab Reveals Key Differences Between IV and Subcutaneous Dosing for Generalized Pustular Psoriasis

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A poster¹ presented at the 2024 Elevate-Derm West Conference highlighted pharmacokinetic data of spesolimab (Spevigo; Boehringer Ingelheim) via intravenous (IV) and subcutaneous routes. The parent study aimed to determine the respective drug exposure profiles and implications for clinical dosing of the methods in patients with generalized pustular psoriasis (GPP).

Traditionally, spesolimab, an IL-36 receptor antagonist, has shown promise in managing GPP flares and is typically administered intravenously for its rapid onset of action, according to poster authors Hawkes et al. However, the practicality of IV administration for long-term management is limited, prompting the investigation of subcutaneous administration as a potentially more feasible alternative for outpatient care.

Researchers utilized a population pharmacokinetic model to simulate and assess the drug exposure of spesolimab under various dosing conditions. The simulation incorporated data from phase 2 clinical trials involving patients with GPP and healthy individuals who received both IV and subcutaneous doses of spesolimab.

IV doses of 300 mg and 900 mg were administered over a 90-minute period, while subcutaneous doses of 300 mg, 600 mg, and 2250 mg spesolimab were administered via injections.

Pharmacokinetic metrics such as the maximum concentration, time to maximum concentration, and the area under the concentration-time curve (AUC) for 14 and 84 days were calculated to evaluate drug exposure differences between the 2 administration routes.

The pharmacokinetic modeling of spesolimab revealed notable differences in drug exposure between IV and subcutaneous routes of administration.

When comparing IV 300 mg versus subcutaneous 300 mg administration, researchers observed that the 300 mg IV dose reached a peak plasma concentration approximately 7.5 times higher than the 300 mg subcutaneous dose. Additionally, the IV dose achieved its peak concentration almost instantaneously, while the subcutaneous dose took several days to reach its peak, highlighting a delayed absorption with subcutaneous administration.

Over both 14 and 84 days, the AUC for the IV 300 mg dose was significantly higher than the subcutaneous 300 mg dose, indicating that the IV route results in more sustained, higher drug exposure within the initial days following administration.

When comparing IV 600 mg versus subcutaneous 600 mg administration, the 600 mg IV dose achieved a peak concentration about 6.2 times higher than the subcutaneous 600 mg dose. Additionally, the time to reach peak concentration for the IV dose was again much shorter, with the IV dose achieving rapid drug absorption compared to the subcutaneous route. The 600 mg IV dose also maintained a higher AUC over 14 and 84 days than the 600 mg subcutaneous dose.

When comparing IV 900 mg versus subcutaneous 600 mg and 2250 mg administration, the 900 mg IV dose reached a peak concentration approximately 7 times higher than the 600 mg subcutaneous dose, indicating a substantial difference in how quickly the drug is absorbed into the bloodstream. The subcutaneous 600 mg dose showed significantly lower peak levels than the IV dose. As with the lower doses, the IV dose reached its peak concentration much faster than the subcutaneous doses.

The AUC for the 900 mg IV dose remained higher than the subcutaneous 600 mg dose over both the 14- and 84-day periods. However, when compared to the subcutaneous 2250 mg dose, the AUC for the subcutaneous regimen over 84 days was comparable to the AUC from the 900 mg IV dose.

Lastly, when comparing subcutaneous 2250 mg versus 900 mg administration, the 2250 mg subcutaneous dose provided approximately 2.5 times higher exposure than the 900 mg subcutaneous dose.

The AUC for the subcutaneous 2250 mg dose over 84 days was significantly higher than the 900 mg subcutaneous dose, confirming that a higher subcutaneous dose can sustain therapeutic drug levels for an extended period. Furthermore, the subcutaneous 2250 mg dose achieved a prolonged plasma concentration similar to IV dosing but with a slower absorption curve.

According to Hawkes et al, these findings indicate that while IV administration is ideal for acute flare management, subcutaneous administration, particularly at higher doses, could offer a viable alternative for maintenance therapy, offering flexibility and convenience for GPP patients in outpatient settings.

“The intermediate and high bioavailability of IV spesolimab compared with SC spesolimab are supportive of the use of IV spesolimab in acute GPP flare treatment and SC spesolimab in treating GPP when not experiencing a flare,” wrote Hawkes et al.

Reference

1. Hawkes JE, Guercio JR, Kurup S, Li X, Lebwohl MG. Expected spesolimab plasma exposure following intravenous and subcutaneous dosing in patients with generalized pustular psoriasis. Poster presented at: Elevate-Derm West Conference; November 7-10, 2024; Scottsdale, Arizona.

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