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Depemokimab is the first ultra-long-acting biologic with enhanced interleukin-5 (IL-5) binding affinity, high potency, and extended half-life, enabling twice-yearly dosing. Depemokimab has demonstrated efficacy and safety in patients with asthma and chronic rhinosinusitis with nasal polyps. These analyses aimed to characterize the pharmacokinetic/pharmacodynamic (PK/PD) profile of depemokimab. Data from three Phase I studies (NCT03287310/NCT05140200/NCT05602025) and four Phase III studies (SWIFT-1/-2: NCT04719832/NCT04718103; ANCHOR-1/-2: NCT05274750/NCT05281523) were used to develop a PK model for depemokimab and PK/PD model for blood eosinophil count (BEC) reduction, a key biomarker of type 2 inflammation. Participants received subcutaneous depemokimab or placebo (one dose in Phase I [2-300 mg in NCT03287310; 100 mg or 300 mg in NCT05140200/NCT05602025] and two 100 mg doses in Phase III) and ≥1 post-first-dose PK/PD (BEC) observation. PK analysis included 961 participants and PK/PD analysis included 1324 participants. Predicted geometric mean half-life was 47 days, with negligible accumulation in PK. Depemokimab 100 mg rapidly reduced BEC to <25% of baseline, with a small increase observed at the end of the 26-week dosing interval. No clinically relevant covariates were identified for either model. All participants had trough depemokimab concentrations above the half maximal effective concentration (EC₅₀) at the end of the dosing interval (90% above the EC₉₀ level). PK/PD modeling showed that single-dose depemokimab 100 mg provides durable BEC reduction throughout a 26-week dosing interval, suggesting sustained suppression of IL-5 activity. These data support twice-yearly recommended dosing for depemokimab 100 mg, with no dose adjustments required based on intrinsic or extrinsic factors.