Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion

Dragatin, Christian; Polus, Florine; Bodenlenz, Manfred; Calonder, Claudio; Aigner, Birgit; Tiffner, Katrin I.; Mader, Julia K.; Ratzer, Maria; Woessner, Ralph; Pieber, Thomas R.; Cheng, Yi; Loesche, Christian; Sinner, Frank; Bruin, Gerard

doi:10.1111/exd.12863

Cited by 41 publications

(40 citation statements)

References 10 publications

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“…The dOFM devices (sterile probes, wearable pumps, accessories; CE certified for human use) were developed by HEALTH—Joanneum Research GmbH (Graz, Austria). The devices and their clinical use have been described in detail previously [23, 24]. In this study, the newest version of a CE-certified dOFM probe (DEA15003) was used.…”

Section: Methodsmentioning

confidence: 99%

Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence

et al. 2016

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BackgroundThe availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products.ObjectiveTo evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference (R) product either to itself or to a different test (T) product.MethodsIn a single-center clinical study, R or T products were applied to six randomized treatment sites on the skin of 20 healthy human subjects. Two dOFM probes were inserted in each treatment site to monitor the intradermal acyclovir concentration for 36 h. Comparative BA (of R vs. R and T vs. R) was evaluated based on conventional BE criteria for pharmacokinetic endpoints (area under the curve and maximum plasma concentration) where the 90 % confidence interval of the geometric mean ratio between the T and R falls within 0.80–1.25.ResultsThe positive control products (R vs. R) were accurately and reproducibly confirmed to be bioequivalent, while the negative control products (T vs. R) were sensitively discriminated not to be bioequivalent.ConclusionsdOFM accurately, sensitively, and reproducibly characterized the dermal BA in a manner that can support BE evaluations for topical acyclovir 5 % creams in a study with n = 40 (20 subjects in this study).

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Section: Methodsmentioning

confidence: 99%

Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence

et al. 2016

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“…Secukinumab clearance values allow physicians to predict drug washout; assuming a washout period of 5 half‐lives, secukinumab will be washed out approximately 135 days after cessation of therapy. Distribution into skin, the target organ in psoriasis patients, appears to be fast, as skin interstitial fluid level of secukinumab is measurable after a single subcutaneous dose of 300 mg, reaching 28%–39% of the serum concentration 7 and 14 days postdose (6–8 μg/mL of secukinumab in the dermal interstitial fluid) …”

Section: Discussionmentioning

confidence: 99%

“…Overall, the pharmacokinetic (PK) properties of secukinumab are typical of an IgG1 antibody because it exhibits good stability, long persistence in the body, and high selectivity and specificity . Furthermore, with a novel technique, open‐flow microperfusion, the concentration of secukinumab was reported as 6.8 μg/mL in lesional skin 7 days after a single 300‐mg subcutaneous injection of secukinumab . In patients with psoriasis, interstitial fluid concentrations of secukinumab in lesional and nonlesional skin were in the range of 28% to 39% relative to serum concentrations .…”

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confidence: 99%

“…Furthermore, with a novel technique, open‐flow microperfusion, the concentration of secukinumab was reported as 6.8 μg/mL in lesional skin 7 days after a single 300‐mg subcutaneous injection of secukinumab . In patients with psoriasis, interstitial fluid concentrations of secukinumab in lesional and nonlesional skin were in the range of 28% to 39% relative to serum concentrations . Relevant cytokines and markers were also analyzed directly in the skin through this method.…”

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Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis

Bruin

Loesche

Nyirady

et al. 2017

The Journal of Clinical Pharmacology

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Secukinumab is a human monoclonal antibody with demonstrated efficacy for moderate to severe psoriasis; it binds to and neutralizes interleukin (IL)‐17A. The pharmacokinetic (PK) parameters of secukinumab were best described by a 2‐compartment model. Only weight was included in the final model, as other covariates did not affect clinical relevance. The estimated serum clearance of secukinumab was 0.19 L/day, with interindividual variability (IIV) of 32% coefficient of variation (CV), and low total volume of distribution (central compartment volume, 3.61 L with IIV of 30% CV; peripheral compartment volume, 2.87 L with IIV of 18% CV). The bioavailability of secukinumab after subcutaneous dosing was approximately 73%, with an absorption rate of 0.18/day with IIV of 35% CV. The PK profile of secukinumab was linear, with no evidence of a dose dependence of clearance. Clearance and volume of secukinumab varied with body weight in an allometric relationship. The time to maximum serum concentration at steady state occurred approximately 6 days after dosing for both secukinumab 300 mg and secukinumab 150 mg. Overall, the PK properties of secukinumab were typical of a 150‐kDa human IgG1 antibody interacting with a soluble target.

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“…GSK2330811 was successfully detected in skin blister fluid at concentrations ranging from 19% to 45% of those observed in plasma, in line with the results of Dragatin et al . 34. The skin blisters were well tolerated, with no AEs related to blister healing reported.…”

Section: Discussionmentioning

confidence: 82%

In vivo affinity and target engagement in skin and blood in a first‐time‐in‐human study of an anti‐oncostatin M monoclonal antibody

Reid

Zamuner

Edwards

et al. 2018

Brit J Clinical Pharma

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AimsThe oncostatin M (OSM) pathway drives fibrosis, inflammation and vasculopathy, and is a potential therapeutic target for inflammatory and fibrotic diseases. The aim of this first‐time‐in‐human experimental medicine study was to assess the safety, tolerability, pharmacokinetics and target engagement of single subcutaneous doses of GSK2330811, an anti‐OSM monoclonal antibody, in healthy subjects.MethodsThis was a phase I, randomized, double‐blind, placebo‐controlled, single‐dose escalation, first‐time‐in‐human study of subcutaneously administered GSK2330811 in healthy adults (NCT02386436). Safety and tolerability, GSK2330811 pharmacokinetic profile, OSM levels in blood and skin, and the potential for antidrug antibody formation were assessed. The in vivo affinity of GSK2330811 for OSM and target engagement in serum and skin blister fluid (obtained via a skin suction blister model) were estimated using target‐mediated drug disposition (TMDD) models in combination with compartmental and physiology‐based pharmacokinetic (PBPK) models.ResultsThirty subjects were randomized to receive GSK2330811 and 10 to placebo in this completed study. GSK2330811 demonstrated a favourable safety profile in healthy subjects; no adverse events were serious or led to withdrawal. There were no clinically relevant trends in change from baseline in laboratory values, with the exception of a reversible dose‐dependent reduction in platelet count. GSK2330811 exhibited linear pharmacokinetics over the dose range 0.1–6 mg kg–1. The estimated in vivo affinity (nM) of GSK2330811 for OSM was 0.568 [95% confidence interval (CI) 0.455, 0.710] in the compartmental with TMDD model and 0.629 (95% CI 0.494, 0.802) using the minimal PBPK with TMDD model.ConclusionsSingle subcutaneous doses of GSK2330811 were well tolerated in healthy subjects. GSK2330811 demonstrated sufficient affinity to achieve target engagement in systemic circulation and target skin tissue, supporting the progression of GSK2330811 clinical development.

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Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion

Abstract: Abbreviations: dOFMdermal open flow microperfusion; dISF, dermal interstitial fluid; TSS, total sum score; PASI, psoriasis area and severity index.

Cited by 41 publications

References 10 publications

Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence

Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence

Population Pharmacokinetic Modeling of Secukinumab in Patients With Moderate to Severe Psoriasis

In vivo affinity and target engagement in skin and blood in a first‐time‐in‐human study of an anti‐oncostatin M monoclonal antibody

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