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Summary: Background: Obesity is a common comorbidity of psoriasis and can attenuate response to biologic treatment. Objectives: To investigate the efficacy, safety and tolerability of secukinumab 300 mg every 2 weeks (Q2W) vs. secukinumab 300 mg every 4 weeks (Q4W) in patients with a higher bodyweight. Methods: In this multicentre, double‐blind, parallel‐group trial, 331 patients with moderate‐to‐severe chronic plaque psoriasis weighing ≥ 90 kg were randomized to receive secukinumab 300 mg Q2W or secukinumab 300 mg Q4W. Patients who did not achieve Psoriasis Area and Severity Index (PASI) 90 at week 16 on the Q4W regimen were reallocated to remain on the Q4W regimen or uptitrate to Q2W. Results: At week 16, Q2W dosing (n = 165) led to significantly higher PASI 90 responses vs. Q4W [n = 166; 73.2% vs. 55.5%, one‐sided P‐value = 0.0003, odds ratio estimate (95% confidence intervals): 2.3 (1.4–3.8)]. At week 52, higher efficacy responses were maintained in the Q2W arm (n = 165) vs. Q4W (n = 83); PASI 75: 88.9% vs. 74.8%; PASI 90: 76.4% vs. 52.4%; PASI 100: 46.7% vs. 27.3%; Investigator's Global Assessment 0/1: 75.9% vs. 55.6% and Dermatology Life Quality Index 0/1: 66.1% vs. 48.8%. PASI 90 nonresponders at week 16 who uptitrated to Q2W (n = 31) showed higher efficacy responses at week 32 (16 weeks post‐uptitration, PASI 90: 38.7% vs. 16.5%) vs. those who remained on Q4W (n = 40). Safety results were comparable across treatment arms and consistent with the established secukinumab safety profile. Conclusions: Secukinumab 300 mg Q2W demonstrated superior and sustained efficacy compared with Q4W in patients with moderate‐to‐severe plaque psoriasis weighing ≥ 90 kg. PASI 90 nonresponders derived additional benefits from uptitration to a Q2W regimen (ClinicalTrials.gov identifier: NCT03504852). What is already known about this topic?Obesity is a common comorbidity of psoriasis and can attenuate response to biologic treatment.Secukinumab is a fully human monoclonal antibody that selectively neutralizes interleukin‐17A in the treatment of moderate‐to‐severe plaque psoriasis.Subgroup analyses of previous study results and pharmacokinetic/pharmacodynamic modelling data suggest that heavier patients may benefit from higher exposure to secukinumab through an increased dosing frequency [300 mg every 2 weeks (Q2W) vs. every 4 weeks (Q4W)]. What does this study add?Over 52 weeks, secukinumab 300 mg Q2W demonstrated superior efficacy compared with secukinumab 300 mg Q4W in patients with moderate‐to‐severe plaque psoriasis weighing ≥90 kg, with comparable safety results, consistent with the established secukinumab safety profile.In patients who did not achieve PASI 90 at week 16 on the Q4W regimen, uptitration to the Q2W regimen at week 16 resulted in improved efficacy responses through week 52 after switching. [ABSTRACT FROM AUTHOR]

Evidence shows good tolerability in patients for subcutaneous injection volumes up to 3 mL. We investigated efficacy, pharmacokinetics, and tolerability of secukinumab 300 mg/2 mL pre-filled syringe (PFS) in patients with moderate to severe plaque psoriasis. ALLURE was a 52-week, multicenter, randomized (1:1:1), double-blind, placebo-controlled, parallel-group study. Co-primary endpoints were secukinumab Psoriasis Area Severity Index (PASI) 75 and Investigator's Global Assessment modified 2011 0/1 (IGA mod 2011 0 or 1) responses at week 12 versus placebo. Other endpoints included the Self-Injection Assessment Questionnaire (SIAQ), and the ability to follow the instructions for use (IFU). Overall, 214 patients were randomized. The secukinumab 300 mg/2 mL PFS showed superiority over placebo for both PASI 75 (88.9% versus 1.7%; p<.0001) and IGA mod 2011 0 or 1 (76.4% versus 1.4%; p<.0001) responses at week 12. All secondary efficacy endpoints were met. The SIAQ scores were similar across groups and improved similarly over 12 weeks. All patients completed critical steps in the IFU at week 1. The secukinumab 300 mg/2 mL PFS groups showed superiority versus placebo, and it was a safe, effective, and convenient option for patients with psoriasis. NCT02748863. [ABSTRACT FROM AUTHOR]

Convenient administration is an important factor for treatment adherence in patients with psoriasis. MATURE study reports the efficacy, safety, tolerability, and pharmacokinetics (PKs) of secukinumab 300 mg 2 ml autoinjector (AI) from MATURE trial (NCT03589885). Eligible patients were randomized to secukinumab 300 mg 2 ml AI or 2× 1 ml prefilled syringe (PFS) or placebo. The co‐primary endpoints were psoriasis area and severity index (PASI) 75 and investigator's global assessment (IGA) 0/1 response rates at Week 12 versus placebo. Other endpoints included PASI90/100 response, dermatology life quality index (DLQI) 0/1, PKs, 2 ml AI usability rated using self‐injection assessment questionnaire (SIAQ), and safety. The study met both co‐primary and secondary endpoints (p < 0.0001). Secukinumab 300 mg 2 ml AI and 2× 1 ml PFS treatments led to superior PASI75/90/100 (2 ml AI: 95.1%/75.6%/43.9%; 2× 1 mL PFS: 83.2%/62.6%/37.5% and placebo: 10%/5.0%/0.0%, respectively), IGA, and DLQI 0/1 responses compared with placebo, and efficacy was sustained through 52 weeks. SIAQ results showed high usability of self‐injection with 2 mL AI device. No new safety signals were observed. Study design may bias the interpretation of safety profile after Week 12, due to different exposure of secukinumab versus placebo. Secukinumab 300 mg administered with the 2 mL AI demonstrated superior efficacy over placebo, good tolerability, and convenient administration. [ABSTRACT FROM AUTHOR]

In miniaturized separation techniques, such as capillary electrophoresis (CE) or capillary liquid chromatography (LC), conventional on-line radioactivity detection of labeled compounds is restricted, because of insufficient sensitivity. It will be shown that a microplate scintillation counter for 96-well plates (TopCount) can be used as a sensitive and easy-to-handle radioactivity detector for capillary LC and CE. The attractive combination of capillary LC, eluent fractionation, and subsequent off-line counting is described. The new method is applied for rapid and sensitive separation and detection of (super 3)H-labeled parent drug and its metabolites at levels between 25 and 700 cpm in rat urine. The advantages of capillary LC coupled to the TopCount, and combined with LC-MS data, can be of benefit in many analytical areas, including the characterization of metabolites at low concentration within complex biological fluids. With the same setup, the fractionation with subsequent off-line counting is equally applicable to CE. This is demonstrated with electrophoretically separated (super 14)C-labeled impurities, nicely resolved from a negatively charged main compound, at low levels.

A novel refractive index detector suitable for capillary separations is presented and demonstrated in the capillary electrophoretic separation of metal cations in 10-micrometer-i.d. tubes. The principle of the detector is interferometric; it features a laser diode and, as the main optical element, a holographic optical element which performs several optical functions allowing the use of capillaries with inner diameters as small as 5 micrometers. In contrast to the 'off-axis' method, the use of holographic plates permits probing of the capillary through its center, where the optical path is larger and diffraction effects are smaller. With an i.d. = 10 micrometers capillary the detector resolves 2 microns RIU and covers a linear dynamic range of three to four decades. Joule heat effects preclude the detector to operate at its maximum sensitivity which is delivered in the absence of electrical fields. For this reason, the use of smaller inner diameter capillaries and buffers having low conductivities is recommended. Under field-amplified sample injection conditions, the detection limits for the studied cations are in the low nanomolar range. The performance of this detector is compared with indirect UV-absorption detection, which also helps to elucidate the mechanisms leading to refractive index changes in ionic solutions.

Aims: The aim of the study was to compare the pharmacokinetics (PK), safety and tolerability of secukinumab with different devices for subcutaneous (s.c.) administration of 2 mL. Methods: A phase 1 study in healthy subjects with 6 devices to administer 2 mL injection volumes was conducted to evaluate the serum PK, safety and tolerability of secukinumab following single s.c. injection of 300 mg in the abdomen (either side) or in the thigh (either leg). Primary PK endpoints were maximum observed serum concentration and area under the serum concentration–time curve. The impact of device, site and side of injection on serum exposure was evaluated. In a phase 3 study in psoriasis patients, PK of secukinumab was evaluated following multiple s.c. injections of 300 mg by either 2 × 1‐mL prefilled syringe or 1 × 2‐mL prefilled syringe. Results: Mean serum concentration–time profiles for administration as 2 × 1 mL injections or as 1 × 2 mL injections were similar. With an injection volume of 2 mL, perceived injection pain was not different from 2 × 1 mL injections. A nonclinically significant difference in PK endpoints was observed between thigh and abdomen. Results with a 2 mL prefilled syringe in a 1‐year phase 3 study in patients confirmed PK results observed in the phase 1 study. Conclusion: Collective evidence from both studies demonstrated that 2‐mL injections of secukinumab into the abdomen or thigh using different devices resulted in comparable PK characteristics and were all well tolerated without noticeable local reactions. [ABSTRACT FROM AUTHOR]

This open‐label disease‐drug–drug interaction study assessed whether blockade of the interleukin (IL)‐17A pathway by secukinumab and subsequent downregulation of inflammatory cytokines like IL‐6 or high‐sensitivity C‐reactive protein affects the pharmacokinetics (PKs) of a sensitive probe substrate of the cytochrome P450 3A4 isoform (CYP3A4). The PKs of midazolam, metabolized by CYP3A4, was evaluated before and after 7 and 35 days of treatment initiation of subcutaneous secukinumab at a dose of 300 mg weekly in 24 patients with moderate‐to‐severe psoriasis. Although demonstrating the expected decrease in downstream inflammatory cytokines, secukinumab had no clinically relevant effects on the PKs of midazolam, provided substantial clinical benefit, and was generally well tolerated. In summary, blockade of IL‐17A signaling in patients with moderate‐to‐severe psoriasis does not significantly affect CYP3A4 enzyme activities and, therefore, the use of secukinumab is unlikely to influence the PKs of CYP3A4 substrates. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion, published in a previous issue is presented.

Psoriasis, psoriatic arthritis, and axial spondyloarthritis are systemic inflammatory diseases, each commonly manifesting as a spectrum of symptoms, complications, and comorbidities that arise differently in individual patients. Drugs targeting inflammatory cytokines common to the pathogenesis of each of these conditions have been developed, although their specific actions in the different tissues involved are variable. For a drug to be effective, it must be efficiently delivered to and locally bioactive in disease-relevant tissues. Detailed clinical data shed light on the therapeutic effects of individual biologics on specific domains or clinical manifestations of disease and assist in guiding treatment decisions. Pharmacologic, molecular, and functional properties of drugs strongly impact their observed safety and efficacy, and an understanding of these properties provides complementary insight. Secukinumab, a fully human monoclonal IgG1/κ antibody selectively targeting interleukin (IL)-17A, has been in clinical use for >6 years in the treatment of moderate to severe psoriasis, psoriatic arthritis, and both radiographic (also known as ankylosing spondylitis) and nonradiographic axial spondyloarthritis. In this review, we discuss pharmacokinetic and pharmacodynamic data for secukinumab to introduce clinicians to the pharmacological properties of this widely used drug. Understanding how these properties affect the observed clinical efficacy, safety, and tolerability of this drug in the treatment of IL-17A–mediated systemic inflammatory diseases is important for all physicians treating these conditions. [ABSTRACT FROM AUTHOR]

Therapeutic proteins (TPs) comprise a variety of modalities, including antibody-based drugs, coagulation factors, recombinant cytokines, enzymes, growth factors, and hormones. TPs usually cannot traverse cellular barriers and exert their pharmacological activity by interacting with targets on the exterior membrane of cells or with soluble ligands in the tissue interstitial fluid/blood. Due to their large size, lack of cellular permeability, variation in metabolic fate, and distinct physicochemical characteristics, TPs are subject to different absorption, distribution, metabolism, and excretion (ADME) processes as compared with small molecules. Limited regulatory guidance makes it challenging to determine the most relevant ADME data required for regulatory submissions. The TP ADME working group was sponsored by the Translational and ADME Sciences Leadership Group within the Innovation and Quality (IQ) consortium with objectives to: (1) better understand the current practices of ADME data generated for TPs across IQ member companies, (2) learn about their regulatory strategies and interaction experiences, and (3) provide recommendations on best practices for conducting ADME studies for TPs. To understand current ADME practices and regulatory strategies, an industry-wide survey was conducted within IQ member companies. In addition, ADME data submitted to the U.S. Food and Drug Administration was also collated by reviewing regulatory submission packages of TPs approved between 2011 and 2020. This article summarizes the key learnings from the survey and an overview of ADME data presented in biologics license applications along with future perspectives and recommendations for conducting ADME studies for internal decision-making as well as regulatory submissions for TPs. SIGNIFICANCE STATEMENT: This article provides comprehensive assessment of the current practices of absorption, distribution, metabolism, and excretion (ADME) data generated for therapeutic proteins (TPs) across the Innovation and Quality participating companies and the utility of the data in discovery, development, and regulatory submissions. The TP ADME working group also recommends the best practices for condu-cting ADME studies for internal decision-making and regulatory submissions., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Characterization of the pharmacokinetics and biodistribution of therapeutic proteins (TPs) is a hot topic within the pharmaceutical industry, particularly with an ever-increasing catalog of novel modality TPs. Here, we review the current practices, and provide a summary of extensive cross-company discussions as well as a survey completed by International Consortium for Innovation and Quality members on this theme. A wide variety of in vitro, in vivo and in silico techniques are currently used to assess pharmacokinetics and biodistribution of TPs, and we discuss the relevance of these from an industry perspective, focusing on pharmacokinetic/pharmacodynamic understanding at the preclinical stage of development, and translation to human. We consider that the 'traditional in vivo biodistribution study' is becoming insufficient as a standalone tool, and thorough characterization of the interaction of the TP with its target(s), target biology, and off-target interactions at a microscopic scale are key to understand the overall biodistribution on a full-body scale. Our summary of the current challenges and our recommendations to address these issues could provide insight into the implementation of best practices in this area of drug development, and continued cross-company collaboration will be of tremendous value. SIGNIFICANCE STATEMENT: The Innovation and Quality Consortium Translational and ADME Sciences Leadership Group working group for the absorption, distribution, metabolism, and excretion of therapeutic proteins evaluates the current practices and challenges in characterizing the pharmacokinetics and biodistribution of therapeutic proteins during drug development, and proposes recommendations to address these issues. Incorporating the in vitro, in vivo and in silico approaches discussed herein may provide a pragmatic framework to increase early understanding of pharmacokinetic/pharmacodynamic relationships, and aid translational modeling for first-in-human dose predictions., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

The ability of polymeric nanoparticles to promote glass bead and pentlandite (Pn, nickel sulfide mineral) attachment to air bubbles in flotation was measured as a function of the nanoparticle glass transition temperature using six types of nanoparticles based on styrene/N-butylacrylate copolymers. Nanoparticle size, surface charge density, and hydrophobicity were approximately constant over the series. The ability of the nanoparticles to promote air bubble attachment and perform as flotation collectors was significantly greater for softer nanoparticles. We propose that softer nanoparticles were more firmly attached to the glass beads or mineral surface because the softer particles had a greater glass/polymer contact areas and thus stronger overall adhesion. The diameters of the contact areas between polymeric nanoparticles and glass surfaces were estimated with the Young-Laplace equation for soft, liquidlike particles, whereas JKR adhesion theory was applied to the harder polystyrene particles. The diameters of the contact areas were estimated to be more than an order of magnitude greater for the soft particles compared to harder polystyrene particles.

Deferasirox (ICL670) is a novel once-daily, orally administered iron chelator to treat chronic iron overload in patients with transfusion-dependent anemias. Absorption, distribution, metabolism, and excretion of [14C]deferasirox at pharmacokinetic steady state was investigated in five adult beta-thalassemic patients. Deferasirox (1000 mg) was given orally once daily for 6 days to achieve steady state. On day 7, patients received a single oral 1000-mg dose (approximately 20 mg/kg) of [14C]deferasirox (2.5 MBq). Blood, plasma, feces, and urine samples collected over 7 days were analyzed for radioactivity, deferasirox, its iron complex Fe-[deferasirox]2, and metabolites. Deferasirox was well absorbed. Deferasirox and its iron complex accounted for 87 and 10%, respectively, of the radioactivity in plasma (area under the curve at steady state). Excretion occurred largely in the feces (84% of dose), and 60% of the radioactivity in the feces was identified as deferasirox. Apparently unchanged deferasirox in feces was partly attributable to incomplete intestinal absorption and partly to hepatobiliary elimination of deferasirox (including first-pass elimination) and of its glucuronide. Renal excretion was only 8% of the dose and included mainly the glucuronide M6. Oxidative metabolism by cytochrome 450 enzymes to M1 [5-hydroxy (OH) deferasirox, presumably by CYP1A] and M4 (5'-OH deferasirox, by CYP2D6) was minor (6 and 2% of the dose, respectively). Direct and indirect evidence indicates that the main pathway of deferasirox metabolism is via glucuronidation to metabolites M3 (acyl glucuronide) and M6 (2-O-glucuronide).

Deferasirox (Exjade, ICL670, CGP72670) is an iron-chelating drug for p.o. treatment of transfusional iron overload in patients with beta-thalassemia or sickle cell disease. The pharmacokinetics and disposition of deferasirox were investigated in rats. The animals received single intravenous (10 mg/kg) or p.o. (10 or 100 mg/kg) doses of 14C-radiolabeled deferasirox. Biological samples were analyzed for radioactivity (liquid scintillation counting, quantitative whole-body autoradioluminography), for deferasirox and its iron complex [high-performance liquid chromatography (HPLC)/UV], and for metabolites (HPLC with radiodetection, liquid chromatography/mass spectrometry, 1H and 13C NMR, and two-dimensional NMR techniques). At least 75% of p.o.-dosed deferasirox was absorbed. The p.o. bioavailability was 26% at the 10 mg/kg dose and showed an overproportional increase at the 100 mg/kg dose, probably because of saturation of elimination processes. Deferasirox-related radioactivity was distributed mainly to blood, excretory organs, and gastrointestinal tract. Enterohepatic recirculation of deferasirox was observed. No retention occurred in any tissue. The placental barrier was passed to a low extent. Approximately 3% of the dose was transferred into the breast milk. Excretion of deferasirox and metabolites was rapid and complete within 7 days. Key clearance processes were hepatic metabolism and biliary elimination via multidrug resistance protein 2. Deferasirox, iron complex, and metabolites were excreted largely via bile and feces (total > or = 90%). Metabolism included glucuronidation at the carboxylate group (acyl glucuronide M3) and at phenolic hydroxy groups, as well as, to a lower degree, cytochrome P450-catalyzed hydroxylations. Two hydroxylated metabolites (M1 and M2) were administered to rats and were shown not to contribute substantially to iron elimination in vivo.