Analysis of the absorption kinetics of macromolecules following intradermal and subcutaneous administration

Milewski, Mikolaj; Manser, Kimberly; Nissley, Becky; Mitra, Amitava

doi:10.1016/j.ejpb.2014.11.013

Cited by 19 publications

(14 citation statements)

References 20 publications

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“…In the present study, we show that plasma concentrations of Nexvax2 peptides 45 min after intradermal injection are dose-dependent, which confirms systemic bioavailability that would facilitate engagement of cognate T cells at distant sites, including the gut, within 45 min of administration. Thus, the pharmacokinetics of Nexvax2 is consistent with other intradermally administered peptides that show dose-dependent pharmacokinetics and achieve maximal concentrations within 1 h, and dose exposure similar to subcutaneous administration ( Milewski et al, 2015 ). Plasma concentrations of each of the three Nexvax2 peptides were similar at 45 min post-treatment.…”

Section: Discussionsupporting

confidence: 71%

Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Daveson

Andrews

et al. 2017

EBioMedicine

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BackgroundNexvax2® is a novel, peptide-based, epitope-specific immunotherapy intended to be administered by regular injections at dose levels that increase the threshold for clinical reactivity to natural exposure to gluten and ultimately restore tolerance to gluten in patients with celiac disease. Celiac disease patients administered fixed intradermal doses of Nexvax2 become unresponsive to the HLA-DQ2·5-restricted gluten epitopes in Nexvax2, but gastrointestinal symptoms and cytokine release mimicking gluten exposure, that accompany the first dose, limit the maximum tolerated dose to 150 μg. Our aim was to test whether stepwise dose escalation attenuated the first dose effect of Nexvax2 in celiac disease patients.MethodsWe conducted a randomized, double-blind, placebo-controlled trial at four community sites in Australia (3) and New Zealand (1) in HLA-DQ2·5 genotype positive adults with celiac disease who were on a gluten-free diet. Participants were assigned to cohort 1 if they were HLA-DQ2·5 homozygotes; other participants were assigned to cohort 2, or to cohort 3 subsequent to completion of cohort 2. Manual central randomization without blocking was used to assign treatment for each cohort. Initially, Nexvax2-treated participants in cohorts 1 and 2 received an intradermal dose of 30 μg (consisting of 10 μg of each constituent peptide), followed by 60 μg, 90 μg, 150 μg, and then eight doses of 300 μg over six weeks, but this was amended to include doses of 3 μg and 9 μg and extended over a total of seven weeks. Nexvax2-treated participants in cohort 3 received doses of 3 μg, 9 μg, 30 μg, 60 μg, 90 μg, 150 μg, 300 μg, 450 μg, 600 μg, 750 μg, and then eight of 900 μg over nine weeks. The dose interval was 3 or 4 days. Participants, care providers, data managers, sponsor personnel, and study site personnel were blinded to treatment assignment. The primary outcome was the number of adverse events and percentage of participants with adverse events during the treatment period. This completed trial is registered with ClinicalTrials.gov, number NCT02528799.FindingsFrom the 73 participants who we screened from 19 August 2015 to 31 October 2016, 24 did not meet eligibility criteria, and 36 were ultimately randomized and received study drug. For cohort 1, seven participants received Nexvax2 (two with the starting dose of 30 μg and then five at 3 μg) and three received placebo. For cohort 2, 10 participants received Nexvax2 (four with starting dose of 30 μg and then six at 3 μg) and four received placebo. For cohort 3, 10 participants received Nexvax2 and two received placebo. All 36 participants were included in safety and immune analyses, and 33 participants completed treatment and follow-up; in cohort 3, 11 participants were assessed and included in pharmacokinetics and duodenal histology analyses. Whereas the maximum dose of Nexvax2 had previously been limited by adverse events and cytokine release, no such effect was observed when dosing escalated from 3 μg up to 300 μg in HLA-DQ2·5 homozygotes or to 900 μg in HLA-D...

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Section: Discussionsupporting

confidence: 71%

Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Daveson

Andrews

et al. 2017

EBioMedicine

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“…20,21 We speculate this may in part be affected by more consistent and technically simpler delivery with subcutaneous as opposed to intradermal injection. While geometric mean ratio (subcutaneous to intradermal) point estimates for AUC(0-inf) and C max were contained within the standard 90% confidence interval (bioequivalency) limits of 80%-125%, the upper bound consistently fell above the range.…”

Section: Discussionmentioning

confidence: 99%

“…In alignment with prior reports of protein-based therapies, peak plasma concentrations occurred earlier for intradermal vs subcutaneous administration, and total exposure was greater for the latter delivery route. 20,21 We speculate this may in part be affected by more consistent and technically simpler delivery with subcutaneous as opposed to intradermal injection. Notably, the present study used the same injection number and volume for each administration route, though it is not anticipated that using a single subcutaneous as opposed to several intradermal injections for each 900-μg dose would have made a meaningful difference in results.…”

Section: Pharmacokinetics Of Individual Peptides and The Drug Productmentioning

confidence: 99%

Randomised clinical trial: a placebo‐controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease

Truitt¹,

Daveson

et al. 2019

Aliment Pharmacol Ther

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Background: Nexvax2 contains three gluten-derived peptides, intended to tolerize coeliac disease patients to gluten. Sequences cover six epitopes that trigger immune activation in human leucocyte antigen-DQ2.5-positive patients, most notably after an initial dose. Patients experience gastrointestinal symptoms with increases in serum interleukin-2. Consistent with Nexvax2's induction of non-responsiveness, reactivity disappears after repeated doses, or is avoided with gradual dose escalation.Early clinical trials used intradermal dosing, but pharmacokinetics and rapid onset of effect suggest that subcutaneous delivery may also be effective. Aims:To document the relative bioavailability of Nevax2 peptides after subcutaneous and intradermal dosing, and the tolerability and ability of subcutaneous dosing to induce non-responsiveness to Nexvax2 peptides. Methods:A randomised, double-blind, placebo-controlled study was conducted to assess plasma pharmacokinetics after subcutaneous and intradermal Nexvax2 dosing in HLA DQ2.5-positive patients, who had symptoms after an oral gluten challenge.Randomisation was to semi-weekly Nexvax2 (n = 12) or placebo (n = 2) injections, over a 5-week subcutaneous dose escalation and 2-week maintenance period, the latter with four doses of 900 µg, two subcutaneous and two intradermal. Post-dose circulating peptide and interleukin-2 levels were assessed. Investigators recorded adverse events experienced by patients.Results: Subcutaneous dosing resulted in slightly greater exposure. Interleukin-2 responses were seen with the gluten challenge but not after subcutaneous or intradermal dosing of 900 µg. Adverse events were generally mild and self-limited.Conclusions: Subcutaneous and intradermal dosing of Nexvax2 yield similar bioavailability of constituent peptides; subcutaneous dose escalation avoids an immune response to dominant gluten epitopes.

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“…Blisters formed due to repeated intradermal injection of rmIL-23 increase hydrostatic pressure in the interstitium, which might cause rapid absorption of rmIL-23 into capillaries. It has been observed that intradermal administration of proteins produced higher maximum serum concentration (C max ) and a left shift in serum concentration profiles compared to the subcutaneous route (Milewski et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Development and Translational Application of a Minimal Physiologically Based Pharmacokinetic Model for a Monoclonal Antibody against Interleukin 23 (IL-23) in IL-23-Induced Psoriasis-Like Mice

Chen

Jiang

Doddareddy

et al. 2018

J Pharmacol Exp Ther

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The interleukin (IL)-23/T17/IL-17 immune pathway has been identified to play an important role in the pathogenesis of psoriasis. Many therapeutic proteins targeting IL-23 or IL-17 are currently under development for the treatment of psoriasis. In the present study, a mechanistic pharmacokinetics (PK)/pharmacodynamics (PD) study was conducted to assess the target-binding and disposition kinetics of a monoclonal antibody (mAb), CNTO 3723, and its soluble target, mouse IL-23, in an IL-23-induced psoriasis-like mouse model. A minimal physiologically based pharmacokinetic model with target-mediated drug disposition features was developed to quantitatively assess the kinetics and interrelationship between CNTO 3723 and exogenously administered, recombinant mouse IL-23 in both serum and lesional skin site. Furthermore, translational applications of the developed model were evaluated with incorporation of human PK for ustekinumab, an anti-human IL-23/IL-12 mAb developed for treatment of psoriasis, and human disease pathophysiology information in psoriatic patients. The results agreed well with the observed clinical data for ustekinumab. Our work provides an example on how mechanism-based PK/PD modeling can be applied during early drug discovery and how preclinical data can be used for human efficacious dose projection and guide decision making during early clinical development of therapeutic proteins.

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Analysis of the absorption kinetics of macromolecules following intradermal and subcutaneous administration

Cited by 19 publications

References 20 publications

Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Randomised clinical trial: a placebo‐controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease

Development and Translational Application of a Minimal Physiologically Based Pharmacokinetic Model for a Monoclonal Antibody against Interleukin 23 (IL-23) in IL-23-Induced Psoriasis-Like Mice

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