Pharmacokinetics and safety of sirukumab following a single subcutaneous administration to healthy Japanese and Caucasian subjects

Zhuang, Yanli; Xu, Zekuan; De, de Vries; Q, Wang; Shishido, Akira; Comisar, Craig; Ja, Ford; Keen, Monica; Achira, Meguru; Tsukamoto, Yoshitsugu; Kj, Petty; Hm, Davis; Zhou, Honghui

doi:10.5414/cp201785

Cited by 22 publications

(31 citation statements)

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“…In a randomized, placebo-controlled trial, sirukumab demonstrated desirable pharmacokinetics, low immunogenicity rates and a well-tolerated safety profile when intravenously administered to healthy subjects [153]. A subsequent Phase I study found that subcutaneous administration of sirukumab resulted in linear pharmacokinetics and drug tolerability in healthy male subjects [154]. Sirukumab has since been tested for its effects within lupus and RA, within a Phase I and Phase II trial, respectively [155,156].…”

Section: Adjunctive Anti-inflammatory Treatment For Mddmentioning

confidence: 99%

Novel investigational drugs targeting IL-6 signaling for the treatment of depression

Fonseka

McIntyre

Soczynska

et al. 2015

Expert Opinion on Investigational Drugs

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To improve drug development for the treatment of MDD, there is a critical need to identify promising targets. Target identification will require guidance from a strategic framework such as The Research Domain Criteria, and convincing evidence relating known targets to brain function under both physiological and pathological conditions. Although current evidence provides rationale for administering anti-IL-6 treatments in MDD, further studies confirming safety, target affinity and therapeutic benefits are warranted.

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Section: Adjunctive Anti-inflammatory Treatment For Mddmentioning

confidence: 99%

Novel investigational drugs targeting IL-6 signaling for the treatment of depression

Fonseka

McIntyre

Soczynska

et al. 2015

Expert Opinion on Investigational Drugs

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“…In a study evaluating the effects of sirukumab in healthy human subjects, sirukumab was reported to have a median half-life of 18.5–29.6 days following 10–15 min intravenous (IV) infusions of 0.3-10 mg/kg doses [33]. The mean half-life of sirukumab following subcutaneous (SC) administration of sirukumab for healthy subjects is reportedly shorter than the mean half-life following IV administration (i.e., 15–18 vs. 19–30 days, respectively) [36]. …”

Section: Resultsmentioning

confidence: 99%

Sirukumab: A Potential Treatment for Mood Disorders?

et al. 2016

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Convergent evidence indicates that abnormalities in the innate immune system may be pertinent to the pathogenesis, phenomenology, and possible treatment of several mental disorders. In keeping with this view, the targeting of interleukin-6 with the human monoclonal antibody sirukumab may represent a possible treatment and disease modification approach, for adults with brain-based disorders (e.g., major depressive disorder). A PubMed/Medline database search was performed using the following search terms: sirukumab; anti-IL-6; IL-6; major depressive disorder; inflammation. A systematic review was conducted of both preclinical and clinical trials reporting on the pharmacology of sirukumab or investigating the efficacy of targeting IL-6 signaling. Overall, sirukumab has been reported to be a safe and well-tolerated agent, capable of modulating the immune response in healthy populations as well as in subjects with inflammatory disorders (e.g., rheumatoid arthritis). Sirukumab’s effects on cytokine networks as part of the innate immune system provide a coherent rationale for possible application in neuropsychiatric disorders with possible benefits across several domains of the biobehavioral Research Domain Criteria matrix (e.g., general cognitive processes, positive valence systems). Amongst individuals with complex brain-based disorders (e.g., mood disorders), the dimensions/domains most likely to benefit with sirukumab are negative valence disturbances (e.g., anxiety, depression, rumination), positive valence disturbances (e.g., anhedonia) as well as general cognitive processes. We suggest that sirukumab represents a prototype and possibly a proof-of-concept that agents that engage IL-6 targets have salutary effects in psychiatry.

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“…On the other hand, the IL-6 level in RA patients after sirukumab treatment was assumed to be similar as that in healthy subjects in the current PBPK model, since sirukumab binds to IL-6 with very high affinity (k d = 0.175 pM) (32), and a complete neutralization of free IL-6 in the system till day 42 after sirukumab treatment is expected. The predicted blood concentrations of sirukumab on days 15, 29, and 50 of the TP-DI study (day 7, day 21, and day 42 following a 300-mg subcutaneous sirukumab dose) are around 169, 77.6, and 27.3 nM, respectively, based on the PK information of sirukumab following a 100-mg subcutaneous dose (33), and the fact that sirukumab exhibited linear pharmacokinetics in human across a wide dosing range (0.3 to 10 mg/kg) (34). Consistently, the model prediction (Fig.…”

Section: Discussionmentioning

confidence: 99%

Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein–Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6

Jiang

Zhuang

et al. 2016

AAPS J

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Abstract. Disease-mediated therapeutic protein-drug interactions have recently gained attention from regulatory agencies and pharmaceutical industries in the development of new biological products. In this study, we developed a physiologically based pharmacokinetic (PBPK) model using SimCYP to predict the impact of elevated interleukin-6 (IL-6) levels on cytochrome P450 (CYP) enzymes and the treatment effect of an anti-IL-6 monoclonal antibody, sirukumab, in patients with rheumatoid arthritis (RA). A virtual RA patient population was first constructed by incorporating the impact of systemic IL-6 level on hepatic and intestinal expression of multiple CYP enzymes with information from in vitro studies. Then, a PBPK model for CYP enzyme substrates was developed for healthy adult subjects. After incorporating the virtual RA patient population, the PBPK model was applied to quantitatively predict pharmacokinetics of multiple CYP substrates in RA patients before and after sirukumab treatment from a clinical cocktail drug interaction study. The results suggested that, compared with observed clinical data, changes in systemic exposure to multiple CYP substrates by anti-IL-6 treatment in virtual RA patients have been reasonably captured by the PBPK model, as manifested by modulations in area under plasma concentration versus time curves for midazolam, omeprazole, S-warfarin, and caffeine. This PBPK model reasonably captured the modulation effect of IL-6 and sirukumab on activity of CYP3A, CYP2C9, CYP2C19, and CYP1A2 and holds the potential to be utilized to assess the modulation effect of sirukumab on the metabolism and pharmacokinetics of concomitant small-molecule drugs in RA patients.

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Pharmacokinetics and safety of sirukumab following a single subcutaneous administration to healthy Japanese and Caucasian subjects

Cited by 22 publications

References 0 publications

Novel investigational drugs targeting IL-6 signaling for the treatment of depression

Novel investigational drugs targeting IL-6 signaling for the treatment of depression

Sirukumab: A Potential Treatment for Mood Disorders?

Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein–Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6

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