Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis

Aa, Fasanmade; Oj, Adedokun; Olson, Adriana Segura; Strauß, Richard; Hm, Davis

doi:10.5414/cpp48297

Cited by 217 publications

(161 citation statements)

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“…4). The correlation of albumin levels and CL of mAbs is well documented [41,42]. High albumin levels can be indicative of higher expression levels of the neonatal Fc receptors (FcRn), which offer both albumin and immunoglobulins a protective mechanism against lysosomal catabolism by recycling them across the plasma membrane back to the circulatory system [32,43].…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

et al. 2018

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Background and Objectives Risankizumab is a humanized anti-interleukin-23 monoclonal antibody in development for the treatment of several inflammatory diseases. This work characterized the pharmacokinetics of risankizumab and evaluated covariates that may affect its exposures using phase I and II trial data in subjects with psoriasis and Crohn's disease. Methods Plasma concentration measurements from a phase I study and a phase II study in subjects with psoriasis (n = 157; single doses of 0.01-5 mg/kg intravenously, 0.25-1 mg/kg subcutaneously, and 18 mg subcutaneously, and multiple doses of 90 and 180 mg subcutaneously), and a phase II study in subjects with Crohn's disease (n = 115; doses of 200 or 600 mg intravenously every 4 weeks followed by 180 mg subcutaneously every 8 weeks) were analyzed using non-linear mixedeffects modeling. The model was qualified using bootstrap and simulation-based diagnostics. Results A two-compartment model with first-order absorption and elimination described the pharmacokinetics of risankizumab. Considering the body weight and baseline albumin central tendency differences between disease populations, risankizumab clearance, steady-state volume of distribution, and terminal-phase elimination half-life were estimated to be approximately 0.35 L/day, 11.7 L, and 27 days, respectively, for a typical 90-kg subject with psoriasis with an albumin level of 42 g/L, and 0.31 L/day, 8.45 L, and 22 days, respectively, for a typical 65-kg subject with Crohn's disease with an albumin level of 37 g/L. Risankizumab absolute subcutaneous bioavailability and absorption rate constant were 72% and 0.18 day −1 , respectively. Inter-individual variability for clearance was 37%. Conclusions Risankizumab displayed pharmacokinetic characteristics typical for an IgG1 monoclonal antibody with no apparent target-mediated disposition. Accounting for the effects of body weight and baseline albumin explained the small differences in the pharmacokinetics of risankizumab between psoriasis and Crohn's disease, with no further differences between the patient populations. Electronic supplementary materialThe online version of this article (https ://doi.org/10.1007/s4026 2-018-0704-z) contains supplementary material, which is available to authorized users. Key PointsA robust two-compartment model with dose-and timeindependent pharmacokinetic parameters was developed to characterize the disposition of risankizumab, an antiinterleukin-23 monoclonal antibody, in subjects with plaque psoriasis and Crohn's disease.Of the factors evaluated (demographics, disease population, laboratory values, and anti-drug antibody development), only body weight and baseline albumin level were statistically correlated with risankizumab clearance. Body weight had a modest effect on risankizumab exposure while albumin had no meaningful impact.After accounting for differences in body weight and baseline albumin levels between psoriasis and Crohn's disease patient populations, no significant differences in the pharmacokinetics of ri...

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

et al. 2018

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“…The presence of antibodies to infliximab (ATI) is responsible for the adverse events (18) and reduction of the drug's efficacy (15,25,27) . Factors that can also interfere with drug´s efficacy are accelerated clearance of the drug (9) , body weight, concomitant use of other medications, type of disease and degree of inflammation (8,15,25) . , we can classify it according to its extension in: 1) terminal ileitis; 2) colonic disease; 3) ileocolonic disease, and 4) upper gastrointestinal tract involvement.…”

Section: Introductionmentioning

confidence: 99%

Importance of Measuring Levels of Infliximab in Patients Treating Inflammatory Bowel Disease in a Brazilian Cohort

Dbg

et al. 2017

Arq. Gastroenterol.

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-Background -Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases. In such pathologies, there is an increased production of alpha tumor necrosis factor (TNF-α). Patients, in whom the conventional immunosuppressant treatment fails, require the use of immunobiological therapy, such as anti-TNF-α, a monoclonal antibody. infliximab is an anti-TNF-α drug, a chimerical immunoglobulin, with a murine component, which is responsible for the generation of immunogenicity against the drug and formation of anti-TNF-α antibodies. The presence of anti-drug antibodies may be responsible for adverse events and reduction of the drug's effectiveness. Patients with inflammatory bowel diseases undergoing therapy with biological medication, such as infliximab, can relapse overtime and this may not be translated into clinical symptoms. Thus, there is a need for a method to evaluate the efficacy of the drug, through the measurement of serum infliximab levels, as well as antibodies research. Objective -This study aimed to measure serum infliximab levels and anti-infliximab antibodies in patients with inflammatory bowel diseases post-induction phase and during maintenance therapy, and describe the therapeutic modifications that took place based on the serum levels results. Methods -It was a retrospective study, that included forty-five patients, with a total of 63 samples of infliximab measurement. Results -Twenty-one patients had an adequate infliximab serum level, 31 had subtherapeutic levels and 11 had supratherapeutic levels. Seven patients had their medication suspended due to therapeutic failure or high levels of antibodies to infliximab. Conclusion -In conclusion, only a third of the patients had adequate infliximab levels and 36% presented with subtherapeutic levels at the end of the induction phase. Therapy optimization occurred based in about 46% of the samples results, demonstrating the importance of having this tool to help the clinical handling of patients with inflammatory bowel diseases ongoing biologic therapy.

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“…Both the binding to FcRn at acidic pH and the release from FcRn at neutral pH are critical for maintaining the long circulation half-life of an IgG (Vaccaro et al, 2005). Of interest, a recent population pharmacokinetic (PK) analysis of infliximab suggested that intersubject variability in FcRn activity is an important covariance of infliximab PK, which implies that although FcRn is highly efficient in salvaging IgGs from lysosomal degradation, the IgGs failed to be salvaged by FcRn can still consist of a significant portion to normal IgG elimination (Fasanmade et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Monoclonal Antibodies with Identical Fc Sequences Can Bind to FcRn Differentially with Pharmacokinetic Consequences

Wang

Lü²,

Fang³

et al. 2011

Drug Metab Dispos

152

181

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ABSTRACT:The neonatal Fc receptor (FcRn) is a key determinant of IgG homeostasis. It binds to the Fc domain of IgG in a strictly pH-dependent manner and protects IgG from lysosomal degradation. The impact of FcRn salvage pathway on IgG monoclonal antibody (mAb) pharmacokinetics (PK) has been well established. In this report, a set of mAbs with wild-type human Fc sequences but different Fab domains were used to examine the potential impact of Fab domain on in vitro FcRn binding and in vivo PK. We were surprised to find that mAbs with the same wild-type human Fc sequences but different Fab domains were shown to bind FcRn with considerable differences in both the binding at acidic pH and the dissociation at neutral pH, suggesting that the Fab domain may also have an impact on FcRn interaction. For these mAbs, no relationship between the FcRn binding affinity at acidic pH and in vivo PK was found. Instead, an apparent correlation between the in vitro FcRn dissociation at neutral pH and the in vivo PK in human FcRn mice, nonhuman primates and humans was observed. Our results suggested that the Fab domain of mAbs can affect their interaction with FcRn and thus their pharmacokinetic properties and that in vitro FcRn binding/dissociation assays can be a useful screening tool for pharmacokinetic assessment of mAbs with wildtype Fc sequences.

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Serum albumin concentration: a predictive factor of infliximab pharmacokinetics and clinical response in patients with ulcerative colitis

Cited by 217 publications

References 0 publications

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

Importance of Measuring Levels of Infliximab in Patients Treating Inflammatory Bowel Disease in a Brazilian Cohort

Monoclonal Antibodies with Identical Fc Sequences Can Bind to FcRn Differentially with Pharmacokinetic Consequences

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