Physiologically Based Pharmacokinetic Model to Assess the Influence of Blinatumomab‐Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity

Xu, Yang; Hijazi, Youssef; Wolf, Andreas; Wu, Benjamin; Sun, Yuanming; Zhu, Min

doi:10.1002/psp4.12003

Cited by 52 publications

(123 citation statements)

References 37 publications

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“…Although it is possible to use hepatocyte donor cocktails for short-term cultures in an attempt to represent a population average, these pooled hepatocytes are not necessarily amenable to long-term culture because of the difficulties in controlling cell numbers over time. As an alternative, physiologically based PK models have been used for simulation of IL-6-mediated CYP phenomena (Machavaram et al, 2013;Xu et al, 2015), but notably these models often rely on parameters generated from in vitro datasets.…”

Section: Discussionmentioning

confidence: 99%

Modeling Therapeutic Antibody–Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

et al. 2016

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Traditional in vitro human liver cell culture models lose key hepatic functions such as metabolic activity during short-term culture. Advanced three-dimensional (3D) liver coculture platforms offer the potential for extended hepatocyte functionality and allow for the study of more complex biologic interactions, which can improve and refine human drug safety evaluations. Here, we use a perfusion flow 3D microreactor platform for the coculture of cryopreserved primary human hepatocytes and Kupffer cells to study the regulation of cytochrome P450 3A4 isoform (CYP3A4) activity by chronic interleukin 6 (IL-6)-mediated inflammation over 2 weeks. Hepatocyte cultures remained stable over 2 weeks, with consistent albumin production and basal IL-6 levels. Direct IL-6 stimulation that mimics an inflammatory state induced a dose-dependent suppression of CYP3A4 activity, an increase in C-reactive protein (CRP) secretion, and a decrease in shed soluble interleukin-6 receptor (IL-6R) levels, indicating expected hepatic IL-6 bioactivity. Tocilizumab, an anti-IL-6R monoclonal antibody used to treat rheumatoid arthritis, has been demonstrated clinically to impact small molecule drug pharmacokinetics by modulating cytochrome P450 enzyme activities, an effect not observed in traditional hepatic cultures. We have now recapitulated the clinical observation in a 3D bioreactor system. Tocilizumab was shown to desuppress CYP3A4 activity while reducing the CRP concentration after 72 hours in the continued presence of IL-6. This change in CYP3A4 activity decreased the half-life and area under the curve up to the last measurable concentration (AUC last ) of the small molecule CYP3A4 substrate simvastatin hydroxy acid, measured before and after tocilizumab treatment. We conclude that next-generation in vitro liver culture platforms are well suited for these types of long-term treatment studies and show promise for improved drug safety assessment.

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Section: Discussionmentioning

confidence: 99%

Modeling Therapeutic Antibody–Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

et al. 2016

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“…Furthermore, the magnitude of T‐cell activation also contributed to the magnitude of cytokine release. In addition, the magnitude of cytokine elevation was related to the initial doses of blinatumomab . Maximum cytokine levels observed during week 1 in cycle 1 were greater than those at second or later blinatumomab doses, which renders the stepwise dosing paradigm critical for an effective and tolerable treatment with blinatumomab.…”

Section: Discussionmentioning

confidence: 99%

Blinatumomab Pharmacodynamics and Exposure–Response Relationships in Relapsed/Refractory Acute Lymphoblastic Leukemia

Zhu

Kratzer

Johnson

et al. 2017

The Journal of Clinical Pharma

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We evaluated blinatumomab pharmacokinetics, pharmacodynamics (CD3+ T-cell, CD19+ B-cell, and cytokine levels), and their associations with efficacy or safety in relapsed/refractory acute lymphoblastic leukemia. Blinatumomab pharmacokinetics (continuous intravenous infusion) from a phase 2 study (n = 189; NCT01466179) were assessed noncompartmentally. Associations between steady-state concentration (C ) and efficacy (complete remission [CR] or CR with partial hematologic recovery [CRh]) or safety (cytokine release syndrome [CRS] and neurologic events [NEs]) were evaluated with statistical models. Blinatumomab mean ± SD C was 621 ± 502 pg/mL (28 μg/day dose). Cytokines were transiently elevated in >50% of patients; B-cell levels decreased in most patients. Lower B-cell and bone marrow (BM) blast percentages and higher T-cell percentages were associated with higher CR/CRh (P < .001) in univariate analysis. Higher C (OR, 1.90; 95%CI, 1.12-3.21), higher peak IL-10 level (1.59; 1.13-2.22), and lower BM blast percentage (0.78; 0.69-0.89) were associated with higher CR/CRh in multivariate analysis. Higher C (HR, 1.40; 1.01-1.94) and lower B-cell level (0.90; 0.84-0.97) were associated with shorter time to NEs. Cytokine peaks were not associated with NEs or CRS. In conclusion, blinatumomab led to T cell-mediated depletion of target B cells in blood and blasts in the bone marrow. Immune system effectiveness was important for treatment responses.

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“…Although BiTE® antibody constructs do not directly affect CYP enzyme activities, transient cytokine elevation, especially of IL‐6, has been observed in clinical trials with blinatumomab and in preclinical studies with blinatumomab and other BiTE® antibody constructs, and the suppression of CYP enzymes in response to cytokine elevation has been well documented 79. A dedicated DDI study in this population would be impractical, however, so a physiologically based pharmacokinetic (PBPK) model was developed to evaluate the impact of IL‐6 elevation on CYP suppression after blinatumomab administration 80. The predicted suppression of hepatic CYP450 activities was <30%, and IL‐6‐mediated changes in exposure to sensitive substrates of CYP3A4, CYP1A2, and CYP2C9 were <2‐fold and lasted <1 week 80…”

Section: Clinical Pharmacology Of Blinatumomabmentioning

confidence: 99%

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

Yuraszeck

Kasichayanula

Benjamin

2017

Clin Pharma and Therapeutics

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Bispecific T‐cell Engagers (BiTE®) antibody constructs enable a polyclonal T‐cell response to cell‐surface tumor‐associated antigens, bypassing the narrow specificities of T‐cell receptors and the need for antigen presentation through the major histocompatibility complex pathways. Blinatumomab, a CD19xCD3 BiTE® antibody construct, received accelerated approval for the treatment of relapsed/refractory Philadelphia chromosome negative acute lymphoblastic leukemia. Herein we review the pharmacology, safety, and efficacy observed in studies of blinatumomab and other BiTE® antibody constructs. Quantitative systems pharmacology is envisioned as a means to optimize dosing decisions for trials in which BiTE® antibody constructs are administered as monotherapy or in combination with other immunotherapies.

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Physiologically Based Pharmacokinetic Model to Assess the Influence of Blinatumomab‐Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity

Cited by 52 publications

References 37 publications

Modeling Therapeutic Antibody–Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

Modeling Therapeutic Antibody–Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

Blinatumomab Pharmacodynamics and Exposure–Response Relationships in Relapsed/Refractory Acute Lymphoblastic Leukemia

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

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