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Does hepatic impairment affect the exposure of monoclonal antibodies?
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Liver impairment may affect levels of some monoclonal antibodies
19th International Workshop on Clinical Pharmacology of Antiviral Therapy
Mark Mascolini
Concentrations of some licensed monoclonal antibodies (mAbs) proved significantly lower in people with mild or moderate hepatic impairment, according to results of a 22-mAb FDA study [1]. Whether severe hepatic impairment will have a greater impact remains unknown.
An array of mAbs are licensed or in development as therapeutic agents for viral diseases, including HIV, HCV, influenza, respiratory syncytial virus, and enteric viruses [2]. The FDA has licensed the mAb ibalizumab (Trogarzo), in combination with standard antiretrovirals, for people with multidrug-resistant HIV [3]. FDA researchers noted target populations for mAbs include people with hepatic impairment, and that liver impairment may develop or worsen as viral and other diseases progress [1]. Therefore they conducted this analysis of how hepatic impairment may affect concentrations of current mAbs.
The FDA team focused on 22 mAbs with data on hepatic impairment. Most of these mAbs had no data on severe hepatic impairment, and those that did included only 1 person. Six mAbs had data on moderate hepatic impairment in 5 or more people, and in 3 of these 6 moderate impairment had a significant impact on mAb area under the concentration-time curve (AUC), cutting AUC by 35% to 70%. Among 20 mAbs with data on mild hepatic impairment in 10s to 100s of people, 2 mAbs had significantly lower exposure with mild impairment.
The 3 mAbs affected by moderate hepatic impairment are ado-trastuzumab emtansine, evolocumab, and brentuximab vedotin. Ado-trastuzumab emtansine (Kadcyla) contains the mAb trastuzumab and is licensed for HER2-positive metastatic breast cancer [4]. The FDA team reported that people with mild hepatic impairment had 40% lower ado-trastuzumab emtansine AUC, while people with moderate hepatic impairment had 70% lower AUC.
Evolocumab (Repatha) lowers LDL ("bad") cholesterol and is licensed for treatment of hyperlipidemia [5]. The FDA reported that people with mild hepatic impairment had 40% lower evolocumab AUC and people with moderate impairment had 50% lower AUC.
Brentuximab vedotin (Adcetris) is licensed for adults with newly diagnosed stage 3 or 4 classical Hodgkin lymphoma in combination with chemotherapy [6]. People with moderate hepatic impairment had 35% lower brentuximab vedotin AUC.
The FDA reported that the trend to decreased AUC with moderate hepatic impairment also affects other mAbs, including bezlotoxumab (Zinplava) and alirocumab (Praluent).
According to ibalizumab prescribing information, formal studies of how hepatic or renal impairment affects ibalizumab concentrations have not been done [7].
The FDA researchers believe their findings "suggest that hepatic dysfunction may impact the disposition of mAbs." They called for more research on how moderate and severe hepatic impairment may affect mAbs.
References
1. Qin S, Seo S, Liu C, Reynolds K. Does hepatic impairment affect the exposure of monoclonal antibodies? 19th International Workshop on Clinical Pharmacology of Antiviral Therapy. May 22-24, 2018. Baltimore. Abstract 15.
2. Wu Y, Jiang S, Ying T. Single-domain antibodies as therapeutics against human viral diseases. Front Immunol. 2017;8:1802. https://www.frontiersin.org/articles/10.3389/fimmu.2017.01802/full
3. AIDSinfo. Drugs. Ibalizumab. https://aidsinfo.nih.gov/drugs/511/ibalizumab/0/patient
4. Kadcyla. Ado-trastuzumab emtansine. https://www.kadcyla.com/
5. Repatha (evolocumab). https://www.repatha.com
6. Adcetris. Brentuximab vedotin. https://adcetrisavd.com/
7. Highlights of prescribing information. Trogarzo. Ibalizumab-uiyk injection. https://drive.google.com/viewerng/viewer?embedded=true&url=https://theratechnologies.s3.amazonaws.com/prod/media/TrogarzoPrescribingInformation.pdf
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