Clinical application of the dried milk spot method for measuring tocilizumab concentrations in the breast milk of patients with rheumatoid arthritis

Saito, Jumpei; Yakuwa, Naho; Kaneko, Kayoko; Nakajima, Ken; Takai, Chinatsu; Goto, Mikako; Yamatani, Akimasa; Murashima, Atsuko

doi:10.1111/1756-185x.13557

Cited by 15 publications

(20 citation statements)

References 25 publications

(24 reference statements)

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“…The time taken to reach the maximum concentration (Tmax) in breast milk was calculated as 3.2 days. Milk to serum concentration ratios were: 0.0015, 0.00082 and 0.0014 for three patients [119].…”

Section: Tocilizumabmentioning

confidence: 90%

Intrauterine Exposure to Biologics in Inflammatory Autoimmune Diseases: A Systematic Review

Ghalandari

Dolhain

Hazes

et al. 2020

Drugs

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Background Inflammatory autoimmune diseases are chronic diseases that often affect women of childbearing age. Therefore, detailed knowledge of the safety profile of medications used for management of inflammatory autoimmune diseases during pregnancy is important. However, in many cases the potential harmful effects of medications (especially biologics) during pregnancy (and lactation) on mother and child have not been fully identified. Objective Our aim was to update the data on the occurrence of miscarriages and (major) congenital malformations when using biologics during pregnancy based on newly published articles. Additionally, we selected several different secondary outcomes that may be of interest for clinicians, especially information on adverse events in the use of a specific biologic during pregnancy. Material and Methods A search was conducted from 1 January 2015 until 4 July 2019 in Embase.com, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar with specific search terms for each database. Selection of publications was based on title/abstract and followed by full text (double blinded, two researchers). An overview was made based on outcomes of interest. References of the included publications were reviewed to include and minimize the missing publications. Results A total of 143 publications were included. The total number of cases ranged from nine for canakinumab to 4276 for infliximab. The rates of miscarriages and major congenital malformations did not show relevant differences from those rates in the general population. Conclusion Despite limitations to our study, no major safety issues were reported and no trend could be identified in the reported malformations.

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Section: Tocilizumabmentioning

confidence: 90%

Intrauterine Exposure to Biologics in Inflammatory Autoimmune Diseases: A Systematic Review

Ghalandari

Dolhain

Hazes

et al. 2020

Drugs

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“…Data on tocilizumab in breastfeeding is limited to 3 prospective case series/reports which included a total of 7 mother-infant pairs. ( 33 , 34 , 51 ) Tocilizumab was either stopped in the first trimester and resumed after delivery or continued throughout pregnancy and post-partum. All women delivered healthy term infants.…”

Section: Breastfeedingmentioning

confidence: 99%

Tocilizumab for coronavirus disease 2019 in pregnancy and lactation: a narrative review

Jorgensen

Lapinsky

2022

Clinical Microbiology and Infection

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Background Tocilizumab is a monoclonal antibody that interrupts interleukin-6 signaling, reducing downstream effects on inflammation and the innate immune response. It was shown to reduce mortality in patients with severe or critical COVID-19. Pregnant and breastfeeding people were largely excluded from clinical trials and hence, the extent to which results can be applied to these populations is not clear. Objectives To synthesize published data on tocilizumab in pregnancy and lactation, highlight important knowledge gaps, and help inform clinical decision-making about tocilizumab’s use in these populations with COVID-19. Sources PubMed was searched for studies evaluating tocilizumab in pregnancy and lactation for COVID-19 and other indications. Literature on pharmacokinetics and reproductive/fetal safety of monoclonal antibodies in general was also sought. US FDA and EMA guidance for the industry and regulatory approval documents were reviewed. Content Published data on tocilizumab in pregnancy includes 610 cases (n=20 with COVID-19) together with 7 mother-infant breastfeeding pairs. Higher rates of spontaneous abortion and premature birth have been reported compared to the general population, but multiple confounding variables limit interpretation. There is little data on tocilizumab exposure in the second and third trimesters when transplacental transport is highest. The effects of tocilizumab on the developing immune system are unclear. Pregnant patients with COVID-19 who received tocilizumab were often critically ill and corticosteroid use was uncommon. Neonatal follow-up was limited. Tocilizumab appears to be compatible with breastfeeding. Implications Although the available data do not raise serious safety signals, they have significant limitations and are not sufficient to delineate the complete spectrum of potential adverse outcomes that may be associated with tocilizumab exposure during pregnancy and lactation. Diligent follow-up and documentation of pregnancy outcomes will be important moving forward. A more effective regulatory framework to ensure equitable inclusion of pregnant people in research is clearly needed.

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“…Three prospective studies evaluated the safety of tocilizumab (TCZ) during pregnancy and breastfeeding for a total of 7 pregnancies in women treated for RA and adult-onset Still disease. [25][26][27] In all 7 women, TCZ was either stopped during the first trimester or continued throughout pregnancy; all resulted in term delivery of healthy infants. Infant serum was collected at delivery in 1 pregnancy with a low, but detectable, TCZ concentration attributed to placental transfer.…”

Section: Tocilizumabmentioning

confidence: 99%

Transfer of monoclonal antibodies into breastmilk in neurologic and non-neurologic diseases

LaHue

Anderson

Krysko

et al. 2020

Neurol Neuroimmunol Neuroinflamm

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ObjectiveTo review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases.MethodsWe systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and “breastmilk,” “breast milk,” “breastfeeding,” or “lactation.” From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria. One additional study was added after the literature search based on expert knowledge of an additional article. These 30 studies were reviewed. These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women.ResultsDrug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion. Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 1:20 for infliximab. Relative infant dose, a metric comparing the infant with maternal drug dose (<10% is generally considered safe), was evaluated for certolizumab (<1%), rituximab (<1%), and natalizumab (maximum of 5.3%; cumulative effects of monthly dosing are anticipated). Importantly, a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections.ConclusionsThe current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development.

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Clinical application of the dried milk spot method for measuring tocilizumab concentrations in the breast milk of patients with rheumatoid arthritis

Cited by 15 publications

References 25 publications

Intrauterine Exposure to Biologics in Inflammatory Autoimmune Diseases: A Systematic Review

Intrauterine Exposure to Biologics in Inflammatory Autoimmune Diseases: A Systematic Review

Tocilizumab for coronavirus disease 2019 in pregnancy and lactation: a narrative review

Transfer of monoclonal antibodies into breastmilk in neurologic and non-neurologic diseases

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