104 Chapter 6 METHODS Sources The literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [16]. The databases of Embase, PubMed and Cochrane Central Register of controlled trials (CENTRAL) were searched from the start of these databases through April 28th 2020, and was updated on November 13th 2020. The search terms included ‘emicizumab’ and ‘pharmacokinetics’ with their associated synonyms; see Supplemental Data SD1 for an example of the search algorithm of Embase. In the Embase database, the search was conducted using the corresponding EMtree terms, and for PubMed and CENTRAL databases the National Library of Medicine (MeSH) search terms were used. Finally, the included studies were manually searched for relevant references and the European Public Assessment Report (EPAR) of emicizumab was used as a cross-reference for possible missed studies [12]. Study selection The search results from the three databases were merged in Endnote X9 (Clarivate Analytics, Version 19.3.3.13966), and duplicate records (title, abstract or both) were removed automatically. Hereafter, the records were imported into the web-based tool Rayyan (https://rayyan.qcri.org/[17]) and were screened and categorized. First, the records and, secondly, the full-text articles were screened and categorized in duplicate by two reviewers (AD, LB). The following inclusion criteria were applied: emicizumab studies providing (i) data on humans, (ii) original PK data or modelled PK data or PK−PD relationships, and (iii) access to the abstract and to the full text in English. In the event of doubt about eligibility, the records or articles were included. Disagreements were discussed until consensus was reached, and when necessary a third reviewer (TE) was consulted. Data extraction The following data were extracted from the included studies: (i) study characteristics (authors, year of publication, number of subjects, phase, design, dosing regimen, follow-up, funding); (ii) population characteristics (population [volunteer/PwHA], anti-FVIII antibodies, age group, haemophilia A severity, ethnicity); and (iii) evaluated PK and efficacy data. Relevant primary PK parameters included the absorption rate constant (Ka), apparent clearance (CL/F), and apparent volume of distribution (Vd/F); and secondary (exposure) PK parameters included terminal half-life (t1/2), the area under the plasma concentration−time curve extrapolated to infinity (AUCinf), maximum plasma concentration (Cmax), trough plasma concentration in steady-state conditions (Ctrough,ss) and time to reach maximum plasma concentration (tmax). The relevant efficacy parameter was expressed as the annualized bleeding rate (ABR) of different bleeding types (i.e., treated or treated joint bleeds). When relevant data were missing from text, a data request was sent to the corresponding authors or sponsors.
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