Re-discover the value of protein binding assessments in hepatic and renal impairment studies and its contributions in drug labels and dose decisions.

One of the key pharmacokinetic properties of most small molecule drugs is their ability to bind to serum proteins. Unbound or free drug is responsible for pharmacological activity while the balance between free and bound drug can impact drug distribution, elimination, and other safety parameters. In the hepatic impairment (HI) and renal impairment (RI) clinical studies, unbound drug concentration is often assessed; however, the relevance and impact of the protein binding (PB) results is largely limited. We analyzed published clinical safety and pharmacokinetic studies in subjects with HI or RI with PB assessment up to October 2022 and summarized the contribution of PB results on their label dose recommendations. Among drugs with HI publication, 32% (17/53) associated product labels include PB results in HI section. Of these, the majority (9/17, 53%) recommend dose adjustments consistent with observed PB change. Among drugs with RI publication, 27% (12/44) of associated product labels include PB results in RI section with the majority (7/12, 58%) recommending no dose adjustment, consistent with the reported absence of PB change. PB results were found to be consistent with a tailored dose recommendation in 53% and 58% of the approved labels for HI and RI section, respectively. We further discussed the interpretation challenges of PB results, explored treatment decision factors including total drug concentration, exposure-response relationships, and safety considerations in these case examples. Collectively, comprehending the alterations in free drug levels in HI and RI informs treatment decision through a risk-based approach.

The Patient Motivation Pyramid and Patient-Centricity in Early Clinical Development.

BACKGROUND: It has been recognized that patients should be involved in the design of clinical trials. However, there is a lack of agreement on what patient-centricity means. METHODS: In this article, a Patient Motivation Pyramid based on Maslow's theory of human motivation is introduced as a tool to identify patient needs. This pyramid is used to make a comprehensive overview of options to implement a patient-centric trial design. The Pyramid with the described options can help to identify patient-centric activities suitable for given drug development. The current article further describes the potential benefits of patient-centric trial designs with an emphasis on early clinical development. Especially in early clinical development, during which trials have many assessments per patient, and the safety and clinical efficacy are uncertain, patient-centric trial design can improve feasibility. Finally, we present three case examples on patient-centric trial design. The first example is seeking patient input on the trial design for a First-in-Human trial which includes patients with Immune Thrombocytopenic Purpura. The second example is the use of a video-link for home dosing. The final example is the use of digital medicine in a decentralized trial in heart failure patients. RESULTS: A comprehensive overview of patients' needs can be accomplished by building a Patient Motivation Pyramid as a tool. Patient input can lead to improved endpoints, improved feasibility, better recruitment, less dropout, less protocol amendments, and higher patient satisfaction. The use of digital medicine can lead to a trial design with much less visits to the clinical research center in early clinical development and in a later development phase, even to a complete virtual trial. CONCLUSION: We recommend using the Patient Motivation Pyramid as a structural approach for identifying elements of patient-centricity. Secondly, we recommend starting using patient-centric approaches in an early phase of the medicine's lifecycle.

Factors Influencing Infusion-Related Reactions Following Dosing of Reference Rituximab and PF-05280586, a Rituximab Biosimilar.

BACKGROUND: Infusion-related reactions (IRRs) are the most common adverse event (AE) associated with infusion of rituximab, an anti-CD20 monoclonal antibody. OBJECTIVE: Our objective was to evaluate the impact of dosing/infusion patterns and certain baseline characteristics on IRR occurrence during the first rituximab infusion administered as the biosimilar PF-05280586 (RTX-PF) or reference rituximab sourced from the EU (RTX-EU, MabThera®) in patients with CD20+ low-tumor-burden follicular lymphoma. PATIENTS AND METHODS: Rituximab (RTX-PF, n=196; RTX-EU, n=198) was administered (375 mg/m2) on days 1, 8, 15, and 22 (one cycle), with a follow-up period through 52 weeks. The relationships between infusion rate, drug exposure, and IRR incidence were assessed by logistic regression analysis and pharmacokinetic modeling and simulation. Baseline CD20 level, antidrug antibody (ADA) status, and tumor burden according to IRR occurrence (yes/no) were compared descriptively. RESULTS: Median rituximab infusion duration on day 1 was 3.50 h for each of the two groups. There was a positive correlation between infusion rate and all-grade IRRs occurring within 24 h after infusion (p < 0.0001). Patients who developed IRRs had a higher median baseline CD20+ level. IRR incidence was unaffected by baseline ADA status. Drug exposure did not predict IRR incidence. Baseline tumor burden was similar between patients with and without IRRs. CONCLUSIONS: Results of this analysis provide a better understanding of IRRs after the first rituximab (RTX-PF or RTX-EU) infusion and demonstrate a potential correlation of infusion rate and other factors with IRR at the individual and population levels. Infusion-rate escalation steps continue to be needed to manage IRRs. TRIAL REGISTRATION (DATE OF REGISTRATION): ClinicalTrials.gov Identifier: NCT02213263 (11 August 2014); and EudraCT: 2014-000132-41 (10 October 2014).