Clinical Significance of Therapeutic Peptide and Protein Drug Interactions: A Call to Action.

Abstract

Although insulin was discovered more than 100 years ago, the significant shift toward biotherapeutic drug development only began at the start of this century. This issue of Clinical Pharmacology & Therapeutics (CPT) presents two White Papers on therapeutic peptide and protein drug–drug interactions (DDIs). They make the case that the science and best practices in this area have not been keeping up with the rapid growth in the development of these biological modalities. Säll et al. report findings from a cross-industry therapeutic peptide DDI working group consisting of drug metabolism and pharmacokinetics experts from 10 leading pharmaceutical and biotechnology companies, established in 2020 under the sponsorship of the European Federation of Pharmaceutical Industries and Associations (EFPIA; www.efpia.eu). This working group surveyed 10 pharma companies involved in the development of peptide drugs to better understand the type and timing of DDI studies commonly undertaken for such therapeutics, and compiled a database containing in vitro and clinical DDI data from submission packages for peptide drugs approved between January 2008 and August 2021.1 In parallel, Coutant et al.2 compiled a position paper on therapeutic proteins’ DDIs on behalf of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ; www.iqconsortium.org), which originated as a response to the 2020 US Food and Drug Administration (FDA) draft guidance.3 At a high level, both White Papers conclude that DDIs for therapeutic peptides and proteins are still very much emerging scientific areas in drug development and regulatory guidance. At present, there is even a lack of clarity on the distinction between a peptide and a protein in the context of therapeutics development1 (Figure 1). As a rule of thumb, the smaller the peptide the more potential DDIs can be expected to mimic conventional small molecules, whereas DDIs for large proteins will typically be determined by different, complex biological mechanisms, such as cytokine modulation and disease state.1 Coutant and colleagues from the IQ consortium postulate that for therapeutic proteins that modulate cytokine release and action, disease state and severity are the primary determinants DDIs.2 On the basis of this, they recommend, for example, that clinical DDI studies for therapeutic proteins are not necessary in diseases like psoriasis.2 Säll and co-workers from the EFPIA working group should be commended for compiling and making available in vitro and clinical DDI data for 31 therapeutic peptide drugs approved between 2008 and 2021,1 which should be a unique resource for clinical pharmacologists working in this area. The editorial team of CPT encourages others to follow this example and share case studies and databases to advance the science and best practices in this critical area of clinical pharmacology and therapeutics. No funding was received for this work. The author declared no competing interests for this work.