Drugs in COVID‐19 Clinical Trials: Predicting Transporter‐Mediated Drug‐Drug Interactions Using In Vitro Assays and Real‐World Data

Abstract

Numerous drugs are currently under accelerated clinical investigation for the treatment of coronavirus disease 2019 (COVID‐19); however, well‐established safety and efficacy data for these drugs are limited. The goal of this study was to predict the potential of 25 small molecule drugs in clinical trials for COVID‐19 to cause clinically relevant drug‐drug interactions (DDIs), which could lead to potential adverse drug reactions (ADRs) with the use of concomitant medications. We focused on 11 transporters, which are targets for DDIs. In vitro potency studies in membrane vesicles or HEK293 cells expressing the transporters coupled with DDI risk assessment methods revealed that 20 of the 25 drugs met the criteria from regulatory authorities to trigger consideration of a DDI clinical trial. Analyses of real‐world data from electronic health records, including a database representing nearly 120,000 patients with COVID‐19, were consistent with several of the drugs causing transporter‐mediated DDIs (e.g., sildenafil, chloroquine, and hydroxychloroquine). This study suggests that patients with COVID‐19, who are often older and on various concomitant medications, should be carefully monitored for ADRs. Future clinical studies are needed to determine whether the drugs that are predicted to inhibit transporters at clinically relevant concentrations, actually result in DDIs.

Cationic Compounds with SARS-CoV-2 Antiviral Activity and Their Interaction with Organic Cation Transporter/Multidrug and Toxin Extruder Secretory Transporters

“…Whereas Zolk et al (Zolk et al, 2009b) reported an IC 50 of >1 mM for chloroquine's inhibition of MPP transport, Belzer et al (Belzer et al, 2013) reported a value of 129 μM, in close agreement with the results presented here (Table 1). Recently, (Yee et al, 2021) reported an IC 50 of ~100 µM against OCT2-mediated metformin transport, compared to the 15 µM value we measured; they also reported an IC 50 of 0.8 µM against MATE1-mediated metformin transport, similar to our value of 2.4 µM. Modest differences in affinity for substrate and inhibitors have been reported between two common sequence variants of OCT2, the preponderant 'wild type' sequence in which amino acid residue 270 is an alanine, and the p.270Ala>Ser (c.808G>T) variant that is expressed at a frequency of ~10% in different ethnic groups (Leabman et al, 2002) (Chen et al, 2009).…”

New and Emerging Research on Solute Carrier and ATP Binding Cassette Transporters in Drug Discovery and Development: Outlook From the International Transporter Consortium

“…In the COVID‐19 drug study, sildenafil, which is used to treat pulmonary hypertension associated with later stages of COVID‐19, was shown to inhibit BCRP at concentrations, which are expected to be achieved in the intestines following therapeutic doses. Indeed, uric acid levels in patients on sildenafil were significantly increased compared with age, sex, and diagnosis matched patients not on sildenafil 110 . Control studies validating uric acid as a real‐world biomarker were performed in studies that showed that cyclosporin and eltrombopag, the FDA recommended clinical inhibitors of BCRP, 111 were associated with elevated uric acid levels.…”

Transporters in Regulatory Science: Notable Contributions from Dr. Giacomini in the Past Two Decades

“…Giacomini is driven by science, wanting to contribute her transporter biology knowledge to COVID-19 drugs. Her laboratory determined the potencies of the known drugs used during COVID-19 pandemic to assess the potential of these drugs to inhibit eleven important drug transporters (Yee et al 2021). They discovered that one of the drugs, sildenafil, for the treatment of associated pulmonary hypertension in patients with COVID-19, met the cutoff criteria based on in vitro inhibition data to inhibit BCRP in vivo.…”

“…They discovered that one of the drugs, sildenafil, for the treatment of associated pulmonary hypertension in patients with COVID-19, met the cutoff criteria based on in vitro inhibition data to inhibit BCRP in vivo. Her team then used real-world data from electronic health records (EHR) and showed that patients on sildenafil significantly showed higher levels of uric acid, a well-known substrate of BCRP and readily reported in EHR (Yee et al 2021).…”