The Defining Role of Clinical Pharmacology for COVID-19 Drug Development

On March 11, 2020, the World Health Organization (WHO) characterized the COVID-19 outbreak as a pandemic. With no direct pre-existing immunity, the virus has spread rapidly on a global scale. At the time of this writing, 4.8 million confirmed cases and over 315,000 known deaths have been reported since its emergence in December 2019.

This editorial in Clinical Pharmacology and Therapeutics focuses on how clinical pharmacology is playing a critical role in the development of drugs and therapeutics to treat COVID-19. Although 12 years is the typical time required for a new therapeutic to go from discovery to approval, drug development for COVID-19 therapies must follow a shorter timeline due to the global nature and severity of the disease. The accelerated timeline applies to short-term repurposing of existing drugs, the mid-term development of vaccines and diagnostics, and, after comprehensive characterization of the virus, long-term discovery of innovative drugs that target mechanisms of action. Although mid- and long-term development of vaccines and novel drugs follow a conventional development pathway, clinical pharmacology can play a defining role for identifying existing drugs that can be repurposed for COVID-19 therapy. Many researchers believe that identifying a single drug to treat the disease will be difficult. Rather a multi-directional approach will be needed to discover and develop combination therapeutics.1 While the evaluation of repurposing drugs for off-label use has surged since COVID-19 was declared a pandemic –it is still too early to determine which of these therapeutics (and combinations) will be effective against the virus.

The US Food and Drug Administration (FDA) has recently created the Coronavirus Treatment Acceleration Program (CTAP) which acts as an emergency program for developing possible therapies using “every available method to move treatments to patients as quickly as possible “and, simultaneously establish their safety and efficacy. As part of CTAP, two guidances have been developed for near-term Investigational New Drug Applications and recommendations for the development of drugs and biologicals in later stage clinical trials for the treatment and prevention of COVID-19. Clinical pharmacology strategies, including model-informed drug development (MIDD) approaches, can provide the innovation outlined in the guidances to efficiently design studies that will lead to the review and approval of therapeutics to address the COVID-19 pandemic.

Harnessing the knowledge of clinical pharmacologists and integrating Quantitative Systems Pharmacology (QSP) approaches in current “repurposing” clinical trials conveys immediate benefits for optimizing model-informed precision dosing and treatment regimens including:

  • Absorption, distribution, metabolism, excretion (ADME) and Pharmacokinetics (PK)
  • PK in special populations including the evaluation of factors e.g., age, gender, ethnicity, genetics, disease and organ function
  • Identification of drug-drug interactions (DDIs)
  • Exposure and adverse events and others

Recent published reviews highlight the use of models to gain rapid information on the safety, posology, and efficacy of drugs for repurposing trials.2,3,4 The use of models, which integrates information from a broad range of sources, will provide transparency and context to quantify any uncertain results and assumptions. Of utmost importance is the involvement of expert clinical pharmacologists, best skilled at positioning data uncertainty, to provide input into interpreting COVID-19 drug dosing, safety, and efficacy.5,6

Another opportunity to better understand drug efficacy and toxicity in drug repurposing trials is the use of Real World Data (RWD) from electronic health records (EHR). RWD is increasingly being used in pharmacoepidemiology and pharmacovigilance to monitor drug utilization patterns and drug safety, e.g. adverse drug reactions, DDIs, and other outcomes in large populations in a real world setting.  Importantly, there are opportunities for clinical pharmacologists to identify and predict DDIs, which may occur between COVID-19 drugs and drugs required by patients for pre-existing conditions.

Clinical pharmacology provides a valuable opportunity to accelerate COVID-19 drug development using a physiologically-based pharmacokinetic (PBPK) “predict, learn, confirm, and apply” approach. Applying decision analysis to drug development for COVID-19 and future pandemics will aid in optimizing and accelerating candidate therapies.

Accessing current information is paramount to successful drug development. A COVID-19 Clinical Pharmacology Resource Center has been created to provide and share up-to-date information on clinical trials and research studies. In addition, in silico workbench applications are made available to assist researchers and scientists with clinical trial design for exploratory and educational purposes. Certara has also created the COVID-19 Resource Hub for the drug development community with recent and relevant information regarding COVID-19 and facilitating professional development with on-demand resources.

 

References

  1. Repurposing existing drugs for COVID-19 offers a more rapid alternative to a vaccine. ScienceDaily, 7 May 2020.
  2. Garcia-Cremades M., Solans BP., Hughes E., et al. (2020). Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modeling approach for effective drug repurposing. Pharmacol. Ther., doi:10.1002/cpt.1856. Epub ahead of print.
  3. Damle, B., Vourvahis, M., Wang E., Leaney J., and Corrigan B. (2020). Clinical Pharmacology Perspectives on the Antiviral Activity of Azithromycin and Use in COVID-19. (202) Pharmacl. Ther., doi:10.1002/cpt.1857. Epub ahead of print.
  4. Du Y-X, and Chen X-P. (2020). Favipiravir: pharmacokinetics and concerns about clinical trials for COVID-nCoV infection. Pharmacol. Ther. doi: 10.1002/cpt.1844. Epub ahead of print.
  5. Rayner CR, Smith PR, Hershberger K, and Wesche, D. (2020). Optimizing COVID-19 Candidate Therapeutics: Thinking Without Borders. Transl. Sci. doi:10.1111/cts.12790. Epub ahead of print.
  6. Smith, PF, Dodds, M, Bentley D, Yeo K, and Rayner C. (2020). Dosing will be a key success factor in repurposing antivirals for COVID-19. J. Clin. Pharmacol. doi:10.1111/bcp.14314. Epub ahead of print.

Watch this recent webinar to learn more about COVID-19 therapeutic considerations for children and pregnant women.