Concerns about pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) studies in the new therapeutic area of COVID-19 infection

Abstract

In the context of the COVID-19 pandemic, several drugs have been repurposed as potential candidates for the treatment of COVID-19 infection. While preliminary choices were essentially based on in vitro potency, clinical translation into effective therapies may be challenging due to unfavorable in vivo pharmacokinetic properties at the doses chosen for this new indication of COVID-19 infection. However, available pharmacokinetic and pharmacokinetic-pharmacodynamic studies suffer from severe limitations leading to unreliable conclusions, especially in term of dosing optimization. In this paper we propose to highlight these limitations and to identify some of the major requirements that need to be addressed in designing PK and PK-PD studies in this era of COVID. A special attention should be paid to pre-analytical and analytical requirements and to the proper collection of covariates affecting dose-exposure relationships (co-medications, use of specific organ support techniques and other clinical and para-clinical data). We also promote the development of population PK and PK-PD models specifically dedicated to COVID-19 patients since those previously developed for other diseases (SEL, malaria, HIV) and clinical situations (steady-state, non-ICU patients) are not representative of severe patients. Therefore, implementation of well-designed PK and PD studies targeted to COVID-19 patients is urgently needed. For that purpose we call for multi-institutional collaborative work and involvement of clinical pharmacologists in multidisciplinary research consortia.

Keywords: COVID-19; PK-PD; Pharmacodynamics; Pharmacokinetics.

Fig. 1

Observed hydroxychloroquine plasma concentrations (median) after 3–5 days of treatment in patients treated for SARS-CoV-2 infection depending on the scheme of administration: 400 mg QD after a loading dose of 400mgx2 on day 1 and 200 mg TID without any loading dose (C. Solas, internal data from the Pharmacokinetics and Toxicology Laboratory). Solid line represent in vitro EC50 described against SARS-CoV-2 at T48h post incubation.