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.

Spontaneous reported cardiotoxicity induced by lopinavir/ritonavir in COVID-19. An alleged past-resolved problem

“…Lopinavir residual plasma concentrations of 8 ± 6 mg have been described previously [ 37 ]. This discrepancy has also been observed in other COVID-19 units [ 38 , 39 ]. This might be of concern, since the off-label use of LPV/r in COVID-19 requires the same regular posology as HIV treatment.…”

Antiretrovirals for Prophylaxis Against COVID‐19: A Comprehensive Literature Review

“…According to pharmacokinetic studies, ritonavir and lopinavir reach much higher trough concentrations in patients with COVID-19 compared with HIV patients (27,28). But despite this high plasma concentration observed in COVID-19 patients, the unbound fraction, is not affected (24). This higher plasma concentration has been attributed to the hepatic impairment caused by SARS-CoV-2 and the enzymatic inhibitory effects of these drugs.…”

Simultaneous quantification of seven repurposed COVID-19 drugs remdesivir (plus metabolite GS-441524), chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin by a two-dimensional isotope dilution LC–MS/MS method in human serum

“…It is conceivable that dosage regimens of repurposed drugs may lead to subtherapeutic or toxic concentrations without clear clinical benefit. Accordingly, there is an urgent need to generate high-quality pharmacokinetic data for drug repurposing against COVID-19 [ 9 ]. In addition, polytherapy can result in unpredictable drug levels due to relevant drug-drug interactions.…”