Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials

Abstract

The 2014-2015 outbreak of Ebola virus disease is the largest epidemic to date in terms of the number of cases, deaths, and affected areas. In October 2015, no antiviral agents had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried and has since regularly updated a list of potential drug candidates with demonstrated antiviral efficacy in in vitro or animal models. This includes agents belonging to various therapeutic classes, namely direct antiviral agents (favipiravir and BCX4430), a combination of antibodies (ZMapp), type I interferons, RNA interference-based drugs (TKM-Ebola and AVI-7537), and anticoagulant drugs (rNAPc2). Here, we review the pharmacokinetic and pharmacodynamic information presently available for these drugs, using data obtained in healthy volunteers for pharmacokinetics and data obtained in human clinical trials or animal models for pharmacodynamics. Future studies evaluating these drugs in clinical trials are critical to confirm their efficacy in humans, propose appropriate doses, and evaluate the possibility of treatment combinations.

Figure 1

Structure of Ebola virus. EBOV is an enveloped virus presenting a single-stranded RNA genome of nearly 19000 nucleotides, encoding seven proteins: structural nucleoprotein (NP), polymerase cofactor (VP 35), VP 40, transcription activator (VP30), VP24, RNA-dependent RNA polymerase (L) and Glycoprotein (GP). GP, also expressed in a soluble form (sGP), is responsible for host receptor binding and fusion with the cell membrane. Reproduced from Choi and Croyle. Biodrugs 2013[7].

Figure 2

Ebola viral lifecycle and targets of different therapeutic classes. Steps of virus life cycle: (1) attachment, (2) fusion with endosomal membranes, (3) nucleocapsid release, (4) mRNA transcription, (5) viral protein translation, (6) genome replication and (7) viral assembly and release. Polymerase inhibitors hamper replication and transcription processes (4)(6), directly targeting the viral polymerase L. Monoclonal antibodies (ZMapp, MIL-77) binds to viral glycoprotein and therefore inhibit viral attachment (1) but also increase virions and infected cells clearance (not represented). Interfering RNAs inhibit the viral mRNA translation process (5), and enhance viral mRNA degradation. Type I interferons have pleiotropic indirect effects through host cell genes regulation, leading to viral mRNA degradation, inhibition of viral transcription (4) and translation (5), interference with the release of viral particles(7), facilitation apoptosis of infected cells and enhancement of innate and adaptive immune response (not represented). Modified from Yazdanpanah et al, Intensive Care Medicine 2015 [13].

Figure 3

Survival of NHP infected by EBOV and treated with highest doses of candidates drugs. Data from rhesus macaques and cynomolgus macaques are in red and blue, respectively. Colored solid line stands for post exposure prophylaxis experiments (treatment initiation within 24h post challenge), colored dashed line for curative treatment (treatment initiation after 24h post challenge and black line for untreated control) + marks the end of study following. Survival plots were drawn from data reported in [28,29,31,52,53,55,64,72]using the dose where the best survival rate was observed.