Prospective observational study on the pharmacokinetic properties of the Irrua ribavirin regimen used in routine clinical practice in patients with Lassa fever in Nigeria

Abstract

IntroductionLassa fever (LF) is a severe and often fatal systemic disease in humans and affects a large number of countries in West Africa. Treatment options are limited to supportive care and the broad-spectrum antiviral agent ribavirin. However, evidence for ribavirin efficacy in patients with LF is poor and pharmacokinetic (PK) data are not available.Irrua Specialist Teaching Hospital (ISTH) developed an intravenous ribavirin regimen different to the WHO recommendation. Apart from a lower total daily dose the drug is usually administered once per day which reduces the exposure of personnel to patients with LF. The aim of this study is to characterise the PK of the Irrua ribavirin regimen.Methods and analysisThis prospective, observational clinical study will assess PK properties of the Irrua ribavirin regimen on routinely ribavirin-treated patients with LF at ISTH, a referral hospital serving 19 local governmental areas in a LF endemic zone in Nigeria. Participants will be adults with PCR-confirmed LF. The primary objective is to describe classical PK parameters for ribavirin (maximum plasma drug concentration, time to maximum plasma drug concentration, area under the plasma drug concentration vs time curve, half-life time T1/2, volume of distribution). Blood samples will be collected at 0.5, 1, 3, 5, 8, 12 and 24 hours after doses on day 1, day 4 and day 10 of ribavirin treatment. Ribavirin plasma concentrations will be determined using liquid chromatography coupled to tandem mass spectrometry.Ethics and disseminationThe study will be conducted in compliance with the protocol, the Declaration of Helsinki, Good Clinical Practice (GCP) and the Nigerian National Code for Health Research Ethics. The protocol has received approval by the Health Research Ethics Committee of ISTH. Results will be made available to LF survivors, their caregivers, the funders, LF research society and other researchers.Registration detailsISRCTN11104750

Pharmacokinetics of Ribavirin in the Treatment of Lassa Fever: An Observational Clinical Study at the Irrua Specialist Teaching Hospital, Edo State, Nigeria

“…A limitation of this study is that the Irrua regimen used in routine care was adapted individually by treating physicians, including a variability in the decrease of dosing to 12.5 mg/kg between days 6 and 8. At the time of protocol development, 100 mg/kg loading dose on the first day of treatment (if total dose >7 g, then 2/3 administered at presentation and 1/3 8 hours later) followed by 25 mg/kg once daily from days 2 to 5 and 12.5 mg/kg once daily from days 6 to 10 were a widely used variation that is reflected in Figure 2 and in the published study protocol [ 13 ]. The study team did not interfere with treatment decisions of the treating physician including drug dosage and schedule because of the observational nature of the study design.…”

“…This prospective observational study was conducted in adult nonpregnant LF patients with mild disease course admitted to and routinely managed at ISTH, the protocol was published previously [ 13 ]. In brief, adult nonpregnant patients with mild disease progression and real-time reverse transcription polymerase chain reaction (RT-PCR)-confirmed LF infection necessitating routine treatment with intravenous ribavirin were invited to participate.…”

“…The objectives of this study were published previously [ 13 ]. The analysis presented here describes the classical pharmacokinetics (PK) parameters and the evaluation of clinical, hematological, and biochemical parameters in correlation with ribavirin blood levels.…”

“…Medical history, previous and concomitant medication, anthropometric measurements and other baseline characteristics, body temperature, signs and symptoms, physical examination, and blood sampling information were collected as part of the study [ 13 ]. Participant data were recorded on paper source documents and transcribed to electronic case record forms using REDCap (Version 10.0.25, Vanderbilt, TN, USA).…”

Two Cases of Lassa Fever Successfully Treated with Ribavirin and Adjunct Dexamethasone for Concomitant Infections

“…Evidence supporting a beneficial effect of ribavirin for treatment of Lassa fever is scarce, and the pivotal landmark study (2) showed a high risk for bias (5,6). A study focused on evaluation of pharmacokinetics of ribavirin to better characterize its role in treatment for Lassa fever (7). Severe Lassa fever with lethal outcome is associated with encephalopathy, acute kidney injury, and respiratory failure (8).…”