A predictive pharmacokinetic model of ribavirin plasma concentration in lung transplant recipients treated for a paramyxovirus or chronic Hepatitis E virus infection

A.E.S. Zwart, E. eliza Milliken, S. Reuter Lange, A. Riezebos-Brilman, F. Burrows, J.C. Alffenaar, A. Glanville, E.A. Verschuuren

Friday 16 march 2018

10:15 - 10:20h at Willem Burger Foyer

Categories: Clinical, Session (parallel)

Parallel session: Poster session 6: Clinical

Background

Ribavirin (RBV) is a guanosine analogue used for treatment of paramyxovirus (PMV) infections and Hepatitis E in the lung transplant recipients (LTR). The pharmacokinetic profile of RBV in the transplant population is unknown and is likely to be altered due to renal and hepatic impairment and cystic fibrosis in these immunocompomised individuals. The treatment protocol of 2 University hospitals (Netherlands,Sydney) for RBV consists of a loading dose (11mg/kg thrice daily, Groningen: orally, Sydney: IV) followed by oral maintenance dose (10mg/kg bidaily). However, whilst the treatment protocols have demonstrated efficacy, the RBV exposure has not been established. A pharmacokinetic model using observational data and pharmacokinetic modelling was constructed to predict exposure and design an optimal dosing regimen for RBV in the LTR population.

Methods

Twenty-four LTR with PCR-confirmed PMV or chronic HEV were recruited (13 Dutch protocol/ 11 Australian protocol; 12 male/12 female; Age: 45.3 ± 13.9 yrs; BMI: 23.8 ± 4.82 kg/m2; CrCL: 69.2 ± 26.7mL/min).Plasma RBV concentrations were quantified using a validated HPLC-UV analytical method. Patient concentration-time data, combined with previously published RBV pharmacokinetic data, were used to develop a population pharmacokinetic model, using NONMEM® VII software, incorporating inter-individual and residual unexplained variability. Patient factors contributing to parameter variability (such as creatinin clearance, body weight, CF or not) were modelled using standard forward-inclusion/backward-deletion methods. Model selection was based on the objective function value and standard diagnostic plots. The developed model was then used to conduct Monte Carlo simulations examining alternate dosing regimens.

Results and conclusion

Comparable drug exposure can be achieved using oral loading dose of 11mg/kg thrice daily as opposed to IV. In addition, a maintenance dose of 4 mg/kg bd was optimal to maintain target concentrations between 1.5-3.0 mg/L. This protocol reaches target concentration within 24 hrs and the escalation of plasma concentrations above toxic range during maintenance treatment was avoided. The oral administration reduces patient bed days, costs and increasing convenience.Additional research is needed to establish effective plasma RBV concentrations; however, it is anticipated that the developed pharmacokinetic model will allow predictions of optimal dosing regimens.