Ledipasvir/Sofosbuvir versus Etravirine
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Study Design
Multicenter and observational study was conducted in HCV infected and HCV-HIV co-infected adults receiving ledipasvir/sofosbuvir (90/400mg QD) and etravirine (daily 400mg) containing regimen (boosted PI excluded). Time between last drug intake and sampling were recorded. Steady-state (at W4) average ledipasvir plasma concentrations (CLDV) was determined using UPLC-MS/MS (LOQ <10ng/mL). Results are presented as median (IQR25-75%) and compared using Mann-Whitney tests between patients receiving etravirine (LDV-ETR) or not (LDV). Then, a population pharmacokinetic model (non-linear mixed effect modeling approach) was developed using SAEM algorithm (Monolix Suite 2016R1). Effect of etravirine on ledipasvir pharmacokinetic parameters was assessed on each model parameter following an ascending procedure.
Study Results
141 patients were eligible (median age 53 years old [IQR 48-58], 75% men), including 17 HCV-HIV co-infected adults. CLDV were significantly higher in LDV group than in LDVETR: 262 ng/mL (162-468; n=151 samples) and 119 (81-214; n=25 samples), respectively (p<0.0001). Ledipasvir plasma pharmacokinetics were adequately described by a linear one compartment model with first order absorption and first order elimination. Population estimates for elimination rate constant (kel) and V/F, (RSE %) were 0.031h-1 (25%), 360L (25%), respectively. Due to sparseness of data, the absorption rate constant (ka) and absorption lagtime (ALAG) were fixed at 0.32h-1 and 0.42h, respectively as previously published (German P et al., AASLD 2014). Inter-individual variabilities expressed as CV% (RSE%) of kel and V/F were 26.6%(4%) and 14.2%(62%), respectively. Modified kel with etravirine was 0.059h-1 corresponding to an elimination half-life of 11.5h (versus 23.0h in LDV group) (p<0.001). No effect of ETR was found on V/F.
Study Conclusions
Using both descriptive and population modeling method, etravirine presented similar and significant effect on ledipasvir pharmacokinetics. Indeed, a 50% decrease of CLDV and 50% decrease of elimination half-life were observed in LDV-ETR group, mediated through efflux transporters (Pgp or BCRP) interaction. Despite the magnitude of the interaction, etravirine might be coadministered with ledipasvir/sofosbuvir without any dose adjustment, due to the long half-life of phosphorylated metabolites.
References
San C, Le M, Gervais A, Chas J, Valantin M, Lopez-Zaragoza J, Salmon D. Pharmacokinetic interaction between ledipasvir/sofosbuvir and etravirine containing regimen. International Workshop On Clinical Pharmacology Of Antiviral Therapy. Chicago, IL, USA. 18; June 2017.
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