Viral Hepatitis C Therapy: Pharmacokinetic and Pharmacodynamic Considerations: A 2019 Update

Abstract

It has been estimated by the World Health Organization (WHO) that over 71 million people were infected with the hepatitis C virus (HCV) in 2015. Since then, a number of highly effective direct-acting antiviral (DAA) regimens have been licensed for the treatment of chronic HCV infection: sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, elbasvir/grazoprevir, sofosbuvir/ velpatasvir, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir. With these treatment regimens, almost all chronic HCV-infected patients, even including prior DAA failures, can be treated effectively and safely. It is therefore likely that further development of DAAs will be limited. In this descriptive review we provide an overview of the clinical pharmacokinetic characteristics of currently available DAAs by describing their absorption, distribution, metabolism, and excretion. Potential drug-drug interactions with the DAAs are briefly discussed. Furthermore, we summarize what is known about the pharmacodynamics of the DAAs in terms of efficacy and safety. We briefly discuss the relationship between the pharmacokinetics of the DAAs and efficacy or toxicity in special populations, such as hard to cure patients and patients with liver cirrhosis, liver transplantation, renal impairment, hepatitis B virus or HIV co-infection, bleeding disorders, and children. The aim of this overview is to educate/update prescribers and pharmacists so that they are able to safely and effectively treat HCV-infected patients even in the presence of underlying co-infections or co-morbidities.

Ultra-short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients

“…In patients with renal function impairment, sofosbuvir's AUC was 61%, 107%, and 171% higher in subjects with mild, moderate, and severe renal impairment, whereas its active metabolite, GS‐331007 AUC was 55%, 88%, and 451% higher, respectively. Furthermore, sofosbuvir and GS‐331007 AUC was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively . Finally, we considered cost‐effectiveness and real‐world feasibility in our approach.…”

“…Furthermore, sofosbuvir and GS-331007 AUC was 28% and 1280% higher when sofosbuvir was dosed 1 hour before hemodialysis compared with 60% and 2070% higher when sofosbuvir was dosed 1 hour after hemodialysis, respectively. 13,14 Finally, we considered cost-effectiveness and real-world feasibility in our approach. It had been our previous experience as well as from published reports that insurance coverage for DAA drugs might frequently be denied due to a presumed lack of "medical necessity."…”

“…Although the optimal duration for DAA in the setting of acute HCV is unknown, we hypothesized that an ultra‐short course of a pangenotypic DAA started perioperatively as prophylaxis could result in prevention of HCV transmission from NAT + donors to NAT‐ recipients (D+/R−) and minimize the need for a full course of therapy. The primary reasons for the rationale behind the design of an ultra‐short prophylactic regimen using sofusbuvir/velpatasvir (SOF/VEL) (Epclusa; Gilead, Foster City, CA) were the following: (1) the pharmacokinetics of sofusbuvir that suggested prolonged half‐life and area under the curve (AUC) in patients with end‐stage kidney disease; (2) the only available fixed‐dose pangenotypic agent at study conception that would allow for avoidance of donor genotyping and kidney discard; (3) the possibility that a small inoculum of donor virus could be sterilized with peritransplant prophylaxis; and (4) cost effectiveness with increased access to patients if the strategy were to be effective.…”

“…Gilead, Foster City, CA) were the following: (1) the pharmacokinetics of sofusbuvir that suggested prolonged half-life and area under the curve (AUC) in patients with end-stage kidney disease 13,14 ; (2) the only available fixed-dose pangenotypic agent at study conception that would allow for avoidance of donor genotyping and kidney discard; (3) the possibility that a small inoculum of donor virus could be sterilized with peritransplant prophylaxis; and (4) cost effectiveness with increased access to patients if the strategy were to be effective.…”

The Reliability of Fibro-test in Staging Orthotopic Liver Transplant Recipients with Recurrent Hepatitis C

“…[15][16][17]20 The issues of drug-drug interactions, varying degrees of concomitant renal insufficiency, and rarely acute rejection also come into consideration in the post-transplant setting, making the treatment of RHC more challenging. 6,17,21 What is more, sustained virological response rates appear to be lower in simultaneous liver-kidney transplant recipients. 17 As such, until a universally accepted, streamlined, 100% effective and caveat-free regimen is found to treat RHC in liver recipients, there will be a need to monitor disease progression in those few who fail or do not tolerate our current options.…”