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Simeprevir for the treatment of hepatitis C and HIV/hepatitis C co-infection Expert Rev. Clin. Pharmacol. 7(6), 691–704 (2014)

Stuart Flanagan, Andrew Crawford-Jones and Chloe Orkin* Department of Infection and Immunology, Royal London Hospital, Whitechapel Road, London E1 1BB *Author for correspondence: Tel.: +44 203 594 6765 [email protected]

Hepatitis C virus (HCV) is a major cause of chronic hepatitis in 170 million people worldwide and can progress to fibrosis, cirrhosis, liver failure and hepatocellular carcinoma, a disease process accelerated in HIV co-infection. Approximately 25% of HIV infected people are co-infected with HCV (worldwide prevalence 4–5 million) and up to 16.7% of deaths in this population are attributable to HCV co-infection. Previous treatment options for HCV were limited to pegylated interferon and ribavirin (PEG-IFN/RBV), a combination that demonstrated lower successful cure rates in genotype 1 HCV mono-infection and HIV/HCV co-infection, and is also associated with a considerable adverse side-effect profile. The development of directly acting antivirals (DAAs) offers the first class of drug to achieve good viral suppression in previously hard-to-treat patient groups. We review the benefits, tolerability and drug interactions with concomitant drugs of the DAA simeprevir for patients who have HCV mono-infection and hep C/HIV co-infection. KEYWORDS: co-infection • directly acting antivirals • hepatitis C • HIV • NS3/4A protease inhibitors • simeprevir

Epidemiology

The hepatitis C virus (HCV) was first isolated and identified as the cause of non-A non-B hepatitis in 1989 [1] and is currently estimated to cause chronic infection in 170 million people worldwide, with approximately 3–4 million new infections per annum [2]. The most common transmission routes include intravenous drug use, infected blood products including hemodialysis, unsterilized medical equipment and through risky, men who have sex with men, sexual activity in which recreational drugs (e.g., crystal methamphetamine or mephadrone) are used to enhance and prolong sexual encounters [3]. Transmission of HCV has also been reported through intranasal cocaine use and household exposure [4]. A total of 75–90% of people infected with HCV ultimately develop chronic hepatitis C [5]. The progression to fibrosis, cirrhosis, liver failure and an increased prevalence of hepatocellular carcinoma caused by HCV can take decades to develop; however, the rate of progression increases significantly in people co-infected with HIV [6].

informahealthcare.com

10.1586/17512433.2014.956091

Approximately 25% of HIV-positive patients are co-infected with HCV, with an estimated worldwide prevalence of 4–5 million [7]. As AIDS-related mortality has declined, liverassociated mortality has emerged as the second most common cause of death in HIV-infected patients, accounting for up to 16.7% of deaths in cohort studies mainly attributable to HCV co-infection [8,9]. Unmet needs of current treatment

Until recently, treatment strategies for HCV universally involved dual therapy with pegylated interferon a (PEG-IFN) and ribavirin (RBV). The duration varied depending on genotype and stage of liver fibrosis. The aim of treatment was to achieve sustained viral response (SVR), defined as a failure to detect HCV RNA by PCR at 24 weeks after the completion of treatment. PEG-IFN/RBV dual therapy achieves SVR in up to 80% of genotype 2 or 3 monoinfected patients; however, average SVR rates for genotype 1 (G1) HCV monoinfection with PEG-IFN/RBV are up to 50% [10,11]. Significantly lower cure rates occur in the HIV/HCV co-infection with SVR rates

 2014 Informa UK Ltd

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Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Nyu Medical Center on 12/03/14 For personal use only.

Drug Profile

Flanagan, Crawford-Jones & Orkin

achieved in only 15–34% of genotype 1 infection and up to 50% in genotype 2/3 [12]. Dual therapy of PEG-IFN/RBV therapy is associated with an unfavorable adverse effect profile, including fatigue, flu-like symptoms, mood lability, cytopenias, hypothyroidism and autoimmune phenomena. Not only do patients fail to achieve SVR, but many also fail due to discontinuation mediated by such side effects. This underpinned the need for newer more effective and tolerable agents to achieve higher rates of SVR across all genotypes and to shorten the treatment duration. Triple therapy with direct-acting antivirals (DAA) became the standard of care treatment for chronic HCV infection in 2012 with the introduction of telaprevir (TLV) and boceprevir (BOC), both first generation nonstructural NS3/4A protease inhibitors (PIs) for HCV [12]. These direct antiviral agents (DAA) have been developed to inhibit specific viral replication targets in the HCV lifecycle. This class of drug acts by preventing the cleavage of a viral polypeptide essential for replication.

that has demonstrated potent and specific inhibition of HCV replication in vitro. In biochemical assays, simeprevir has shown antiviral activity against G1-6 except G3 [23]. In biochemical assays using NS3/4A proteases of HIV genotypes 1–6, half maximal inhibitory concentration values (IC50) below 13 nmol/l were observed, with the exception of genotype 3a protease (37 nmol/l). Different genotype 1a and 1b replicons were inhibited by simeprevir, with half maximal effective concentration (EC50) values ranging between 8 and 28 nmol/l and half maximal cytotoxicity concentration values above 16 mol/l in a range of human cell lines. In replicon cells, simeprevir was synergistic with IFN and an HCV NS5B polymerase inhibitor and additive with RBV. In rats, the compound was extensively distributed to the liver and intestinal tract and the absolute bioavailability was 44% after a single oral administration. Compound concentrations detected in both plasma and liver at 8 h postdosing in rats were above the EC99 value measured in the replicon assay and around the EC50 value at 24 h.

Competitor drugs

Pharmacodynamics

Three NS3/4A PIs are currently licensed for use with PEGIFN/RBV in G1 patients: including TLV, BOC and most recently simeprevir (TMC-435). With the addition of TLV and BOC, SVR 12 and 24 rates have increased to 70% in G1-infected patients from 50% with PEG-IFN/RBV alone [13]. Interestingly, in contrast to PEG-IFN/RBV, which performed worse in HIV/HCV co-infected patients, the SVR 12 and 24 rates when combined with both BOC and TLV were similar to those achieved in HCV monoinfection [13]. However, both TLV and BOC are themselves associated with significant side effects and toxicities including severe rash, anal pruritus, hematological toxicities and alopecia [14,15]. Both drugs also require multiple daily dosing and adherence to specific dietary requirements. These factors are known to impact adherence and may increase treatment failure [16]. Failure to achieve SVR on BOC and TLV causes the rapid development of protease domain resistance mutations at amino acids 156 and 36 [17,18] due to their low genetic barrier to resistance.

T1/2 term was longer in chronic G1 HCV-infected individuals (~ 41 h), which supported a once-daily regimen. Simeprevir is primarily metabolized by cytochrome P450 (CYP) 3A, with renal clearance having little role in elimination of the drug. Simeprevir is readily absorbed as a capsule or as an oral solution. Maximum plasma concentration (tmax) is reached at 4–6 h in healthy subjects, with terminal elimination half-life ranging from 8 to 21 h [25]. In vitro data demonstrates that simeprevir is a moderate inhibitor of CYP2A6, CYP2C8 and CYP2D6 (IC50 >32 mg/ml) and a weak inhibitor of CYP2C19 and CYP3A (IC50 >64 mg/ml). In vivo data suggest simeprevir has no clinically relevant effect on the activity of CYP2C9, CYP2C19 and CYP2D6. While simeprevir does not affect hepatic CYP3A4 activity, it is a mild inhibitor of intestinal CYP3A4 activity. Simeprevir also mildly inhibits CYP1A2. Strong inhibitors of CYP3A4 may increase the plasma exposure of simeprevir, and strong inducers of CYP3A4 may reduce plasma exposure of simeprevir [26].

Introduction to the drug

Pharmacokinetics & metabolism

Simeprevir (formerly TMC435) is a second-generation protease inhibitor for use in combination with PEG-IFN/RBV for G1 HCV. It received regulatory approval in Japan in September 2013 and approval from the US FDA in November 2013 under the trade name Olysio [19]. Simeprevir is the first single pill, once-daily regimen offering greater affinity and tighter binding to the viral target and fewer side effects than TLV and BOC [14,15]. In combination with PEG-IFN/RBV, simeprevir has achieved around 80% SVR 12 in both monoand co-infection studies [20,21] and has received a positive opinion for approval in the EU in March 2014 [22].

The pharmacokinetics of simeprevir were evaluated in a number of Phase I studies. Absorption in healthy subjects was quantifiable 0.5 h after administration in study TMC435-C103. Multiple dosing amounts were studied (TMC435-C101) in both healthy and HCV genotype-infected individuals via multiple blood samplings and analysis of plasma concentrations of the drug using a validated liquid chromatography mass spectrometry method [25]. The 100, 200 and 400 mg once-daily regimens were compared in healthy volunteers and a prolonged absorption was noted with a late Tmax of 4–6 h. Minimal exposure levels for the 200 mg once daily regimen were approximately 275 times the levels found in vitro studies, and as a higher exposure again might be anticipated in patients, the 200 mg once-daily dose was chosen for administration to HCV G1 participants. Over 5 days, the HCV-positive patients

Chemistry

Simeprevir is a second-generation NS3/4A macro-cyclic protease inhibitor developed by Tibotec and Janssen Pharmaceuticals 692

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Simeprevir for the treatment of hepatitis C & HIV/hepatitis C co-infection

presented a similar pharmacokinetic profile as healthy volunteers, with a long absorption phase with Tmax 4–6 h. As in healthy patients, by day 5, the regimen did not attain steady state. Simeprevir is highly protein bound in humans with in vitro plasma protein binding greater than 99.8% [26]. The primary enzyme involved in the metabolism and biotransformation of simeprevir is CYP3A4 and to a lesser extent CYP2C enzymes. Other enzymes involved include CYP3A5, CYP3A7, CYP2B6 and CYP2E1. The majority of the drug is excreted in feces with less than 0.04% excreted in urine, suggesting renal clearance plays an insignificant role in the elimination of simeprevir. Administration of simeprevir with food to healthy subjects increased the relative bioavailability (area under the curve [AUC]) by 61 and 69% after a high-fat, high-calorie (928 kcal) and normal calorie (533 kcal) breakfast, respectively, and delayed the absorption by 1 h and 1.5 h, respectively. Based on these pharmacokinetic parameters, it is recommended that simeprevir be taken with food [26]. Drug exposure in Asian subjects was higher than in Caucasian subject with exposure to 100 mg simeprevir being 1.6-fold higher in Phase I healthy volunteer studies. The Phase II DRAGON study treated Japanese subjects with 100 mg of simeprevir with similar exposures to Caucasian subjects treated with 150 mg [27]. Across three pivotal Phase III studies (QUEST-1, QUEST-2 and PROMISE), the mean AUC24 was 3.4-fold higher in Asian subjects receiving simeprevir 150 mg daily compared with the pooled subjects as a whole [28,20,29] with increased prevalence of adverse events as a result. A 100 mg treatment dose in Asian subjects has been recommended. Phase I studies

Ten Phase I nonclinical studies have provided a basic understanding of the pharmacokinetic characteristics, short-term safety and tolerability and antiviral activity of simeprevir. Two reported clinical Phase I studies demonstrate potency in HCVinfected individuals and are reported below. TMC435350-C101

TMC435350-C101 study was a Phase I, randomized, doubleblind, placebo-controlled trial in 49 healthy volunteers followed by an open-label study in six G1 HCV-positive participants who had previously failed at least one course of IFN-based therapy. Part one investigated the safety, tolerability and pharmacokinetic profile of simeprevir in single and multiple ascending doses in healthy volunteers. A once-daily dose of 200 mg was taken forward into part two in which simeprevir was administered to six IFN-treatment experienced G1 HCV patients. Simeprevir 200 mg once daily was well tolerated and demonstrated potency with a maximal 3.9 log10 IU/ml rapid reduction in plasma HCV RNA levels compared with baseline in all patients over 5 days. The maximal viral load reduction occurred 24 h after the last dose of study drug (day 6). HCV RNA levels remained relatively constant for 3 days posttreatment, suggesting continued viral suppression. No viral informahealthcare.com

Drug Profile

breakthroughs occurred during treatment and by week 4 after the final dose, HCV RNA levels had returned to pretreatment levels in all six patients. In vivo potency value for simeprevir was determined as 0.9993 using a viral kinetic model [25]. TMC 647055 HPC1001

Simeprevir was co-administered with TMC647055 in the Phase I safety, tolerability and pharmacokinetics study of this investigational NS5B non-nucleoside polymerase inhibitor for 10 days to HCV G1 chronically infected participants. While there are no preclinical results available for this agent, the combination of these two agents was taken forward into Phase II studies. It is, however, noted that where low-dose ritonavir would also be co-administered, a need for reduced dose adjustment of simeprevir due to CYP3A interactions was anticipated [30]. Phase II studies OPERA

OPERA-1 is a Phase IIa randomized, blinded, placebo-controlled, proof-of-concept study to evaluate antiviral activity, safety, tolerability and pharmacokinetics of simeprevir, administered once daily for 4 weeks in combination with PEG-IFN/ RBV. Participants were treatment naive (n = 74) or treatment experienced (n = 37) and randomized to receive one of three doses of simeprevir or placebo. Treatment-naive patients received 7 days of simeprevir 25, 75 or 200 mg once daily or placebo co-administered with PEG-IFN/RBV for 7 days then continued PEG-IFN/RBV to week 48. Participants who received simeprevir had a rapid decline in HCV RNA by day 3 with greatest reduction at day 7 for the 75 and 200 mg doses (0.02, -2.63, -3.43 and -4.13 log(10)IU/ml for placebo, 25, 75 and 200 mg doses, respectively). At day 28, all patients who received the 75 or 200 mg dose of simeprevir had HCV RNA levels

hepatitis C co-infection.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis in 170 million people worldwide and can progress to fibrosis, cirrhosis, liver failure a...
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