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Review Telaprevir: Pharmacokinetics and Drug Interactions Antiviral Therapy 2012; 17:1211–1221 (doi: 10.3851/IMP2356) Review Telaprevir: pharmacokinetics and drug interactions Varun Garg1*, Robert S Kauffman1, Maria Beaumont2, Rolf PG van Heeswijk2 1Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA 2Janssen Infectious Diseases BVBA, Beerse, Belgium *Corresponding author e-mail: [email protected] Telaprevir is an inhibitor of the HCV NS3/4A protease. faeces. No dose adjustment of telaprevir is needed in When used in combination with pegylated interferon patients with mild to severe renal impairment or mild and ribavirin, telaprevir has demonstrated a substan- liver impairment. Telaprevir is a substrate and inhibitor tial increase in sustained virological response com- of cytochrome P450 3A and P-glycoprotein and, thus, pared with pegylated interferon and ribavirin used might interact with coadministered drugs that affect alone. Telaprevir has good oral bioavailability, which or are affected by these metabolic/transport pathways. is enhanced when administered with food. Telaprevir This article reviews the pharmacokinetic and drug inter- is extensively metabolized and primarily eliminated via action profile of telaprevir. Introduction Globally, an estimated 170 million people (3% of the [12–14]. Sustained virological response (SVR) in global population) are infected with HCV [1], a mem- treatment-naive genotype 1 HCV-infected patients ber of the Flaviviridae family of viruses that is classified was assessed in the ADVANCE study comparing PEG- into at least six major genotypes [2]. More than 50% IFN-a2a and RBV alone for 48 weeks with telaprevir of HCV infections become chronic, and this can lead in combination with PEG-IFN/RBV administered for to the development of liver fibrosis, cirrhosis and occa- 12 weeks followed by PEG-IFN/RBV alone for an sionally hepatocellular carcinoma [3]. Chronic HCV additional 12 or 36 weeks depending on initial on- infection is the leading cause of liver failure requiring treatment virological response. A higher proportion liver transplantation [4]. The introduction of blood of patients achieved SVR with 12 weeks (79%) of tel- screening diagnostic tests in the 1990s led to a rapid aprevir in combination with PEG-IFN/RBV compared decrease in the incidence of HCV infection. Yet, the with PEG-IFN/RBV alone (46%) [9,10]. burden of pre-existing infections will increase over the In the ILLUMINATE study, a high proportion coming decades [5]. of treatment-naive patients with genotype 1 HCV Telaprevir is a covalent, reversible, selective, orally treated with telaprevir for 12 weeks in combination bioavailable inhibitor of the HCV NS3/4A serine pro- with PEG-IFN/RBV achieved an extended rapid viro- tease. Telaprevir is a peptidomimetic inhibitor derived logical response (eRVR: undetectable HCV RNA at based on the conformation of the viral NS5A/5B sub- both weeks 4 and 12 after start of treatment; 65%) strate, in complex with the NS3/4A protease, using and SVR (74%). Patients achieving eRVR were ran- structure-based drug design techniques [6,7]. At doses domized at weeks 20 to 24 (12 weeks of additional of 750 mg administered orally every 8 h, telaprevir PEG-IFN/RBV) or week 48 (36 weeks of additional monotherapy for 14 days induced a median decline PEG-IFN/RBV) of total treatment duration. The trial of more than 4 log10 units from baseline plasma HCV showed that SVR rates were similar in the two arms RNA levels in patients with chronic HCV genotype 1 indicating that the total duration of treatment could infection [8]. Because of the development of resistance, be reduced to 24 weeks in treatment-naive patients telaprevir is not approved as monotherapy and must be receiving telaprevir in combination with PEG-IFN/ used in combination with pegylated interferon (PEG- RBV if they achieve eRVR [9,10]. IFN) and ribavirin (RBV) [9–11]. Finally, the REALIZE trial assessed the efficacy Three Phase III clinical studies with telaprevir in and safety of a telaprevir-based regimen in genotype combination with PEG-IFN/RBV have been completed 1 HCV-infected patients who had not responded to ©2012 International Medical Press 1359-6535 (print) 2040-2058 (online) 1211 AVT-12-RV-2425_Garg.indd 1211 25/10/2012 13:35:24 V Garg et al. Figure 1. The molecular structure of telaprevir (R) N O O H (S) H H N (S) N N (S) N N N H (S)(S) O O O O The location of the chiral centre (position 21) is indicated with a dashed oval. a previous course of PEG-IFN/RBV therapy. SVR Pharmacokinetics rates in the telaprevir arms compared with the PEG-IFN/RBV control arm, respectively, were 86% Absorption and 22% in prior relapsers, 59% and 15% in prior Telaprevir is orally available and probably absorbed in partial responders and 32% and 5% in prior null the small intestine; there is no evidence for absorption responders [9]. in the colon [9]. For single doses of 375 mg to 1,875 mg Safety results were consistent in all three Phase III telaprevir in healthy volunteers, exposure increased more trials. The most common adverse drug reactions to tel- than proportionally to the dose. However, an increase in aprevir (incidence at least 5% higher than in controls) dose from 750 mg to 1,875 mg in a multiple-dose 5-day were rash, pruritus, anaemia, nausea, haemorrhoids, study in healthy volunteers resulted in a less than pro- diarrhoea, anorectal discomfort, dysgeusia, fatigue, portional increase in exposure. Exposure was similar for vomiting and anal pruritus [9]. healthy volunteers and HCV-infected patients after sin- The present review summarizes the physicochemi- gle-dose administration. Steady state after multiple doses cal properties of telaprevir and discusses, in detail, the of telaprevir every 8 h in HCV-infected patients was pharmacokinetic and drug interaction profile of tel- reached after 3 to 7 days of administration. The mean aprevir obtained from in vitro studies and the extensive accumulation index (ratio of the area under the concen- clinical pharmacology programme. tration–time curve from 0–8 h [AUC0–8 h] at steady state versus AUC0–8 h after a single dose) in healthy volunteers Chemical and physical properties receiving 750 mg telaprevir every 8 h was about 2.2. Telaprevir is a P-glycoprotein (P-gp) substrate with a Telaprevir (molecular weight 679.85 Da) is a single permeability coefficient (Papp) ratio of 20.5, measured diastereomer with the S-configuration at position 21 as Papp basolateral-to-apical/Papp apical-to-basolateral (Figure 1). Telaprevir can epimerize at position 21 ratio in human Caucasian colon adenocarcinoma mon- in vitro and in vivo to form a mixture with the cor- olayers. Thus, telaprevir absorption can be affected by responding R-diastereomer, which is approximately other substrates or inhibitors/inducers of P-gp. Although 30-fold less active than telaprevir against HCV. In telaprevir is not an inhibitor of P-gp at concentrations up vitro, the ratio of S:R epimers at equilibrium in human to 10 mM in vitro, a subsequent clinical study showed a plasma is approximately 60:40. Telaprevir acts as a drug interaction with digoxin, suggesting that telaprevir linear peptidomimetic NS3/4A protease inhibitor that might inhibit P-gp in vivo. The high concentrations of possesses an a-ketoamide group serine trap, forming telaprevir in the gut or liver after dosing could explain a covalent but reversible complex [7]. Telaprevir has a the discrepancy between the in vitro and in vivo findings. slow binding mechanism, presumably due to the con- formational change required to form the tightly bound Food effect complex. This conformational change allows for the Food effect studies were conducted to determine if formation of the covalent bond between the NS3/4A telaprevir should be administered with food. In a pre- protease and telaprevir. Once formed, the covalent liminary study in healthy volunteers, using an early complex dissociates slowly back to free enzyme and formulation of telaprevir, a lower exposure of tel- inhibitor. As such, the bound enzyme–inhibitor com- aprevir was observed in the fed state compared with plex of telaprevir has a long dissociation half-life (t1/2) the fasted state. With the tablet formulation used of 58 min [6]. in pivotal clinical studies, the effect of various meal 1212 ©2012 International Medical Press AVT-12-RV-2425_Garg.indd 1212 25/10/2012 13:35:26 Telaprevir: pharmacokinetics and drug interactions Figure 2. Mean plasma concentration–time profiles of telaprevir administered with different meal types compared with fasting conditions 2,500 High fat (n=29) Standard (n=28) 2,000 Low-calorie high-protein (n=28) Low fat (n=28) Fasting (n=30) 1,500 1,000 Concentration, ng/ml 500 0 04812162024 Time, h A single 750 mg dose of telaprevir was administered under fasting conditions, after a standard breakfast (533 kcal, 21 g fat), a high-calorie high-fat breakfast (928 kcal, 56 g fat), a low-calorie high-protein breakfast (260 kcal, 9 g fat) or a low-calorie low-fat breakfast (249 kcal, 3.6 g fat). types on the absorption of telaprevir was evaluated in the liver as the target organ relative to concentrations in a study with 30 healthy volunteers who received a in plasma: the liver-to-plasma ratio was 35 to 1 [6]. single 750 mg dose of telaprevir under fasting condi- Approximately 59–76% of telaprevir was bound to tions, after a standard breakfast (533 kcal, 21 g fat), human plasma proteins at concentrations ranging from high-calorie high-fat breakfast (928 kcal, 56 g fat), 0.1–20 mM. Thus, telaprevir is considered to be moder- low-calorie high-protein breakfast (260 kcal, 9 g fat) ately bound to human plasma proteins, mainly a1-acid or low-calorie low-fat breakfast (249 kcal, 3.6 g fat).
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