Chemical formula: C₃₆H₅₃N₇O₆ Molecular mass: 679.849 g/mol PubChem compound: 3010818
Telaprevir is an inhibitor of the HCV NS3•4A serine protease, which is essential for viral replication.
In an HCV subtype 1b replicon assay, the telaprevir IC50 value against wild-type HCV was 0.354 μM similar to a subtype 1a infectious virus assay IC50 of 0.28 μM.
HCV variants associated with on-treatment virologic failure or relapse were evaluated by site-directed mutagenesis in the replicon assay. Variants V36A/M, T54A/S, R155K/T, and A156S conferred lower levels of in vitro resistance to telaprevir (3- to 25-fold increase in telaprevir IC50), and the A156V/T and V36M+R155K variants conferred higher levels of in vitro resistance to telaprevir (>25-fold increase in telaprevir IC50). Replicon variants generated from patient-derived sequences showed similar results.
The in vitro replication capacity of telaprevir-resistant variants was lower than that of wild-type virus.
Telaprevir-resistant variants were tested for cross-resistance against representative protease inhibitors in the HCV replicon system. Replicons with single substitutions at position 155 or 156 and double variants with substitutions at residues 36 and 155 showed cross-resistance to all protease inhibitors tested with a wide range of sensitivities. All telaprevir-resistant variants studied remained fully sensitive to interferon-alfa, ribavirin, and representative HCV nucleoside and non-nucleoside polymerase inhibitors in the replicon system. There are no clinical data on re-treating patients who have failed an HCV NS3-4A protease inhibitor-based therapy, such as telaprevir, nor are there data on repeated courses of telaprevir treatment.
The pharmacokinetic properties of telaprevir have been evaluated in healthy adult volunteers and in subjects with chronic HCV infection. Telaprevir can be administered orally with food as 375 mg tablets, 1,125 mg twice daily (b.i.d.) for 12 weeks, in combination with peginterferon alfa and ribavirin. Alternatively, telaprevir can be administered orally with food as 375 mg tablets, 750 mg every 8 hours (q8h) for 12 weeks, in combination with peginterferon alfa and ribavirin. Exposure to telaprevir is higher during co-administration of peginterferon alfa and ribavirin than after administration of telaprevir alone.
Telaprevir exposure is comparable during co-administration with either peginterferon alfa-2a and ribavirin or peginterferon alfa-2b and ribavirin.
Telaprevir is orally available, most likely absorbed in the small intestine, with no evidence for absorption in the colon. Maximum plasma concentrations after a single dose of telaprevir are generally achieved after 4–5 hours. In vitro studies performed with human Caco-2 cells indicated that telaprevir is a substrate of P-glycoprotein (P-gp).
Telaprevir exposure was similar regardless of whether the total daily dose of 2,250 mg was administered as 750 mg every 8 hours (q8h) or 1,125 mg twice daily (b.i.d.). Based upon population pharmacokinetic modelling of telaprevir steady-state exposures, the Geometric Mean Least Square Ratios (90% CI) of 1,125 mg twice daily (b.i.d.) versus 750 mg every 8 hours (q8h) were 1.08 (1.02; 1.13) for AUC24,ss, 0.878 (0.827; 0.930) for Ctrough,ss, and 1.18 (1.12;1.24) for Cmax,ss.
The exposure to telaprevir was increased by 20% when taken following a high-fat caloric meal (56 g fat, 928 kcal) compared to an intake following a standard normal caloric meal (21 g fat, 533 kcal). When compared to administration following a standard normal caloric meal, exposure (AUC) decreased by 73% when telaprevir was taken on an empty stomach, by 26% following a low-calorie high-protein meal (9 g fat, 260 kcal), and by 39% following a low-calorie low-fat meal (3.6 g fat, 249 kcal). Therefore, telaprevir should be taken with food.
Telaprevir is approximately 59% to 76% bound to plasma proteins. Telaprevir binds primarily to alpha 1-acid glycoprotein and albumin.
After oral administration, the typical apparent volume of distribution (Vd) was estimated to be 252 l, with an inter-individual variability of 72.2%.
Telaprevir is extensively metabolised in the liver, involving hydrolysis, oxidation, and reduction. Multiple metabolites were detected in faeces, plasma, and urine. After repeated oral administration, R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the α-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites of telaprevir.
CYP3A4 is partly responsible for the metabolism of telaprevir. Other enzymes are also involved in the metabolism such as aldo-ketoreductases and other proteolytic enzymes. Studies using recombinant human CYP supersomes showed that telaprevir was a CYP3A4 inhibitor, and a time- and concentration-dependent inhibition of CYP3A4 by telaprevir was observed in human liver microsomes. No relevant inhibition by telaprevir of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1 isozymes was observed in vitro. No relevant induction by telaprevir of CYP1A2, CYP2B6, CYP2C, and CYP3A isozymes was observed in vitro. Based on the results of drug-drug clinical interaction studies (e.g., escitalopram, zolpidem, ethinylestradiol), induction of metabolic enzymes by telaprevir cannot be excluded.
In vitro studies demonstrated that telaprevir is not an inhibitor of UGT1A9 or UGT2B7. In vitro studies with recombinant UGT1A3 suggested that telaprevir may inhibit this enzyme. The clinical relevance of this is uncertain as administration of telaprevir with a single dose of buprenorphine, a partial UGT1A3 substrate, to healthy adult subjects did not result in increases in buprenorphine exposures. No relevant inhibition by telaprevir of alcohol dehydrogenase was observed in vitro. However, sufficiently high concentrations were not tested for intestinal inhibition to be excluded.
Suppression by telaprevir and VRT-127394 of CYP enzymes regulated via CAR, PXR and Ah nuclear receptors was observed in vitro in human hepatocytes. Clinical drug-drug interaction studies with substrates of CYP2B6, CYP2C8, CYP2D6, CYP2C19 and UGT1A1, UGT2B7 and UGT1A3 indicate no clinically relevant impact of the suppression observed in vitro. For other enzymes and transporters (e.g., CYP1A1, CYP1A2, BCRP, OATPs) regulated by the same nuclear receptors, the potential clinical impact is unknown.
In vitro studies demonstrated that telaprevir is an inhibitor of OATP1B1 and OATP2B1.
No relevant inhibition by telaprevir of the organic cation transporter (OCT) OCT2 was observed in vitro.
Telaprevir is a weak in vitro inhibitor of the transporters multidrug and toxin extrusion (MATE) MATE1 and MATE2-K with an IC 50 of 28.3 μM and 32.5 μM, respectively. The clinical implications of this finding are currently unknown.
Following administration of a single oral dose of 750 mg 14 C-telaprevir in healthy subjects, 90% of total radioactivity was recovered in faeces, urine and expired air within 96 hours post-dose. The median recovery of the administered radioactive dose was approximately 82% in the faeces, 9% in exhaled air and 1% in urine. The contribution of unchanged 14 C – telaprevir and VRT-127394 towards total radioactivity recovered in faeces was 31.8% and 18.7%, respectively.
After oral administration, the apparent total clearance (Cl/F) was estimated to be 32.4 l/h with an inter-individual variability of 27.2%. The mean elimination half-life after single-dose oral administration of telaprevir 750 mg typically ranged from about 4.0 to 4.7 hours. At steady-state, the effective half-life is about 9-11 hours.
The exposure (AUC) to telaprevir increased slightly greater than proportionally to the dose after single-dose administration of 375 up to 1,875 mg with food, possibly due to saturation of metabolic pathways or efflux transporters.
An increase in dose from 750 mg every 8 hours to 1,875 mg every 8 hours in a multiple-dose study resulted in a less than proportional increase (i.e., about 40%) in telaprevir exposure.
Data in the paediatric population are currently not available.
The pharmacokinetics of telaprevir were assessed after administration of a single dose of 750 mg to HCV-negative subjects with severe renal impairment (CrCl <30 ml/min). The mean telaprevir Cmax and AUC were 10% and 21% greater, respectively, compared to healthy subjects.
Telaprevir is primarily metabolised in the liver. Steady-state exposure to telaprevir was 15% lower in subjects with mild hepatic impairment (Child-Pugh Class A, score 5-6) compared to healthy subjects. Steady-state exposure to telaprevir was 46% lower in subjects with moderate hepatic impairment (Child-Pugh Class B, score 7-9) compared to healthy subjects. Effect on unbound telaprevir concentrations is unknown.
The effect of subject gender on telaprevir pharmacokinetics was evaluated using population pharmacokinetics of data from Phase 2 and 3 studies of telaprevir. No relevant effect of gender was identified.
Population pharmacokinetic analysis of telaprevir in HCV-infected subjects indicated that the exposure to telaprevir was similar in Blacks/African-Americans and Caucasians.
There is limited pharmacokinetic data on the use of telaprevir in HCV patients aged ≥ 65 years and no data in subjects >70 years of age.
In rats and dogs, telaprevir was associated with a reversible reduction of red blood cell parameters accompanied by a regenerative response. In both rats and dogs, AST/ALT elevations were observed in most studies, of which the increase in ALT in rats was not normalised after recovery. Histopathological findings in the liver were similar in both rat and dog studies, of which not all were fully resolved after recovery. In rats (but not in dogs), telaprevir caused degenerative changes in testes which were reversible and did not affect fertility. In general, exposure levels in relation to human values were low in animal pharmacology and toxicology studies.
Telaprevir has not been tested for its carcinogenic potential. Neither telaprevir nor its major metabolite caused damage to DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic activation.
Telaprevir had no effects on fertility or fecundity when evaluated in rats.
Telaprevir readily crosses the placenta in both rat and mouse giving a foetal: maternal exposure of 19-50%. Telaprevir did not have any teratogenic potential in rat or mouse. In a fertility and early embryonic development study in rats, an increase in non-viable conceptuses was observed. Dosing of the animals did not result in any exposure-margin when compared to human exposure.
When administered to lactating rats, levels of telaprevir and its major metabolite were higher in milk compared to those observed in plasma. Rat offspring exposed to telaprevir in utero showed normal body weight at birth. However, when fed via milk from telaprevir-treated dams, body weight gain of rat pups was lower than normal (likely due to taste aversion). After weaning, rat pup body weight gain returned to normal.
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