Mechanism of effect
Telaprevir is a NS3/4a protease inhibitor used to inhibit viral HCV replication. NS3/4a protease is an integral part of viral replication and mediates the cleavage the virally encoded polyprotein to mature proteins (NS4A, NS4B, NS5A and NS5B). Telaprevir inhibits NS3/4A with an IC50 of 10nM.
Pharmacokinetics
Peak plasma time: 4-5 hr
Peak plasma concentration: 3510 ng/mL
AUC: 22,300 (8650) ng•hr/mL
Food: AUC increased by 237% when administered with a standard fat meal (containing 533 kcal and 21 g fat) compared with fasting conditions
Protein bound: 59-76% (primarily alpha 1-acid glycoprotein and albumin)
Vd: 252 L (72% interindividual variability)
Metabolism
Extensively metabolized in liver by hydrolysis, oxidation, and reduction
Metabolites: R-diastereomer of telaprevir (30-fold less active), pyrazinoic acid, and a metabolite that underwent reduction at the alpha-ketoamide bond of telaprevir (not active) were found to be the predominant metabolites
Metabolized by CYP3A4 is the major CYP isoform; after multiple dosing, nonCYP metabolism is also apparent
Inhibits CYP3A and P-gp
Substrate of CYP3A and P-gp
Half-life: 4-4.7 hr (mean); 9-11 hr (at steady state)
Total body clearance: 32.4 L/h
Excretion: feces (82%); exhaled air (9%); urine (1%)
Pharmacogenomics
Among both treatment-naïve and previous treatment failures, subjects of all IL28B genotypes (ie, CT, TT, CC) appeared to have higher SVR rates with telaprevir-containing regimens in clinical trials compared with dual therapy
SVR rates tend to be lower for dual therapy if IL28B CT and TT variants are present compared with IL28B CC
Dosage
Adult
1,125 mg (3 tabs) PO BID (q10-14hr) with food (not low fat)
Administer for 12 weeks in combination with peginterferon alfa and ribavirin (telaprevir must not be used as monotherapy)
Pediatric
Safety and efficacy not established
Interactions
Midazolam , sparfloxacin , nasal Mometasone , Pimozide , Tadalafil , Digoxin , Rifampin , Cisapride , Sildenafil , Ibrutinib , st. john's wort , Phenobarbital , Phenytoin , Carbamazepine , Ethinyl Estradiol , Triazolam , Alfuzosin , Maraviroc , Halofantrine , Fesoterodine , trabectedine , Duvelisib , elagolix , Avanafil , Levomilnacipran , ELBASVIR/GRAZOPREVIR , Larotrectinib , gilteritinib , glasdegib , Eliglustat , Suvorexant , Bepridil , Gefitinib , Dasatinib , vorapaxar , voxelotor , Fidaxomicin , CapmatinibAlerts
Ribavirin may cause birth defects and fetal death; avoid pregnancy in female patients and female partners of male patients; patients must have a negative pregnancy test prior to therapy; use two or more forms of contraception, and have monthly pregnancy tests
Serious skin reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), toxic epidermal necrolysis (TEN), and Stevens-Johnson Syndrome (SJS); discontinue immediately and do not reintroduce (see Black Box Warnings)
Anemia: Addition of telaprevir to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared with peginterferon alfa and ribavirin alone; obtain baseline Hgb, white cell differential, and platelet count and monitor at weeks 2, 4, 8, and 12 during treatment and as clinically needed
Use sensitive real-time RT-PCR assay for monitoring HCV-RNA levels during treatment at weeks 4 and 12 as clinically indicated
Not recommended for with moderate-to-severe hepatic impairment (Child-Pugh B or C, score 7 or greater) or with decompensated liver disease
Black Box Warnings
Fatal and nonfatal serious skin reactions (including Stevens Johnson syndrome, drug reaction with eosinophilia and systemic symptoms [DRESS], and toxic epidermal necrolysis [TEN]) reported in patients taking telaprevir in combination with peginterferon alfa and ribavirin
Deaths reported when patients continued to receive this treatment regimen after developing a worsening, or progressive rash and systemic symptoms
If serious skin reactions occur, immediately discontinue all 3 drugs of the treatment regimen (ie, telaprevir, peginterferon alfa, ribavirin)
Patients should be promptly referred for urgent medical care
Also consider stopping any other medications that may be associated with serious skin reactions
Points of recommendation
You may bleed more easily. Be careful and avoid injury. Use a soft toothbrush and an electric razor.
Have blood work checked as you have been told by the doctor. Talk with the doctor.
Do not take St John's wort with telaprevir. This medicine may not work as well.
This medicine does not stop the spread of diseases like HIV or hepatitis that are passed through blood or having sex. Do not have any kind of sex without using a latex or polyurethane condom. Do not share needles or other things like toothbrushes or razors. Talk with your doctor.
This medicine may cause harm to the unborn baby if you take it while you are pregnant.
Use 2 kinds of birth control that you can trust while using telaprevir and for 6 months after stopping telaprevir.
If you are a man and have sex with a female who could get pregnant, protect her from pregnancy during care and for 6 months after care ends. Use birth control that you can trust.
Do not use a hormone-related kind of birth control.
Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
- To gain the most benefit, do not miss doses.
- Take telaprevir at the same time of day.
- Keep taking telaprevir as you have been told by your doctor or other health care provider, even if you feel well.
- Take with a high-fat meal.
- Swallow whole. Do not chew, break, or crush.
- Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.
- If it has been 6 hours or more since the missed dose, skip the missed dose and go back to your normal time.
- If it has been less than 6 hours since a normal dose, take a missed dose as soon as you think about it and go back to your normal time.
- Do not use 2 doses or extra doses.
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