Simeprevir clinical pharmacology

# Clinical Pharmacology

## Pharmacodynamics

### Evaluation of Effects on Electrocardiogram
The effect of simeprevir 150 mg once daily and 350 mg once daily for 7 days on the QT interval was evaluated in a randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg once daily), 4-way cross-over study in 60 healthy subjects. No meaningful changes in QTc interval were observed with either the recommended dose of 150 mg once daily or the supratherapeutic dose of 350 mg once daily.

## Pharmacokinetics
The pharmacokinetic properties of simeprevir have been evaluated in healthy adult subjects and in adult HCV-infected subjects. Plasma Cmax and the area under the plasma concentration time curve (AUC) increased more than dose-proportionally after multiple doses between 75 mg and 200 mg once daily, with accumulation occurring following repeated dosing. Steady-state was reached after 7 days of once daily dosing. Plasma exposure (AUC) of simeprevir in HCV-infected subjects was about 2- to 3-fold higher compared to that observed in HCV-uninfected subjects. Plasma Cmax and AUC of simeprevir were similar during co-administration of simeprevir with peginterferon alfa and ribavirin compared with administration of simeprevir alone. In HCV-infected subjects, the mean steady-state predose plasma concentration was 1936 ng/mL (standard deviation: 2640) and the mean steady-state AUC24 was 57469 ng.h/mL (standard deviation: 63571).

### Absorption
Simeprevir is orally bioavailable. Maximum plasma concentrations (Cmax) are typically achieved between 4 to 6 hours post dose.
In vitro studies with human Caco-2 cells indicated that simeprevir is a substrate of P-gp.

### Effects of Food on Oral Absorption
Administration of simeprevir with food to healthy subjects increased the relative bioavailability (AUC) by 61% and 69% after a high-fat, high-caloric (928 kcal) and normal-caloric (533 kcal) breakfast, respectively, and delayed the absorption by 1 hour and 1.5 hours, respectively.

### Distribution
Simeprevir is extensively bound to plasma proteins (greater than 99.9%), primarily to albumin and, to a lesser extent, alfa 1-acid glycoprotein. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
In animals, simeprevir is extensively distributed to gut and liver (liver:blood ratio of 29:1 in rat) tissues. In vitro data and physiologically-based pharmacokinetic modeling and simulations indicate that hepatic uptake in humans is mediated by OATP1B1/3.

### Metabolism
Simeprevir is metabolized in the liver. In vitro experiments with human liver microsomes indicated that simeprevir primarily undergoes oxidative metabolism by the hepatic CYP3A system. Involvement of CYP2C8 and CYP2C19 cannot be excluded. Co-administration of OLYSIO with moderate or strong inhibitors of CYP3A may significantly increase the plasma exposure of simeprevir, and co-administration with moderate or strong inducers of CYP3A may significantly reduce the plasma exposure of simeprevir .
Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, the majority of the radioactivity in plasma (mean: 83%) was accounted for by unchanged drug and a small part of the radioactivity in plasma was related to metabolites (none being major metabolites). Metabolites identified in feces were formed via oxidation at the macrocyclic moiety or aromatic moiety or both and by O-demethylation followed by oxidation.

### Elimination
Elimination of simeprevir occurs via biliary excretion. Renal clearance plays an insignificant role in its elimination. Following a single oral administration of 200 mg 14C-simeprevir to healthy subjects, on average 91% of the total radioactivity was recovered in feces. Less than 1% of the administered dose was recovered in urine. Unchanged simeprevir in feces accounted for on average 31% of the administered dose.
The terminal elimination half-life of simeprevir was 10 to 13 hours in HCV-uninfected subjects and 41 hours in HCV-infected subjects receiving 200 mg simeprevir.

### Specific Populations
There is limited data on the use of OLYSIO in patients aged 65 years and older. Age (1873 years) had no clinically meaningful effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV-infected subjects treated with OLYSIO. No dose adjustment of OLYSIO is required in geriatric patients .
Renal elimination of simeprevir is negligible. Compared to HCV-uninfected subjects with normal renal function (classified using the Modification of Diet in Renal Disease  eGFR formula; eGFR greater than or equal to 80 mL/min) the mean steady-state AUC of simeprevir was 62% higher in HCV-uninfected subjects with severe renal impairment (eGFR below 30 mL/min). Based on the observed and expected changes in simeprevir exposure, no dose adjustment of OLYSIO is needed in patients with mild, moderate or severe renal impairment. The safety and efficacy of OLYSIO have not been studied in HCV-infected patients with severe renal impairment or end-stage renal disease, including patients requiring dialysis .
In a population pharmacokinetic analysis of mild or moderate renally impaired HCV-infected subjects treated with OLYSIO 150 mg once daily, creatinine clearance was not found to influence the pharmacokinetic parameters of simeprevir. It is therefore not expected that renal impairment will have a clinically relevant effect on the exposure to simeprevir.
As simeprevir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.
Refer to the respective prescribing information for peginterferon alfa and ribavirin regarding use in patients with renal impairment.
Simeprevir is primarily metabolized by the liver. Compared to HCV-uninfected subjects with normal hepatic function, the mean steady-state AUC of simeprevir was 2.4-fold higher in HCV-uninfected subjects with moderate hepatic impairment (Child-Pugh Class B) and 5.2-fold higher in HCV-uninfected subjects with severe hepatic impairment (Child-Pugh Class C). No dose adjustment of OLYSIO is necessary in patients with mild hepatic impairment (Child-Pugh Class A). The safety and efficacy of OLYSIO have not been studied in HCV-infected patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. No dose recommendation can be given for patients with moderate or severe hepatic impairment (Child-Pugh Class B or C). The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients with moderate or severe hepatic impairment .
Based on a population pharmacokinetic analysis of HCV-infected subjects treated with OLYSIO, liver fibrosis stage did not have a clinically relevant effect on the pharmacokinetics of simeprevir.
Refer to the respective prescribing information for peginterferon alfa and ribavirin regarding use in patients with hepatic impairment.
No dose adjustment is necessary based on gender, body weight or body mass index. These characteristics have no clinically meaningful relevant effect on the pharmacokinetics of simeprevir based on a population pharmacokinetic analysis of HCV-infected subjects treated with OLYSIO.
Based on results from studies in HCV-uninfected subjects and HCV-infected subjects, simeprevir exposures are higher in Asians compared to Caucasians. In the Phase 3 trials, the mean simeprevir plasma exposure in Asian subjects (n=14) was 3.4-fold higher than in the pooled Phase 3 population. In clinical trials, higher simeprevir exposures have been associated with increased frequency of adverse reactions, including rash and photosensitivity. There are insufficient safety data to recommend an appropriate dose for patients of East Asian ancestry. The potential risks and benefits of OLYSIO should be carefully considered prior to use in patients of East Asian ancestry .
Population pharmacokinetic estimates of exposure of simeprevir were comparable between Caucasian and Black/African American HCV-infected subjects.