Etravirine 100 mg · Tablets

Etravirine is an antiretroviral drug [see Microbiology (12.4)] .

The pharmacokinetic properties of etravirine were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult and pediatric subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects (Table 5) than in healthy subjects.

Note: The median protein binding adjusted EC 50 for MT4 cells infected with HIV-1/IIIB in vitro equals 4 ng/mL.

Absorption and Bioavailability — Following oral administration, etravirine was absorbed with a T max of about 2.5 to 4 hours. The absolute oral bioavailability of etravirine is unknown.

In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH.

Effects of Food on Oral Absorption — The systemic exposure (AUC) to etravirine was decreased by about 50% when etravirine tablet was administered under fasting conditions, as compared to when etravirine tablet was administered following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1,160 kilocalories (70 grams fat).

Distribution — Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66% to 99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Metabolism — In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture.

Elimination — After single dose oral administration of 800 mg 14C-etravirine, 93.7% and 1.2% of the administered dose of 14C-etravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (± 20) hours.

Geriatric Patients — Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated [see Use in Specific Populations (8.5)].

Pediatric Patients — The pharmacokinetics of etravirine in 115 treatment-experienced HIV-1-infected pediatric subjects, 2 years to less than 18 years of age showed that the administered weight-based dosages resulted in etravirine exposure comparable to that in adults receiving etravirine 200 mg twice daily [see Dosage and Administration (2.3)] . The pharmacokinetic parameters for etravirine (AUC 12h and C 0h) are summarized in Table 6.

The pharmacokinetics and dose of etravirine in pediatric subjects less than 2 years of age have not been established [see Use in Specific Populations (8.4)].

Additional pediatric use information is approved for Janssen Products, LP’s INTELENCE ® (etravirine) tablets. However, due to Janssen Products, LP’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Male and Female Patients — No significant pharmacokinetic differences have been observed between males and females.

Racial or Ethnic Groups — Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.

Patients with Renal Impairment — The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with 14C-etravirine showed that less than 1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.7)] .