Darunavir 300 mg · Tablets

Darunavir is an HIV-1 antiviral drug [see Microbiology (12.4)].

General : — Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir. When a single dose of darunavir 600 mg was given orally in combination with 100 mg ritonavir twice daily, there was an approximate 14-fold increase in the systemic exposure of darunavir. Therefore, darunavir should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir.

The pharmacokinetics of darunavir, co-administered with low dose ritonavir (100 mg), has been evaluated in healthy adult volunteers and in HIV-1-infected subjects. Table 11 displays the population pharmacokinetic estimates of darunavir after oral administration of darunavir/ritonavir 600/100 mg twice daily (based on sparse sampling in 285 patients in trial TMC114-C214, 278 patients in trial TMC114-C229 and 119 patients [integrated data] from trials TMC114-C202 and TMC114-C213) and darunavir/ritonavir 800/100 mg once daily (based on sparse sampling in 335 patients in trial TMC114-C211 and 280 patients in trial TMC114-C229) to HIV-1-infected patients.

Absorption and Bioavailability — Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a Tmax of approximately 2.5 to 4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively. In vivo data suggest that darunavir/ritonavir is an inhibitor of the P-glycoprotein (P-gp) transporters.

E ffects of Food on Oral Absorption — When darunavir tablets were administered with food, the Cmax and AUC of darunavir, co-administered with ritonavir, is approximately 40% higher relative to the fasting state. Within the range of meals studied, darunavir exposure is similar. The total caloric content of the various meals evaluated ranged from 240 Kcal (12 gms fat) to 928 Kcal (56 gms fat).

Distribution: — Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

M e tabolism: — In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV-1.

E limination: — A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/h and 5.9 L/h, respectively.

Hepatic Impairment: — Darunavir is primarily metabolized by the liver. The steady-state pharmacokinetic parameters of darunavir were similar after multiple dose co-administration of darunavir/ritonavir 600/100 mg twice daily to subjects with normal hepatic function (n=16), mild hepatic impairment (Child- Pugh Class A, n=8), and moderate hepatic impairment (Child-Pugh Class B, n=8). The effect of severe hepatic impairment on the pharmacokinetics of darunavir has not been evaluated [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].

Hepatitis B or Hepatitis C Virus Co-infection: — The 48-week analysis of the data from Studies TMC114-C211 and TMC114-C214 in HIV-1 infected subjects indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure of darunavir.