At steady state, the mean vemurafenib exposure in plasma is stable during the 24-hour interval as indicated by the mean ratio of 1.13 between the plasma concentrations before and 2-4 hours after the morning dose. Following oral dosing, the absorption rate constant for the population of metastatic melanoma patients is estimated to be 0.19 hr-1 (with 101% between patient variability).

Distribution

The population apparent volume of distribution for vemurafenib in metastatic melanoma patients is estimated to be 91 L (with 64.8% between patient variability). It is highly bound to human plasma proteins in vitro (>99%).

Biotransformation

The relative proportions of vemurafenib and its metabolites were characterised in a human mass balance study with a single dose of 14C-labeled vemurafenib administered orally. CYP3A4 is the primary enzyme responsible for the metabolism of vemurafenib in vitro. Conjugation metabolites (glucuronidation and glycosylation) were also identified in humans. However, the parent compound was the predominant component (95%) in plasma. Although metabolism does not appear to result in a relevant amount of metabolites in plasma, the importance of metabolism for excretion cannot be excluded.

Elimination

The population apparent clearance of vemurafenib in patients with metastatic melanoma is estimated to be 29.3 L/day (with 31.9% between patient variability). The population elimination half-life estimated by the population PK analysis for vemurafenib is 51.6 hours (the 5th and 95th percentile range of the individual half-life estimates is 29.8 - 119.5 hours).

In the human mass balance study with vemurafenib administered orally, on average 95% of the dose was recovered within 18 days. The majority of vemurafenib-related material (94%) was recovered in faeces, and <1% in urine. Biliary excretion of unchanged compound may be an important route of elimination. However, due to the unknown absolute bioavailability, the importance of hepatic and renal excretion for the clearance of parent vemurafenib is uncertain. Vemurafenib is a substrate and inhibitor of P-gp in vitro.

Special populations

Older people

Based on the population PK analysis, age has no statistically significant effect on vemurafenib pharmacokinetics.

Gender

The population pharmacokinetic analysis indicated a 17% greater apparent clearance (CL/F) and a 48% greater apparent volume of distribution (V/F) in males than in females. It is unclear whether this is a gender or a body size effect. However, the differences in exposure are not large enough to warrant dose adjustment based on body size or gender.

Renal impairment

In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, mild and moderate renal impairment did not influence the apparent clearance of vemurafenib (creatinine clearance >40 ml/min). There are no data in patients with severe renal impairment (see sections 4.2 and 4.4).

Hepatic impairment

Based on preclinical data and the human mass balance study, major part of vemurafenib is eliminated via the liver. In the population pharmacokinetic analysis using data from clinical trials in patients with metastatic melanoma, increases in AST and ALT up to three times the upper limit of normal did not infl