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Zelboraf (Vemurafenib) - Description and Clinical Pharmacology

 
 



DESCRIPTION

ZELBORAF (vemurafenib) is a kinase inhibitor available as 240 mg tablets for oral use. Vemurafenib has the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide. It has the molecular formula C23H18ClF2N3O3S and a molecular weight of 489.9. Vemurafenib has the following chemical structure:

Vemurafenib is a white to off-white crystalline solid. It is practically insoluble in aqueous media.

Tablets of ZELBORAF are for oral administration. Each tablet contains 240 mg of vemurafenib.

The inactive ingredients of ZELBORAF are: Tablet Core: hypromellose acetate succinate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, and hydroxypropyl cellulose. Coating: pinkish white: poly(vinyl alcohol), titanium dioxide, polyethylene glycol 3350, talc, and iron oxide red.

CLINICAL PHARMACOLOGY

Mechanism of Action

Vemurafenib is a low molecular weight, orally available, inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAFV600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5 and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAFV600E.

Pharmacokinetics

The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of dosing at 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. A one-compartment disposition model with first-order absorption and first-order elimination adequately describes the vemurafenib concentration-time profile. At steady state, vemurafenib exhibits linear pharmacokinetics within the 240 mg to 960 mg dose range.

Absorption

The bioavailability of vemurafenib has not been determined. Following oral administration of vemurafenib at 960 mg twice daily for 15 days to patients with metastatic melanoma, the median Tmax was approximately 3 hours.

Following 15 days of dosing at 960 mg twice daily, the mean (± SD) Cmax and AUC0-12 were 62 µg/mL ± 17 and 601 ± 170 µg*h/mL, respectively. The median accumulation ratio estimate from the population pharmacokinetic analysis for the twice daily regimen is 7.36, with steady state achieved at approximately 15 to 22 days following dosing at 960 mg twice daily. At steady state, the mean vemurafenib exposure in plasma is stable (concentrations before and 2-4 hours after the morning dose) as indicated by the mean ratio of 1.13.

The potential effect of food on vemurafenib absorption has not been studied. In clinical trials, vemurafenib was administered without regard to food.

Distribution

Vemurafenib is highly bound (> 99%) to human albumin and alpha-1 acid glycoprotein plasma proteins. The population apparent volume of distribution for vemurafenib in metastatic melanoma patients is estimated to be 106 L (with 66% inter-patient variability).

Metabolism

Following oral administration of 14C-vemurafenib 960 mg in the tablet formulation, plasma samples were analyzed over 48 hours for vemurafenib and its metabolites. Mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma, respectively.

Elimination

Following oral administration of 14C-vemurafenib 960 mg in the tablet formulation, approximately 94% of the radioactive dose was recovered in feces and approximately 1% was recovered in the urine. The population apparent clearance of vemurafenib in patients with metastatic melanoma is estimated to be 31 L/day (with 32% inter-patient variability). The median of the individual elimination half-life estimates for vemurafenib is 57 hours (the 5th and 95th percentile range is 30 to 120 hours).

Pharmacokinetics in Special Populations

Hepatic Impairment: The pharmacokinetics of vemurafenib were examined in patients with metastatic melanoma enrolled in the clinical trials with normal hepatic function (n=158, total bilirubin ≤ ULN) and pre-existing mild (n=58, total bilirubin 1.0-1.5 — ULN), moderate (n=27, total bilirubin 1.5-3 — ULN), or severe (n=3, total bilirubin > 3 — ULN) hepatic impairment. Patients received vemurafenib 960 mg orally twice daily. The apparent clearance of vemurafenib in patients with pre-existing mild and moderate hepatic impairment was similar to that in patients with normal hepatic function. The potential need for dose adjustment in patients with severe hepatic impairment cannot be determined as clinical and pharmacokinetic data were available for only three patients [see Use in Specific Populations].

Renal Impairment: The pharmacokinetics of vemurafenib were examined in patients with metastatic melanoma enrolled in the clinical trials with normal renal function (CLcr ≥ 90 mL/min) and pre-existing mild (n=94, CLcr > 60 to 89 mL/min), moderate (n=11, CLcr 30 to 59 mL/min) or severe (n=1, CLcr < 29 mL/min) renal impairment. Patients received vemurafenib 960 mg orally twice daily. The apparent clearance of vemurafenib in patients with pre-existing mild and moderate renal impairment was similar to that in patients with normal renal function. The potential need for dose adjustment in patients with severe renal impairment cannot be determined as clinical and pharmacokinetic data were available for only one patient [see Use in Specific Populations].

Age: Based on the population pharmacokinetic analysis, age has no statistically significant effect on vemurafenib pharmacokinetics.

Body Weight and Gender: Based on the population pharmacokinetic analysis, there was no clinically relevant effect of body weight or gender on vemurafenib pharmacokinetics.

Race: There are insufficient data to evaluate potential differences in the pharmacokinetics of vemurafenib by race.

Pediatrics: No studies have been conducted to investigate the pharmacokinetics of vemurafenib in children.

Drug Interactions: In vitro studies with human hepatic microsomes showed that vemurafenib is an inhibitor of CYP1A2, 2A6, 2C9, 2C19, 2D6, and 3A4/5, with IC50 values of 32.5, > 50, 5.9, 22.5, 33.2, and > 50 µM, respectively.

In an in vivo phenotypic cocktail drug-drug interaction study in patients with cancer, a single dose of the CYP probe substrate cocktail (for CYP1A2, 2D6, 3A4, 2C19 and 2C9) was administered before and concomitantly with vemurafenib (following 15 days of dosing at 960 mg twice daily). Coadministration of vemurafenib increased the AUC of caffeine (CYP1A2 substrate) 2.6-fold and increased the Cmax and AUC of dextromethorphan (CYP2D6 substrate) by 36% and 47%, respectively, while it decreased the Cmax and AUC of midazolam (CYP3A4 substrate) by 35% and 39%, respectively. Coadministration of vemurafenib increased the AUC of S-warfarin (CYP2C9 substrate) by 18%. Coadministration of vemurafenib did not change the systemic exposure to omeprazole (CYP2C19 substrate) [see Drug Interactions].

In vitro studies have demonstrated that vemurafenib is both a substrate and an inhibitor of the efflux transporter P-glycoprotein (P-gp).

In vitro studies with human hepatic microsomes showed that vemurafenib is a CYP3A4 substrate. The effect of strong CYP3A4 inhibitors or strong CYP3A4 inducers on the concentrations of vemurafenib has not been evaluated in vivo [see Drug Interactions].

QT Prolongation

The effect of vemurafenib 960 mg administered twice daily on QTc interval was evaluated in a multi-center, open-label, single-arm study in 132 patients with BRAF V600E mutation-positive metastatic melanoma. No large changes in mean QTc interval (i.e., >20 ms) from baseline were detected in the trial. Vemurafenib is associated with concentration-dependent QTc interval prolongation. In the first month of treatment, the largest mean change from baseline of 12.8 ms (upper boundary of the 2-sided 90% confidence interval of 14.9 ms) was observed at 2 hours post-dose on Day 15. In the first 6 months of treatment, the largest observed mean change from baseline of 15.1 ms (upper boundary of the 2-sided 90% confidence interval of 17.7 ms) was detected at a pre-dose time point.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

There have been no formal studies conducted assessing the carcinogenic potential of vemurafenib. ZELBORAF increased the development of cutaneous squamous cell carcinomas in patients in clinical trials.

Vemurafenib did not cause genetic damage when tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) or in the in vivo rat bone marrow micronucleus test.

No specific studies with vemurafenib have been conducted in animals to evaluate the effect on fertility; nevertheless, no histopathological findings were noted in reproductive organs in males and females in repeat-dose toxicology studies in rats at doses up to 450 mg/kg/day (approximately 0.6 and 1.6 times the human exposure based on AUC in males and females, respectively) and dogs at doses up to 450 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC in both males and females, respectively).

Animal Toxicology and/or Pharmacology

Consistent with the increased incidence of cutaneous squamous cell carcinomas in patients treated with vemurafenib, the treatment of mice implanted with human cuSCC cells with vemurafenib caused a dose dependent acceleration of the growth of the implanted tumors.

CLINICAL STUDIES

Treatment Naive Patients

The efficacy and safety of ZELBORAF in patients with treatment naive, BRAFV600E mutation-positive unresectable or metastatic melanoma as detected by the cobas® 4800 BRAF V600 Mutation Test were assessed in an international, randomized, open-label trial (Trial 1). The trial enrolled 675 patients; 337 were allocated to receive ZELBORAF 960 mg by mouth twice daily and 338 to receive dacarbazine 1000 mg/m2 intravenously on Day 1 every 3 weeks. Randomization was stratified according to disease stage, lactate dehydrogenase (LDH), ECOG performance status and geographic region. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate.

Baseline characteristics were balanced between treatment groups. Most patients were male (56%) and Caucasian (99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG performance status of 0 or 1, and the majority of patients had metastatic disease (95%).

Efficacy results are summarized in Table 4 and Figure 1.

Table 4 Efficacy of ZELBORAF in Treatment Naive Patients with BRAFV600E Mutation-Positive MelanomaAs detected by the cobas® 4800 BRAF V600 Mutation Test
ZELBORAF
(N=337)
Dacarbazine
(N=338)
p-value Unstratified log-rank test
Overall Survival
  Number of Deaths 78 (23%) 121 (36%)
  Hazard Ratio
  (95% CI) 1
0.44
(0.33, 0.59)
<0.0001
  Median Survival (months)
  (95 % CI) 2
Not Reached
(9.6, Not Reached)
7.9
(7.3, 9.6)
-
  Median Follow-up (months)
  (range)
6.2
(0.4, 13.9)
4.5
(<0.1, 11.7)
Progression-free survival
  Hazard Ratio
  (95% CI)
0.26
(0.20, 0.33)
<0.0001
  Median PFS (months)
  (95% CI)
5.3
(4.9, 6.6)
1.6
(1.6, 1.7)
-

1 Hazard ratio estimated using Cox model; a hazard ratio of < 1 favors ZELBORAF
2 Kaplan-Meier estimate

Figure 1 Kaplan-Meier Curves of Overall Survival — Treatment Naive Patients

The confirmed, investigator-assessed best overall response rate was 48.4% (95% CI: 41.6%, 55.2%) in the ZELBORAF arm compared to 5.5% (95% CI: 2.8%, 9.3%) in the dacarbazine arm. There were 2 complete responses (0.9%) and 104 partial responses (47.4%) in the ZELBORAF arm and all 12 responses were partial responses (5.5%) in the dacarbazine arm.

Patients Who Received Prior Systemic Therapy

A single-arm, multicenter, multinational trial (Trial 2) was conducted in 132 patients with BRAFV600E mutation-positive metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, who had received at least one prior systemic therapy. The median age was 52 years with 19% of patients being older than 65 years. The majority of patients were male (61%) and Caucasian (99%). Forty-nine percent of patients received ≥ 2 prior therapies. The median duration of follow-up was 6.87 months (range, 0.6 to 11.3).

The confirmed best overall response rate as assessed by an independent review committee (IRC) was 52% (95% CI: 43%, 61%). There were 3 complete responses (2.3%) and 66 partial responses (50.0%). The median time to response was 1.4 months with 75% of responses occurring by month 1.6 of treatment. The median duration of response by IRC was 6.5 months (95% CI: 5.6, not reached).

Patients with wild-type BRAF melanoma

ZELBORAF has not been studied in patients with wild-type BRAF melanoma.

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