Chemical formula: C₂₃H₂₀F₃N₅O₂S₂ Molecular mass: 519.562 g/mol PubChem compound: 44462760
Dabrafenib is an inhibitor of RAF kinases. Oncogenic mutations in BRAF lead to constitutive activation of the RAS/RAF/MEK/ERK pathway. The most commonly observed BRAF mutation is V600E, which has been identified in 19% of paediatric LGG and approximately 5% of paediatric HGG, and accounts for approximately 90% of the BRAF mutations that are seen in melanoma.
Preclinical data generated in biochemical assays demonstrated that dabrafenib inhibits BRAF kinases with activating codon 600 mutations (Table 5).
Table 5. Kinase inhibitory activity of dabrafenib against RAF kinases:
Kinase | Inhibitory concentration 50 (nM) |
---|---|
BRAF V600E | 0.65 |
BRAF V600K | 0.50 |
BRAF V600D | 1.8 |
BRAF WT | 3.2 |
CRAF WT | 5.0 |
Dabrafenib demonstrated suppression of a downstream pharmacodynamic biomarker (phosphorylated ERK) and inhibited cell growth of BRAF V600 mutant melanoma cell lines, in vitro and in animal models.
In subjects with BRAF V600 mutation-positive melanoma, administration of dabrafenib resulted in inhibition of tumour phosphorylated ERK relative to baseline.
Trametinib is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and kinase activity. MEK proteins are components of the extracellular signal-related kinase (ERK) pathway. In human cancers, this pathway is often activated by mutated forms of BRAF which activates MEK. Trametinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity.
Thus, trametinib and dabrafenib inhibit two kinases in this pathway, MEK and RAF, and therefore the combination provides concomitant inhibition of the pathway. The combination of dabrafenib with trametinib has shown anti-tumour activity in BRAF V600 mutation-positive cancer cell lines in vitro and delays the emergence of resistance in vivo in BRAF V600 mutation-positive xenografts.
The pharmacokinetic properties of dabrafenib have mostly been determined in adult patients using the solid (capsule) formulation. The pharmacokinetics of dabrafenib following single or repeat weightadjusted dosing were also evaluated in 243 paediatric patients. The population pharmacokinetic analysis included 61 patients aged 1 to <6 years, 77 patients aged 6 to <12 years and 105 patients aged 12 to <18 years. Clearance was comparable with clearance in adult patients. Weight was identified as a significant covariate of dabrafenib clearance. Age was not a significant additional covariate. The pharmacokinetic exposures of dabrafenib at the recommended weight-adjusted dose in paediatric patients were within range of those observed in adults.
Dabrafenib is absorbed orally with median time to achieve peak plasma concentration of 2 hours post-dose. Mean absolute bioavailability of oral dabrafenib is 95% (90% CI: 81, 110%). Dabrafenib exposure (Cmax and AUC) increased in a dose proportional manner between 12 and 300 mg following single-dose administration, but the increase was less than dose-proportional after repeat twice daily dosing. A decrease in exposure was observed with repeat dosing, likely due to induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. Following administration of 150 mg twice daily, geometric mean Cmax, AUC(0-τ) and predose concentration (Cτ) were 1 478 ng/ml, 4 341 ng*hr/ml and 26 ng/ml, respectively.
Administration of dabrafenib with food reduced the bioavailability (Cmax and AUC decreased by 51% and 31% respectively) and delayed absorption of dabrafenib capsules when compared to the fasted state.
The dabrafenib dispersible tablet suspension was absorbed rapidly with a median time to achieve peak plasma concentration of 1.5 hours post-dose. The mean absolute oral bioavailability of dabrafenib capsules was 94.5%. The suspension is expected to have 20% lower bioavailability. Based on data from adult patients with the capsule formulation, a decrease in exposure was observed with repeat dosing, likely due to induction of its own metabolism. Mean accumulation AUC Day 18/Day 1 ratio was 0.73.
Dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner between 12 mg and 300 mg following single-dose administration, but the increase was less than dose-proportional after repeat twice-daily dosing.
In the pivotal paediatric study, steady-state geometric mean (CV) Cmax and AUCtau were 1330 ng/ml (93.5) and 4910 ng*hr/ml (54.0%) in the LGG cohort and 1520 ng/ml (65.9%) and 4300 ng*hr/ml (44.7%) in the HGG cohort.
The impact of food on the pharmacokinetics of the dispersible tablets suspension has not been investigated.
Dabrafenib binds to human plasma protein and is 99.7% bound. The steady-state volume of distribution following intravenous microdose administration is 46 L.
The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib, which is further oxidised via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenib can be decarboxylated via a non-enzymatic process to form desmethyl-dabrafenib. Carboxy-dabrafenib is excreted in bile and urine. Desmethyl-dabrafenib may also be formed in the gut and reabsorbed. Desmethyl-dabrafenib is metabolised by CYP3A4 to oxidative metabolites. Hydroxy-dabrafenib terminal half-life parallels that of parent with a half-life of 10 hrs while the carboxy- and desmethyl-metabolites exhibited longer half-lives (21-22 hours).
Mean metabolite-to-parent AUC ratios following repeat-dose administration were 0.9, 11 and 0.7 for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib while the activity of carboxy-dabrafenib is not likely to be significant.
In paediatric patients, the mean metabolite-to-parent AUC ratios (% CV) following repeat-dose administration of the capsules or of the dispersible tablet suspension were 0.64 (28%), 15.6 (49%) and 0.69 (62%) for hydroxy-, carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to the clinical activity of dabrafenib while the activity of carboxy-dabrafenib is not likely to be significant.
Terminal half-life of dabrafenib following an intravenous single microdose is 2.6 hours. Dabrafenib terminal half-life after a single oral dose is 8 hours due to absorption-limited elimination after oral administration (flip-flop pharmacokinetics). IV plasma clearance is 12 l/hr.
After an oral dose, the major route of elimination of dabrafenib is metabolism, mediated via CYP3A4 and CYP2C8. Dabrafenib related material is excreted primarily in faeces, with 71% of an oral dose recovered in faeces; 23% of the dose was recovered in urine in the form of metabolites only.
Dabrafenib is a substrate of human P-glycoprotein (P-gp) and human BCRP in vitro. However, these transporters have minimal impact on dabrafenib oral bioavailability and elimination and the risk for clinically relevant drug-drug interactions with inhibitors of P-gp or BCRP is low. Neither dabrafenib nor its 3 main metabolites were demonstrated to be inhibitors of P-gp in vitro.
Although dabrafenib and its metabolites, hydroxy-dabrafenib, carboxy-dabrafenib and desmethyl-dabrafenib, were inhibitors of human organic anion transporter (OAT) 1 and OAT3 in vitro, and dabrafenib and its desmethyl metabolite were found to be inhibitors of organic cation transporter 2 (OCT2) in vitro, the risk of a drug-drug interaction at these transporters is minimal based on clinical exposure of dabrafenib and its metabolites.
A population pharmacokinetic analysis indicates that mildly elevated bilirubin and/or AST levels (based on National Cancer Institute [NCI] classification) do not significantly affect dabrafenib oral clearance. In addition, mild hepatic impairment as defined by bilirubin and AST did not have a significant effect on dabrafenib metabolite plasma concentrations. No data are available in patients with moderate to severe hepatic impairment. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, administration of dabrafenib should be undertaken with caution in patients with moderate to severe hepatic impairment.
A population pharmacokinetic analysis suggests that mild renal impairment does not affect oral clearance of dabrafenib. Although data in moderate renal impairment are limited these data may indicate no clinically relevant effect. No data are available in subjects with severe renal impairment.
Based on the population pharmacokinetic analysis, age had no significant effect on dabrafenib pharmacokinetics. Age greater than 75 years was a significant predictor of carboxy- and desmethyl-dabrafenib plasma concentrations with a 40% greater exposure in subjects ≥75 years of age, relative to subjects <75 years old.
Based on the population pharmacokinetic analysis, gender and weight were found to influence dabrafenib oral clearance; weight also impacted oral volume of distribution and distributional clearance. These pharmacokinetic differences were not considered clinically relevant.
The population pharmacokinetic analysis showed no significant differences in the pharmacokinetics of dabrafenib between Asian and Caucasian patients. There are insufficient data to evaluate the potential effect of other races on dabrafenib pharmacokinetics.
Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay.
In combined female fertility, early embryonic and embryo-foetal development studies in rats numbers of ovarian corpora lutea were reduced in pregnant females at 300 mg/kg/day (approximately 3 times human clinical exposure based on AUC), but there were no effects on oestrous cycle, mating or fertility indices. Developmental toxicity including embryo-lethality and ventricular septal defects and variation in thymic shape were seen at 300 mg/kg/day, and delayed skeletal development and reduced foetal body weight at ≥20 mg/kg/day (≥0.5 times human clinical exposure based on AUC).
Male fertility studies with dabrafenib have not been conducted. However, in repeat dose studies, testicular degeneration/depletion was seen in rats and dogs (≥0.2 times human clinical exposure based on AUC). Testicular changes in rat and dog were still present following a 4-week recovery period.
Cardiovascular effects, including coronary arterial degeneration/necrosis and/or haemorrhage, cardiac atrioventricular valve hypertrophy/haemorrhage and atrial fibrovascular proliferation were seen in dogs (≥2 times human clinical exposure based on AUC). Focal arterial/perivascular inflammation in various tissues was observed in mice and an increased incidence of hepatic arterial degeneration and spontaneous cardiomyocyte degeneration with inflammation (spontaneous cardiomyopathy) was observed in rats (≥0.5 and 0.6 times human clinical exposure for rats and mice, respectively). Hepatic effects, including hepatocellular necrosis and inflammation, were observed in mice (≥0.6 times human clinical exposure). Bronchoalveolar inflammation of the lungs was observed in several dogs at ≥20 mg/kg/day (≥9 times human clinical exposure based on AUC) and was associated with shallow and/or laboured breathing.
Reversible haematological effects have been observed in dogs and rats given dabrafenib. In studies of up to 13 weeks, decreases in reticulocyte counts and/or red cell mass were observed in dogs and rats (≥10 and 1.4 times human clinical exposure, respectively).
In juvenile toxicity studies in rats, effects on growth (shorter long bone length), renal toxicity (tubular deposits, increased incidence of cortical cysts and tubular basophilia and reversible increases in urea and/or creatinine concentrations) and testicular toxicity (degeneration and tubular dilation) were observed (≥0.2 times human clinical exposure based on AUC).
Dabrafenib was phototoxic in an in vitro mouse fibroblast 3T3 Neutral Red Uptake (NRU) assay and in vivo at doses ≥100 mg/kg (>44 times human clinical exposure based on Cmax) in an oral phototoxicity study in hairless mice.
In a study in dogs in which dabrafenib and trametinib were given in combination for 4 weeks, signs of gastrointestinal toxicity and decreased lymphoid cellularity of the thymus were observed at lower exposures than in dogs given trametinib alone. Otherwise, similar toxicities were observed as in comparable monotherapy studies.
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