Chemical formula: C₂₂H₂₇FN₄O₂ Molecular mass: 398.474 g/mol PubChem compound: 5329102
Sunitinib inhibits multiple RTKs that are implicated in tumour growth, neoangiogenesis, and metastatic progression of cancer. Sunitinib was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), VEGF receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.
The PK of sunitinib were evaluated in 135 healthy volunteers and 266 patients with solid tumours. The PK were similar in all solid tumours populations tested and in healthy volunteers.
In the dosing ranges of 25 to 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionally with dose. With repeated daily administration, sunitinib accumulates 3- to 4-fold and its primary active metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite are 62.9-101 ng/ml, which are target concentrations predicted from preclinical data to inhibit receptor phosphorylation in vitro and result in tumour stasis/growth reduction in vivo. The primary active metabolite comprises 23% to 37% of the total exposure. No significant changes in the PK of sunitinib or the primary active metabolite are observed with repeated daily administration or with repeated cycles in the dosing schedules tested.
After oral administration of sunitinib, Cmax are generally observed from 6 to 12 hours time to maximum concentration (tmax) postadministration.
Food has no effect on the bioavailability of sunitinib.
In vitro, binding of sunitinib and its primary active metabolite to human plasma protein was 95% and 90%, respectively, with no apparent concentration dependence. The apparent volume of distribution (Vd) for sunitinib was large, 2230 L, indicating distribution into the tissues.
The calculated in vitro Ki values for all cytochrome P450 (CYP) isoforms tested (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11) indicated that sunitinib and its primary active metabolite are unlikely to induce metabolism, to any clinically relevant extent, of other actives substances that may be metabolised by these enzymes.
Sunitinib is metabolised primarily by CYP3A4, the CYP isoform which produces its primary active metabolite, desethyl sunitinib, which is then further metabolised by the same isoenzyme.
Co-administration of sunitinib with potent CYP3A4 inducers or inhibitors should be avoided because the plasma levels of sunitinib may be altered.
Excretion is primarily via faeces (61%), with renal elimination of unchanged active substance and metabolites accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were the major compounds identified in plasma, urine, and faeces, representing 91.5%, 86.4%, and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and faeces, but generally were not found in plasma. Total oral clearance (CL/F) was 34-62 L/h. Following oral administration in healthy volunteers, the elimination half-lives of sunitinib and its primary active desethyl metabolite are approximately 40-60 hours and 80-110 hours, respectively.
In vitro, sunitinib is a substrate of the efflux transporter BCRP. In study A6181038 the co-administration of gefitinib, a BCRP inhibitor, did not result in a clinically relevant effect on the Cmax and AUC for sunitinib or total drug (sunitinib + metabolite). This study was a multi-centre, open-label, Phase ½ study examining the safety/tolerability, the maximum tolerated dose, and the antitumour activity of sunitinib in combination with gefitinib in subjects with MRCC. The PK of gefitinib (250 mg daily) and sunitinib (37.5 mg [Cohort 1, n=4] or 50 mg [Cohort 2, n=7] daily on a 4-weeks on followed by 2 weeks-off schedule) when co-administered was evaluated as a secondary study objective. Changes in sunitinib PK parameters were of no clinical significance and did not indicate any drug-drug interactions; however, considering the relatively low number of subjects (i.e. N=7+4) and the moderate-large interpatient variability in the pharmacokinetic parameters, caution needs to be taken when interpreting the PK drug-drug interaction findings from this study.
Sunitinib and its primary metabolite are mainly metabolised by the liver. Systemic exposures after a single dose of sunitinib were similar in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to subjects with normal hepatic function. Sunitinib was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment.
Studies in cancer patients have excluded patients with ALT or AST >2.5 x ULN (upper limit of normal) or >5.0 x ULN if due to liver metastasis.
Population PK analyses indicated that sunitinib apparent clearance (CL/F) was not affected by creatinine clearance (CLcr) within the range evaluated (42-347 ml/min). Systemic exposures after a single dose of sunitinib were similar in subjects with severe renal impairment (CLcr<30 ml/min) compared to subjects with normal renal function (CLcr>80 ml/min). Although sunitinib and its primary metabolite were not eliminated through haemodialysis in subjects with ESRD, the total systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared to subjects with normal renal function.
Population PK analyses of demographic data indicate that no starting dose adjustments are necessary for weight or Eastern Cooperative Oncology Group (ECOG) performance status.
Available data indicate that females could have about 30% lower apparent clearance (CL/F) of sunitinib than males: this difference, however, does not necessitate starting dose adjustments.
Experience on the use of sunitinib in paediatric patients is limited. Population PK analyses of a pooled dataset from adult patients with GIST and solid tumours and paediatric patients with solid tumours were completed. Stepwise covariate modelling analyses were performed to evaluate the effect of age and body size (total body weight or body surface area) as well as other covariates on important PK parameters for sunitinib and its active metabolite. Among age and bodysize related covariates tested, age was a significant covariate on apparent clearance of sunitinib (the younger the age of the paediatric patient, the lower the apparent clearance). Similarly, body surface area was a significant covariate on the apparent clearance of the active metabolite (the lower the body surface area, the lower the apparent clearance).
Furthermore, based on an integrated population PK analysis of pooled data from the 3 paediatric studies (2 paediatric solid tumour studies and 1 paediatric GIST study; ages: 6 years to 11 years and 12 years to 17 years), baseline body surface area (BSA) was a significant covariate on apparent clearance of sunitinib and its active metabolite. Based on this analysis, a dose of approximately 20 mg/m² daily in paediatric patients, with BSA values between 1.10 and 1.87 m², is expected to provide plasma exposures to sunitinib and its active metabolite comparable (between 75 and 125% of the AUC) to those in adults with GIST administered sunitinib 50 mg daily on Schedule 4/2 (AUC 1233 ng.hr/mL). In paediatric studies, the starting dose of sunitinib was 15 mg/m² (based on the MTD identified in the Phase 1 dose-escalation study), which in paediatric patients with GIST increased to 22.5 mg/m² and subsequently to 30 mg/m² (not to exceed the total dose of 50 mg/day) based on individual patient safety/tolerability. Furthermore, according to the published literatures in paediatric patients with GIST, the calculated starting dose ranged from 16.6 mg/m² to 36 mg/m², increased to doses as high as 40.4 mg/m² (not exceeding the total dose of 50 mg/day).
In rat and monkey repeated-dose toxicity studies up to 9-months duration, the primary target organ effects were identified in the gastrointestinal tract (emesis and diarrhoea in monkeys); adrenal gland (cortical congestion and/or haemorrhage in rats and monkeys, with necrosis followed by fibrosis in rats); haemolymphopoietic system (bone morrow hypocellularity and lymphoid depletion of thymus, spleen, and lymph node); exocrine pancreas (acinar cell degranulation with single cell necrosis); salivary gland (acinar hypertrophy); bone joint (growth plate thickening); uterus (atrophy); and ovaries (decreased follicular development). All findings occurred at clinically relevant sunitinib plasma exposure levels. Additional effects observed in other studies included: QTc interval prolongation, LVEF reduction and testicular tubular atrophy, increased mesangial cells in kidney, haemorrhage in gastrointestinal tract and oral mucosa, and hypertrophy of anterior pituitary cells. Changes in the uterus (endometrial atrophy) and bone growth plate (physeal thickening or dysplasia of cartilage) are thought to be related to the pharmacological action of sunitinib. Most of these findings were reversible after 2 to 6 weeks without treatment.
The genotoxic potential of sunitinib was assessed in vitro and in vivo. Sunitinib was not mutagenic in bacteria using metabolic activation provided by rat liver. Sunitinib did not induce structural chromosome aberrations in human peripheral blood lymphocyte cells in vitro. Polyploidy (numerical chromosome aberrations) was observed in human peripheral blood lymphocytes in vitro, both in the presence and absence of metabolic activation. Sunitinib was not clastogenic in rat bone marrow in vivo. The major active metabolite was not evaluated for genotoxic potential.
In a 1-month, oral gavage dose-range finding study (0, 10, 25, 75, or 200 mg/kg/day) with continuous daily dosing in rasH2 transgenic mice, carcinoma and hyperplasia of Brunner’s glands of the duodenum were observed at the highest dose (200 mg/kg/day) tested.
A 6-month, oral gavage carcinogenicity study (0, 8, 25, 75 [reduced to 50] mg/kg/day), with daily dosing was conducted in rasH2 transgenic mice. Gastroduodenal carcinomas, an increased incidence of background haemangiosarcomas, and/or gastric mucosal hyperplasia were observed at doses of ≥ 25 mg/kg/day following 1- or 6-months duration (≥7.3 times the AUC in patients administered the recommended daily dose RDD).
In a 2-year rat carcinogenicity study (0, 0.33, 1, or 3 mg/kg/day), administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in increases in the incidence of phaeochromocytomas and hyperplasia in the adrenal medulla of male rats given 3 mg/kg/day following >1 year of dosing (≥7.8 times the AUC in patients administered the RDD). Brunner’s glands carcinoma occurred in the duodenum at ≥1 mg/kg/day in females and at 3 mg/kg/day in males, and mucous cell hyperplasia was evident in the glandular stomach at 3 mg/kg/day in males, which occurred at ≥0.9, 7.8, and 7.8 times the AUC in patients administered the RDD, respectively. The relevance to humans of the neoplastic findings observed in the mouse (rasH2 transgenic) and rat carcinogenicity studies with sunitinib treatment is unclear.
No effects on male or female fertility were observed in reproductive toxicity studies. However, in repeated-dose toxicity studies performed in rats and monkeys, effects on female fertility were observed in the form of follicular atresia, degeneration of corpora lutea, endometrial changes in the uterus, and decreased uterine and ovarian weights at clinically relevant systemic exposure levels. Effects on male fertility in rat were observed in the form of tubular atrophy in the testes, reduction of spermatozoa in epididymides, and colloid depletion in prostate and seminal vesicles at plasma exposure levels 25 times the systemic exposure in humans.
In rats, embryo-foetal mortality was evident as significant reductions in the number of live foetuses, increased numbers of resorptions, increased postimplantation loss, and total litter loss in 8 of 28 pregnant females at plasma exposure levels 5.5 times the systemic exposure in humans. In rabbits, reductions in gravid uterine weights and number of live foetuses were due to increases in the number of resorptions, increases in postimplantation loss and complete litter loss in 4 of 6 pregnant females at plasma exposure levels 3 times the systemic exposure in humans. Sunitinib treatment in rats during organogenesis resulted in developmental effects at 5 mg/kg/day consisting of increased incidence of foetal skeletal malformations, predominantly characterised as retarded ossification of thoracic/lumbar vertebrae and occurred at plasma exposure levels 5.5 times the systemic exposure in humans. In rabbits, developmental effects consisted of increased incidence of cleft lip at plasma exposure levels approximately equal to that observed in clinic, and cleft lip and cleft palate at plasma exposure levels 2.7 times the systemic exposure in humans.
Sunitinib (0.3, 1.0, 3.0 mg/kg/day) was evaluated in a pre-and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at ≥1 mg/kg/day but no maternal reproductive toxicity was observed up to 3 mg/kg/day (estimate exposure ≥2.3 times the AUC in patients administered the RDD). Reduced offspring body weights were observed during the preweaning and postweaning periods at 3 mg/kg/day. No development toxicity was observed at 1 mg/kg/day (approximate exposure ≥0.9 times the AUC in patients administered the RDD).
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