Action And Clinical Pharmacology
SUTENT (sunitinib malate) is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumour growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as a potent inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor 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). Inhibition of the activity of these RTKs by sunitinib has been demonstrated in biochemical and/or cellular assays, and inhibition of function has been demonstrated in cell proliferation or viability assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. (see DETAILED PHARMACOLOGY).
Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumour xenografts expressing RTK targets in vivo and demonstrated inhibition of tumour growth or tumour regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumour cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumour angiogenesis in vivo.
The pharmacokinetics of sunitinib and its primary active metabolite have been evaluated in 135 healthy volunteers and in 266 patients with solid tumours.
Absorption and Distribution
Maximum plasma concentrations (Cmax) of sunitinib are generally observed from 6 to 12 hours (Tmax) post-dose. Food has no effect on the bioavailability of sunitinib. Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. After repeated daily administration, in the dosing ranges of 25 to 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax for sunitinib and total drug increases proportionally with dose. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary 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 trough plasma concentrations of sunitinib and its active metabolite are 62.9-101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite are observed with repeated daily administration or with repeated cycles in the dosing regimens tested. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L.
The pharmacokinetics were similar in healthy volunteers and in the solid tumour patient populations tested, including patients with GIST, MRCC, and pancreatic NET (See CLINICAL TRIALS).
Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no apparent concentration dependence.
Metabolism and Elimination
Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23 to 37% of the total exposure. Elimination is primarily via feces. In a human mass balance study of [14C] sunitinib, 61% of the radioactive dose was eliminated in feces, with renal elimination of drug and metabolites accounting for 16% of the administered radioactive dose. Sunitinib and its primary active metabolite are the major drug-related compounds identified in plasma, urine and feces, representing 91.5 %, 86.4 % and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and feces, but were generally not found in plasma. Total oral clearance (CL/F) was 34 - 62 L/hr with an inter-patient variability of 40%.
Population pharmacokinetic analyses of demographic data suggest that there are no clinically relevant effects of age, body weight, creatinine clearance, race, gender or ECOG score on the pharmacokinetics of sunitinib or the active metabolite.
There are no pharmacokinetic data available in pediatric patients.
A single 50 mg dose of SUTENT was administered to patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, and to control group of patients with normal hepatic function. The pharmacokinetic parameters evaluated demonstrated that dose adjustments to starting dose might not be necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. However, SUTENT was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. In addition, repeated administration of SUTENT was not studied in subjects with hepatic impairment.
Safety and efficacy of SUTENT have not been established in patients with severe renal impairment or with end-stage renal disease (ESRD) on hemodialysis. Phase 3 studies that were conducted excluded patients with serum creatinine >2.0 x ULN. However, in a small Phase 1 study, systemic exposures after a single 50mg dose of SUTENT were similar in 8 subjects with severe renal impairment (CLcr<30 mL/min) compared to 8 subjects with normal renal function (CLcr>80 mL/min), although the variability was greater in the patients with severe renal impairment. Even though sunitinib and its primary metabolite were not eliminated through hemodialysis in 8 subjects with ESRD, the total systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared to 8 subjects with normal renal function, most likely due to a lower absorption of sunitinib in subjects with ESRD.
Based on pharmacokinetic data from this Phase 1 study, no adjustment to starting dose is required when administering SUTENT to patients with renal impairment (mild-severe) or with end-stage renal disease (ESRD) on hemodialysis. Subsequent dose modifications should be based on individual safety and tolerability [see DOSAGE AND ADMINISTRATION, Dose Modification]. Repeated administration of SUTENT was not studied in subjects with renal impairment.
Cases of renal impairment and failure, including fatalities, have been reported with SUTENT use. Caution and careful monitoring of patients with severe renal impairment or ESRD on hemodialysis is required while on SUTENT.
In a population pharmacokinetic analysis, no relationship was observed between renal function (as measured by calculated creatinine clearance, range 42-347 mL/min) and sunitinib pharmacokinetics.
QT/QTc Interval Prolongation
In a phase I clinical QT study, patients with advanced solid tumours received SUTENT 150 mg on Days 3 and 9, and SUTENT 50 mg daily Days 4 to 8 (positive control given Day 1 and placebo given Day 2). Manual serial ECG readings were conducted in accordance with current guidelines. At approximately twice therapeutic concentrations, SUTENT was associated with QTc prolongation. On both Day 3 and Day 9, SUTENT was associated with a progressive increase in the QTc interval that continued throughout the 24-hour observation period, without reaching any obvious peak, plateau, or offset. Because of this, the peak effect could not be characterized with confidence. At the last observation (24 h), the maximum mean placebo-adjusted increase from baseline was 9.6 (90% CI 4.1, 15.1) msec for Day 3 and 15.4 (90% CI 8.4, 22.4) msec for Day 9 using a time-matched baseline and Fridericia’s heart rate correction. The magnitude of these increases is considered to justify cause for concern. However, no subjects experienced an effect on the QTc interval greater than grade 2 (CTCAE version 3.0). No patient presented with a cardiac arrhythmia (see WARNINGS AND PRECAUTIONS section).
T wave Morphology
At baseline, the incidence of patients with T wave abnormalities and the proportion of ECGs with abnormal T waves was high in this population of cancer patients. After 7 days of SUTENT therapy, however, these incidences had increased.
QTc prolongation in association with changes in T wave morphology has been suggested to merit intensified concern with respect to proarrhythmic potential.
PR Interval and Heart Rate
Mean placebo-adjusted changes in the PR interval were positive at all time points, with the maximum increase occurring 7 to 12 hours post-dosing, followed by a decline at 24 hours. Outlier analyses for the PR interval (>200 msec) were consistent with a shift toward a higher proportion of outliers in patients treated with SUTENT. Excessive PR interval prolongation can result in AV block. Progressive levels of AV block are associated with increasing morbidity and mortality.
On Days 3 and 9, heart rate decreased progressively over the 24 hours period following SUTENT dosing, but was not affected by the positive control. During the study, an event of bradycardia occurred that was considered treatment-related, and dizziness was experienced by 7 of 48 patients.
Bradycardia and AV block are recognized risk factors for torsade de pointes. For this reason, a drug that causes QTc prolongation in associated with prolongation of the PR and RR intervals raises particular concerns with respect to proarrhythmic potential.
In vitro studies indicate that sunitinib does not induce or inhibit major CYP enzymes.
In vitro Studies of CYP Inhibition and Induction: The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.
CYP3A4 Inhibitors: Concurrent administration of SUTENT with the potent CYP3A4 inhibitor, ketoconazole, resulted in a 49% and 51% increase in the combined (sunitinib + active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers.
Administration of SUTENT with potent inhibitors of the CYP3A4 family may increase SUTENT concentrations. Concomitant administration of SUTENT with inhibitors should be avoided or the selection of an alternate concomitant medication with no, or minimal potential to inhibit CYP3A4 should be considered. If this is not possible, the dose of SUTENT may need to be reduced (see DOSAGE AND ADMINISTRATION). NOTE: In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inhibitors has not been established.
CYP3A4 Inducers: Concurrent administration of SUTENT with the potent CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + active metabolite) Cmax and AUC0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers.
Administration of SUTENT with potent inducers of CYP3A4 may decrease SUTENT concentrations. Concomitant administration of SUTENT should be avoided or selection of an alternate concomitant medication with no or minimal potential to induce CYP3A4 should be considered. If this is not possible, the dose of SUTENT may need to be increased (see DOSAGE AND ADMINISTRATION). NOTE: In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inducers have not been established.