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Mechanism of Action
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.
Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsinlike activity when measured in blood 1 hour after the first dose. On Day 1 of Cycle 1, proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 mg/m², and from 82% to 83% at 20 mg/m². In addition, carfilzomib administration resulted in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m². Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing.
The Cmax and AUC following a single intravenous dose of 27 mg/m² was 4232 ng/mL and 379 ng•hr/mL, respectively. Following repeated doses of carfilzomib at 15 and 20 mg/m², systemic exposure (AUC) and half-life were similar on Days 1 and 15 or 16 of Cycle 1, suggesting there was no systemic carfilzomib accumulation. At doses between 20 and 36 mg/m², there was a dose-dependent increase in exposure.
The mean steady-state volume of distribution of a 20 mg/m² dose of carfilzomib was 28 L. When tested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over the concentration range of 0.4 to 4 micromolar.
Carfilzomib was rapidly and extensively metabolized. The predominant metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450-mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity.
Following intravenous administration of doses ≥ 15 mg/m², carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely cleared extrahepatically. The pathways of carfilzomib elimination have not been characterized in humans.
Analysis of population pharmacokinetics data after the first dose of Cycle 1 (Day 1) in 154 patients who had received an IV dose of 20 mg/m² showed no clinically significant difference in exposure between patients < 65 years and ≥ 65 years of age.
Mean dose-normalized AUC and Cmax values were comparable between male and female patients in the population pharmacokinetics study.
No pharmacokinetic studies were performed with KYPROLIS in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].
A pharmacokinetic study was conducted in which 43 multiple myeloma patients who had various degrees of renal impairment and who were classified according to their creatinine clearances (CLcr) into the following groups: normal function (CLcr > 80 mL/min, n = 8), mild impairment (CLcr 50–80 mL/min, n = 12), moderate impairment (CLcr 30–49 mL/min, n =8), severe impairment (CLcr < 30 mL/min, n = 7), and chronic dialysis (n = 8). KYPROLIS was administered intravenously over 2 to 10 minutes, on two consecutive days, weekly for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period every 28 days. Patients received an initial dose of 15 mg/m², which could be escalated to 20 mg/m² starting in Cycle 2 if 15 mg/m² was well tolerated in Cycle 1. In this study, renal function status had no effect on the clearance or exposure of carfilzomib following a single or repeat-dose administration [see Use In Specific Populations].
In an in vitro study using human liver microsomes, carfilzomib showed modest direct and time-dependent inhibitory effect on human cytochrome CYP3A4/5. In vitro studies indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism of carfilzomib. A clinical trial of 17 patients using oral midazolam as a CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration. KYPROLIS is not expected to inhibit CYP3A4/5 activities and/or affect the exposure to CYP3A4/5 substrates.
Carfilzomib is a P-glycoprotein (P-gp) substrate and showed marginal inhibitory effects on P-gp in a Caco-2 monolayer system. Given that KYPROLIS is administrated intravenously and is extensively metabolized, the pharmacokinetic profile of KYPROLIS is unlikely to be affected by P-gp inhibitors or inducers.
Animal Toxicology and/or Pharmacology
Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m² based on body surface area) experienced hypotension, increased heart rate, and increased serum levels of troponin-T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m² based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area.
Relapsed Multiple Myeloma
The safety and efficacy of KYPROLIS were evaluated in a single-arm, multicenter clinical trial. Two hundred and sixty-six patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) were enrolled. Patients were enrolled in the trial whose disease had a less than or equal to 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial with total bilirubin levels ≥ 2 × upper limit of normal (ULN); creatinine clearance rates < 30 mL/min; New York Heart Association Class III to IV congestive heart failure; symptomatic cardiac ischemia; myocardial infarction within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; and pleural effusion.
KYPROLIS was administered intravenously over 2 to 10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20 mg/m² at each dose in Cycle 1, and 27 mg/m² in subsequent cycles. To reduce the incidence and severity of fever, rigors, chills, dyspnea, myalgia, and arthralgia, dexamethasone 4 mg by mouth or by intravenous infusion was administered prior to all KYPROLIS doses during the first cycle and prior to all KYPROLIS doses during the first dose-escalation (27 mg/m²) cycle. Dexamethasone premedication (4 mg orally or intravenously) was reinstated if these symptoms reappeared during subsequent cycles.
Baseline patient and disease characteristics are summarized in Table 5.
Table 5: Demographics and Baseline Disease
|Characteristic||Number of Patients (%)|
|Enrolled patients||266 (100)|
|Median age, years (range)||63.0 (37, 87)|
|Age group, < 65 / ≥ 65 (years)||146 (54.9) / 120 (45.1)|
|Gender (male / female)||155 (58.3) / 111 (41.7)|
|Race (White / Black / Asian / Other)||190 (71.4) / 53 (19.9) / 6 (2.3) / 17 (6.4)|
|Number of Prior Regimens (median)||5a|
|Prior Transplant||198 (74.4)|
|Refractory Status to Most Recent Therapyb|
|Refractory: Progression during most recent therapy||198 (74.4)|
|Refractory: Progression within 60 days after completion of most recent therapy||38 (14.3)|
|Refractory: ≤ 25% response to treatment||16 (6.0)|
|Relapsed: Progression after 60 days post treatment||14 (5.3)|
|Years since diagnosis, median (range)||5.35 (0.5, 22.3)|
|Plasma cell involvement ( < 50% / ≥ 50% / unknown or missing)||143 (53.8) / 106 (39.8) / 17 (6.4)|
|Cytogenetics or FISH analyses|
|Poor Prognosis||75 (28.2)|
|Unknown/Not tested||32 (12.0)|
|Serum Beta-2 Microglobulin|
|median (range)||4.3 (0.4, 20.5)|
|Creatinine clearance < 30 (mL/min)||6 (2.3)|
|aRange: 1, 20.
bCategories for refractory status are derived by programmatic assessment using available laboratory data.
The median number of cycles started was four.
The primary endpoint was the overall response rate (ORR) as determined by Independent Review Committee assessment using International Myeloma Working Group criteria. The ORR (stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]) was 22.9% (95% CI: 18.0, 28.5) (N = 266) (see Table 6). The median duration of response (DOR) was 7.8 months (95% CI: 5.6, 9.2).
Table 6: Response Categories
|Characteristic||Study Patients n (%)|
|Number of patients (%)||266 (100)|
|Complete response||1 (0.4)|
|Very good partial response||13 (4.9)|
|Partial response||47 (17.7)|
|Overall response||61 (22.9)|
|95% CIb||(18.0, 28.5)|
|aAs assessed by the Independent Review Committee.
bExact confidence interval.
Last reviewed on RxList: 7/25/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Kyprolis Information
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