Carfilzomib

Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that selectively and irreversibly binds to the N-terminal threonine containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome, and displays little to no activity against other protease classes. Carfilzomib had antiproliferative and proapoptotic activities in preclinical models in haematologic tumours.

In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumour growth in models of multiple myeloma. In vitro, carfilzomib was found to have minimal neurotoxicity and minimal reaction to non-proteasomal proteases.

Pharmacodynamic effects

Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood 1 hour after the first dose. Doses of ≥15 mg/m² consistently induced an (≥80%) inhibition of the CT-L activity of the proteasome. In addition, carfilzomib administration resulted in inhibition of the latent membrane protein 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (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. Combination dosing with lenalidomide and dexamethasone did not affect proteasome inhibition.

At the higher dose of 56 mg/m², there was not only a greater inhibition of CT-L subunits (≥90%) compared to those at 15 to 20 mg/m², but also a greater inhibition of other proteasome subunits (LMP7, MECL1, and LMP2). There was an approximately 8%, 23% and 34% increase in the inhibition of LMP7, MECL1, and LMP2 subunits respectively at the dose of 56 mg/m² compared to those at 15 to 20 mg/m². Similar proteasome inhibition by carfilzomib was achieved with 2 to 10 minute and 30 minute infusions at the 2 dose levels (20 and 36 mg/m²) at which it was tested.

Absorption

The C_max and AUC following a 2 to 10 minute intravenous infusion of 27 mg/m² was 4,232 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 56 mg/m², there was a dose-dependent increase in exposure.

A 30 minute infusion resulted in a similar half-life and AUC, but 2- to 3-fold lower C_max compared to that observed with a 2 to 10 minute infusion of the same dose. Following a 30 minute infusion of the 56 mg/m² dose, the AUC (948 ng•hr/mL) was approximately 2.5-fold that observed at the 27 mg/m² level, and C_max (2,079 ng/mL) was lower compared to that of 27 mg/m² over the 2 to 10 minute infusion.

Distribution

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.

Biotransformation

Carfilzomib was rapidly and extensively metabolised. 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.

Elimination

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. Carfilzomib is eliminated primarily via metabolism with subsequent excretion of its metabolites in urine.

Special populations

Population pharmacokinetic analyses indicate there are no effects of age, gender or race on the pharmacokinetics of carfilzomib.

Hepatic impairment

A pharmacokinetic study evaluated 33 patients with relapsed or progressive advanced malignancies (solid tumours; n=31 or haematologic malignancies; n=2) who had normal hepatic function (bilirubin ≤ upper limit of normal [ULN]; aspartate aminotransferase [AST] ≤ ULN, n=10), mild hepatic impairment (bilirubin >1-1.5 x ULN or AST > ULN, but bilirubin ≤ ULN, n=14), or moderate hepatic impairment (bilirubin >1.5-3 x ULN; any AST, n=9). The pharmacokinetics of carfilzomib has not been studied in patients with severe hepatic impairment (bilirubin >3 x ULN and any AST). Carfilzomib, as a single agent, was administered intravenously over 30 minutes at 20 mg/m² on days 1 and 2 and at 27 mg/m² on days 8, 9, 15 and 16 of cycle 1. If tolerated, patients received 56 mg/m² starting in cycle 2. Baseline hepatic function status had no marked effect on the total systemic exposure (AUC_last) of carfilzomib following single or repeat-dose administration (geometric mean ratio in AUC_last at the 27 mg/m² dose in cycle 1, day 16 for mild and moderate impairment versus normal hepatic function were 144.4% and 126.1%, respectively; and at the 56 mg/m² dose in cycle 2, day 1 were 144.7% and 121.1%). However, in patients with mild or moderate baseline hepatic impairment, all of whom had solid tumours, there was a higher subject incidence of hepatic function abnormalities, ≥ grade 3 adverse events and serious adverse events compared with subjects with normal hepatic function.

Renal impairment

The pharmacokinetics of carfilzomib was studied in two dedicated renal impairment studies.

The first study was conducted in 50 multiple myeloma patients with normal renal function (CrCL >80 mL/min, n=12), mild (CrCL 50-80 mL/min, n=12), moderate (CrCL 30-49 mL/min, n=10), and severe (CrCL <30 mL/min, n=8) renal impairment, and patients on chronic dialysis (n=8). Carfilzomib, as a single agent, was administered intravenously over 2 to 10 minutes at doses up to 20 mg/m². Pharmacokinetic data were collected from patients following the 15 mg/m² dose in cycle 1 and the 20 mg/m² dose in cycle 2. The second study was conducted in 23 relapsed multiple myeloma patients with creatinine clearance ≥75 mL/min (n=13) and patients with end stage renal disease (ESRD) requiring dialysis (n=10). Pharmacokinetic data were collected from patients following administration of a 27 mg/m² dose as a 30 minute infusion on cycle 1, day 16 and the 56 mg/m² dose on cycle 2, day 1.

Results from both studies show that renal function status had no marked effect on the exposure of carfilzomib following single or repeat-dose administration. The geometric mean ratio in AUC_last at the 15 mg/m² dose cycle 1, day 1 for mild, moderate, severe renal impairment and chronic dialysis versus normal renal function were 124.36%, 111.07%, 84.73% and 121.72%, respectively. The geometric mean ratios in AUC_last at the 27 mg/m² dose cycle 1, day 16 and at the 56 mg/m² dose cycle 2, day 1 for ESRD versus normal renal function were 139.72% and 132.75%, respectively. In the first study the M14 metabolite, a peptide fragment and the most abundant circulating metabolite, increased 2- and 3-fold in patients with moderate and severe renal impairment, respectively, and 7-fold in patients requiring dialysis (based on AUC_last). In the second study, the exposures for M14 were greater (approximately 4-fold) in subjects with ESRD than in subjects with normal renal function. This metabolite has no known biological activities. Serious adverse events related to worsening renal function were more common in subjects with baseline renal dysfunction.

Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.

Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (which corresponds to 36 mg/m² and is similar to the recommended dose in humans of 27 mg/m² based on BSA) 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 haemorrhage/degeneration), gastrointestinal (necrosis/haemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (haemorrhage/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 BSA. The highest non-severely toxic dose of 0.5 mg/kg in monkeys resulted in interstitial inflammation in the kidney along with slight glomerulopathy and slight heart inflammation. Those findings were reported at 6 mg/m² which are below the recommended dose in humans of 27 mg/m².

Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies. Carfilzomib caused embryo-foetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Carfilzomib administered to pregnant rats during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day, which is approximately half the recommended dose in humans of 27 mg/m² based on BSA.