ADCETRIS® Clinical Pharmacology

12.1 Mechanism of Action

CD30 is a member of the tumor necrosis factor receptor family and is expressed on the surface of sALCL cells and on Hodgkin Reed-Sternberg (HRS) cells in cHL. CD30 is variably expressed in other T-cell lymphomas. Expression of CD30 on healthy tissue and cells is limited. In vitro data suggest that signaling through CD30-CD30L binding may affect cell survival and proliferation.

Brentuximab vedotin is an antibody-drug conjugate (ADC). The antibody is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting agent. MMAE is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of ADCETRIS is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC‑CD30 complex, and the release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cells. Additionally, in vitro data provide evidence for antibody-dependent cellular phagocytosis (ADCP).

12.2 Pharmacodynamics

Cardiac Electrophysiology

At the recommended dose of 1.8 mg/kg, brentuximab vedotin had no large QTc prolongation (>10ms).

12.3 Pharmacokinetics

The pharmacokinetics of brentuximab vedotin were evaluated in monotherapy and combination chemotherapy in patients with hematological malignancies. The pharmacokinetics of brentuximab vedotin in combination therapy were similar to those in monotherapy. Total antibody and ADC had similar pharmacokinetic profiles. The pharmacokinetics of the ADC and MMAE are presented.

ADC

Maximum concentrations of ADC were observed near the end of infusion. Exposures were approximately dose proportional from 1.2 to 2.7 mg/kg (1.5 times the highest approved recommended dosage).

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1.8 mg/kg Q3W: Steady state was achieved within 21 days, and minimal to no accumulation of ADC was observed.

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1.2 mg/kg Q2W: Steady state was achieved within 56 days, 1.27-fold accumulation (14-day AUC) was observed.

MMAE

Maximum concentrations of MMAE were observed approximately 1 to 3 days after end of infusion. Exposures decreased with continued administration of ADCETRIS with approximately 50% to 80% of the exposure of the first dose observed at subsequent doses.

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1.8 mg/kg Q3W: Steady state was achieved within 21 days.

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1.2 mg/kg Q2W: Steady state was achieved within 56 days.

Distribution

In humans, the mean steady state volume of distribution was approximately 6–10 L for ADC.

In vitro, the binding of MMAE to human plasma proteins ranged from 68–82%. MMAE is not likely to displace or to be displaced by highly protein-bound drugs.

Elimination

ADC elimination exhibited a multi-exponential decline with a t1/2 of approximately 4 to 6 days.

MMAE elimination exhibited a mono-exponential decline with a t1/2 of approximately 3 to 4 days. Elimination of MMAE appeared to be limited by its rate of release from ADC.

Metabolism

A small fraction of MMAE released from brentuximab vedotin is metabolized. In vitro data indicate that the MMAE metabolism that occurs is primarily via oxidation by CYP3A4/5.

Excretion

After a single dose of 1.8 mg/kg of ADCETRIS in patients, approximately 24% of the total MMAE administered was recovered in both urine and feces over a 1-week period, approximately 72% of which was recovered in the feces, and the majority was excreted unchanged.

Specific Populations

Sex and race do not have a meaningful effect on the pharmacokinetics of brentuximab vedotin.

Pediatric Patients

The pharmacokinetics of brentuximab vedotin and MMAE were evaluated in 65 pediatric patients aged 3 to <6 years (N=3), 6 to <12 years (N=30) and 12 to <17 years (N=32). Following the recommended dosage of brentuximab vedotin 1.8 mg/kg Q3W, the dose-normalized steady state Cavg of brentuximab vedotin in patients 12 to <17 years of age were generally consistent with those in adult patients administered brentuximab vedotin 1.2 mg/kg Q2W. The median AUC of ADC was 22% lower in patients 6 to <12 years of age (median [range] body weight = 28.8 kg [16.2, 80.8 kg]), and 37% lower in patients 3 to <6 years of age (median [range] body weight = 17.0 kg [10.7, 31.1 kg]), respectively, compared to that in patients 12 to <17 years of age (median [range] body weight = 52.7 kg [28.5, 123.9 kg]). The AUC of MMAE was 25% lower in patients 6 to <12 years of age, and 41% lower in patients 3 to <6 years of age, respectively, compared to that in patients 12 to <17 years of age. After accounting for body weight, other factors such as age, sex, race, and baseline albumin had no clinically significant effect on the PK of ADC and MMAE in pediatric patients 3 to <17 years of age.

Renal Impairment

The pharmacokinetics of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (CrCL >50–80 mL/min; n=4), moderate (CrCL 30–50 mL/min; n=3) and severe (CrCL <30 mL/min; n=3) renal impairment. The AUC of MMAE was approximately 2-fold higher in patients with severe renal impairment compared to patients with normal renal function and not meaningfully altered in patients with mild or moderate renal impairment.

Hepatic Impairment

The pharmacokinetics of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg/kg of ADCETRIS to patients with mild (Child-Pugh A; n=1), moderate (Child-Pugh B; n=5) and severe (Child-Pugh C; n=1) hepatic impairment. The AUC of MMAE was approximately 2.3-fold higher in patients with hepatic impairment compared to patients with normal hepatic function.

Drug Interaction Studies

Effects of Other Drugs on ADCETRIS

Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%.

Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effects of ADCETRIS on Other Drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate.

In vitro studies using human liver microsomes indicate that MMAE inhibits CYP3A4/5 but not other CYP450 isoforms. MMAE did not induce any major CYP450 enzymes in human hepatocytes.

In vitro studies indicate that MMAE is a substrate and not an inhibitor of the efflux transporter P‑glycoprotein (P-gp).

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with incidence of ADA in other studies, including those of ADCETRIS or of other brentuximab vedotin products.

Among adult patients with relapsed or refractory cHL and relapsed or refractory systemic ALCL in Studies 1 and 2 [see Clinical Studies (14.1) and (14.3)], treatment-emergent ADA (or anti-brentuximab vedotin antibodies) developed in 37% (58/156) of patients who were tested for anti-brentuximab vedotin antibodies. Approximately 7% of patients in these trials developed persistently positive antibodies (positive test at more than 2 time points) and 30% developed transiently positive antibodies (positive at 1 or 2 post-baseline time points). Two of the patients (1%) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment. Overall, a higher incidence of infusion related reactions was observed in patients who developed persistently positive antibodies. The incidence of treatment-emergent neutralizing antibodies against brentuximab vedotin was 62% (36/58). The effect of anti-brentuximab vedotin antibodies on efficacy is not known.

Among pediatric patients with previously untreated high risk cHL in Study 7 [see Clinical Studies (14.1)], of the 26 patients tested, none of the patients tested positive for anti-brentuximab vedotin antibodies.