Article6 - Kadcyla eMagazine

This article covers the following sections in the KADCYLA Prescribing Information: Section 11 (Description), Section 12 (Clinical Pharmacology), and Section 13 (Nonclinical Toxicology).

11. Description

KADCYLA (ado-trastuzumab emtansine), which may also be referred to as T-DM1, is a HER2-targeted antibody-drug conjugate (ADC) which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the microtubule inhibitory drug DM1 (a maytansine derivative) via the stable linker MCC. Emtansine refers to the DM1-MCC complex.

The chemical structure of KADCYLA and an accompanying schematic are shown in the figure below.

KADCYLA: A HER-2-Targeted ADC

Section 12.1 Mechanism of Action

Let's now take a look at the proposed mechanism of action of KADCYLA. We will begin with an overview and then do a closer step-by-step review. As stated earlier, ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate(ADC). The antibody is the humanized anti-HER2 IgG1, trastuzumab. The small molecular cytotoxin, DM1, is a microtubule inhibitor. Upon binding to sub-domain IV of the HER2 receptor, ado-trastuzumab emtansine undergoes receptor-mediated internalization and subsequent lysosomal degradation, resulting in intracellular release of DM1-containing cytotoxic catabolites. Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in cell cycle arrest and apoptotic cell death. In vitro studies have shown that similar to trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling, mediates antibody-dependent cell-mediated cytotoxicity and inhibits shedding of the HER2 extracellular domain in human breast cancer cells that overexpress HER2.

Trastuzumab is believed to work through a variety of mechanisms, including, but not limited to:

Inducing antibody-dependent cellular cytotoxicity (ADCC)
Suppressing HER2 signaling
Blocking HER2 shedding
Potentiating the efficacy of chemotherapy

Proposed Mechanism of Action of KADCYLA

Select each numbered hotspot in order to review the proposed MOA for KADCYLA.

HER2 binding: Trastuzumab selectively binds to the HER2 receptor at sub-domain IV.

HER2+ antitumor activities: Trastuzumab:

Disrupts HER2 signaling (antiproliferative and apoptotic effects)
Mediates ADCC
Inhibits HER2 shedding

Internalization: Once bound, the KADCYLA/HER2-receptor complex is internalized via endocytosis.

DM1 release: KADCYLA is degraded inside the tumor to release DM1.

DM1 cytotoxicity: DM1 binds to microtubules and inhibits their polymerization, causing cell-cycle arrest and cell death.

12.2 Pharmacodynamics

Pharmacodynamics refers to the effects of a drug on a living organism. This includes the magnitude of pharmacologic response and the duration and magnitude of response relative to the concentration of the drug at the site of action within the body. The Pharmacodynamics section of the KADCYLA Prescribing Information discusses the effects of multiple doses of KADCYLA on the electrical activity of the heart (ie, cardiac electrophysiology), specifically, the QT interval. Some medications can prolong the QT interval and interfere with the ability of the heart to “recharge” between each beat, which can lead to an arrhythmia or other serious cardiac issues.

The effect of multiple doses of KADCYLA (3.6 mg/kg every 3 weeks) on the QTc interval was evaluated in an open label, single arm study in 51 patients with HER2+ MBC. No large changes in the mean QT interval were detected in the study.

12.3 Pharmacokinetics

Pharmacokinetics refers to the biological processes of a drug in an organism. These processes include absorption, distribution, metabolism, and excretion.

Select each of the hot spots in the figure below to learn more.

Pharmacokinetic Processes

A drug must be absorbed from its site of administration to enter the bloodstream. The rate and efficiency of absorption varies based on route of administration and the drug's physiochemical properties. The amount absorbed into the systemic circulation divided by the amount administered constitutes its bioavailability. A drug administered intravenously has 100% bioavailability.

The distribution phase is marked by movement from the site of administration into the tissues. Many factors affect the rate of distribution, including blood flow rate, organ size, and solubility of the drug.

Metabolism is one form of elimination. The metabolism of a substance that occurs immediately as it enters the body, and before it can exert any effect or be measured at its target organ, is termed first-pass metabolism. The action of a drug may be terminated before it is excreted because it is metabolized by the body.

The rate of elimination determines the duration of action for many drugs. Excretion is one form of elimination, and usually involves the kidneys.

KADCYLA pharmacokinetics were evaluated in a phase 1 study and in a population pharmacokinetic analysis for the ado-trastuzumab emtansine conjugate using pooled data from 5 trials in patients with breast cancer. Select the arrows to review details regarding the pharmacokinetic properties of KADCYLA.

Distribution

Maximum concentrations of ADC and DM1 were observed close to the end of infusion. In EMILIA, mean ADC and DM1 cycle 1 C_max following KADCYLA administration was 83.4 (16.5) μg/mL and 4.61 (1.61) ng/mL, respectively. In KATHERINE, mean ADC and DM1 cycle 1 C_max following KADCYLA administration was 72.6 (24.3) μg/mL and 4.71 (2.25) ng/mL, respectively. Based on the population pharmacokinetic analysis, the central volume of distribution of ADC was 3.13 L.

Metabolism

In vitro studies indicated that DM1, the small molecule component of KADCYLA, undergoes metabolism by CYP3A4/5. DM1 did not inhibit or induce major CYP450 enzymes in vitro. In human plasma, ado-trastuzumab emtansine catabolites were detected at low levels.

Elimination

Based on population pharmacokinetic analysis, following intravenous infusion of KADCYLA, the clearance of the ADC was 0.68 L/day and the elimination half-life was approximately 4 days. No accumulation of KADCYLA was observed after repeated dosing of intravenous infusion every 3 weeks.

Effect of Renal Impairment

Based on population pharmacokinetic analysis in 668 patients, including patients with moderate and mild renal impairment, the pharmacokinetics of the ADC is not affected by mild or moderate renal impairment compared to normal renal function.

Effect of Hepatic Impairment

The pharmacokinetics of ado-trastuzumab emtansine were evaluated in patients with normal, mild, and moderate hepatic impairment. Plasma concentrations of DM1 and its catabolites were low and comparable between patients with and without hepatic impairment. Systemic exposures of ado-trastuzumab emtansine at cycle 1 in patients with mild and moderate hepatic impairment were approximately 38% and 67% lower than that of patients with normal hepatic function. Ado-trastuzumab emtansine exposure at Cycle 3 after repeated dosing in patients with mild or moderate hepatic dysfunction was within the range observed in patients with normal hepatic function.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis studies have not been conducted with ado-trastuzumab emtansine. DM1 was mutagenic in an in vivo single-dose rate bone marrow assay at exposures that were comparable to mean maximum concentrations of DM1 measured in humans given KADCYLA. Based on results from animal toxicity studies, KADCYLA may impair fertility in humans.

Progress Check

Which of the following statements regarding KADCYLA is false?

A. KADCYLA is a HER2-targeted antibody.

B. KADCYLA is an ADC.

C. DM1 and trastuzumab are linked in KADCYLA.

D. The full generic name of KADCYLA is ado-trastuzumab emtansine.

Trastuzumab is believed to work through which of the following mechanisms?

A. Inducing ADCC

B. Suppressing HER2 signaling

C. Blocking HER2 shedding

D. All of the above

Complete the diagram below by choosing the correct labels from the answer bank.

Answer Bank

DM1 cytotoxicity

DM1 release

Trastuzumab HER2+
antitumor activities

Trastuzumab
HER2 binding

Internalization