Copanlisib

Uses

Copanlisib is a medication used to treat relapsed follicular lymphoma who have attempted at least two other treatments.

Indicated for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.

Copanlisib is also used to associated treatment for these conditions: Relapsed Follicular Lymphoma

How Copanlisib works

Follicular lymphoma is a B-cell lymphoma that is one of the most common type of non-Hodgkin lymphoma (NHL). It involves unregulated growth and proliferation of lymphocytes that eventually may travel to other organs including the lymph nodes, spleen, and the bone marrow, to form tumors. The phosphatidylinositol 3-kinase (PI3K)-mediated pathway is involved in promoting cell survival proliferation and differentiation however abberant activation of this pathway may lead to tumorigenesis . Copanlisib mediates an inhibitory action on p110α and p110δ isoforms of phosphatidylinositol-3-kinase (PI3K) expressed in malignant B cells. It induces tumor cell death via apoptosis and inhibits the proliferation of primary malignant B cell lines . Copanlisib inhibits several key cell-signaling pathways, including B-cell receptor (BCR) signaling, CXCR12 mediated chemotaxis of malignant B cells, and NFκB signaling in lymphoma cell lines .

Toxicity

Copanlisib is not shown to exhibit mutagenetic actions in vitro or in vivo. In the repeat dose toxicity studies, copanlisib led to adverse events in the reproductive systems of male and female rats. The effects on male rats included adverse events on the testes (germinal epithelial degeneration, decreased weight, and/or tubular atrophy), epididymides (spermatic debris, decreased weight, and/or oligospermia/aspermia), and prostate (reduced secretion and/or decreased weight). Copanlisib induced adverse events on ovaries (hemorrhage, hemorrhagic cysts, and decreased weight), uterus (atrophy, decreased weight), vagina (mononuclear infiltration), and a dose-related reduction in the numbers of female rats in estrus .

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of copanlisib.
• Avoid St. John's Wort. This herb induces the CYP3A metabolism of copanlisib and may reduce its serum concentration.

[Moderate] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of copanlisib.

The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of copanlisib by certain compounds present in grapefruit.

When a single 60 mg intravenous dose of copanlisib was administered to cancer patients in combination with the potent CYP450 3A4 and P-gp inhibitor, itraconazole (200 mg once daily for 10 days), mean copanlisib peak plasma concentration (Cmax) did not change but systemic exposure (AUC) increased by 53%.

The interaction has not been studied with grapefruit juice.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to copanlisib may increase the risk of adverse effects such as nausea, vomiting, diarrhea, stomatitis, hyperglycemia, hypertension, noninfectious pneumonitis, cutaneous reactions (e.g., exfoliative dermatitis, maculopapular rash), anemia, neutropenia, thrombocytopenia, and infections.

MANAGEMENT: Patients should avoid the consumption of grapefruit and grapefruit juice during treatment with copanlisib.

Copanlisib Hypertension interaction

[Moderate] Hypertension has occurred in patients treated with copanlisib.

Before starting copanlisib patients should achieve optimal blood pressure control and dose should be reduced, or therapy temporarily discontinued depending on the severity and persistence of hypertension.

It is recommended to monitor blood pressure before and after the infusion with copanlisib.

Copanlisib Drug Interaction

Unknown: tretinoin topical, multivitamin with minerals, ocular lubricant ophthalmic, omega-3 polyunsaturated fatty acids, acetaminophen, albuterol, cholecalciferol

Copanlisib Disease Interaction

Moderate: hepatic impairment, hyperglycemia, hypertension, infections, renal impairment

Volume of Distribution

The in vitro mean blood-to-plasma ratio is 1.7 (range: 1.5 to 2.1). The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L.

Elimination Route

The plasma levels of copanlisib increases in a dose-proportional manner with linear pharmacokinetic properties and no time dependency. Following a steady state exposure at 0.8 mg/kg, the mean peak plasma concentration (Cmax) of copanlisib is 463 ng/mL with the range of 105 to 1670 ng/mL .

Half Life

The geometric mean terminal elimination half-life of copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours .

Clearance

The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr .

Elimination Route

Copanlisib is excreted approximately 50% as unchanged compound and 50% as metabolites in humans. After a single intravenously-administered dose of 12mg radiolableled drug, approximately 64% of the dose is excreted in feces and 22% is excreted in urine within 20 to 34 days. Unchanged copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation metabolism accounted for 41% of the administered dose .

Innovators Monograph

You find simplified version here Copanlisib