Duvelisib

Duvelisib Uses, Dosage, Side Effects, Food Interaction and all others data.

Duvelisib, also known as IPI-145 and INK-1197, is a small-molecule inhibitor of phosphoinositide-3 kinases that was designed initially to prove that simultaneous inhibition of the isoforms delta and gamma can produce a broad adaptative and innate immune cell inhibitory activity. All the work around duvelisib showed that this agent is a potent inhibitor of both forms. Duvelisib was developed by Verastem, Inc and FDA approved on September 24, 2018.

Preclinical data showed that duvelisib presents cytotoxic actions at micromolar doses and antagonizes the activation of downstream signaling even in the presence of the mutation BTK C481S, which allows for the treatment of patients resistant to ibrutinib.

In clinical trials, duvelisib was compared to ofatumumab in patients with chronic lymphocytic leukemia or small lymphocytic leukemia. This trials reported a median progression-free survival of 16.4 months and an overall response rate of 78% which were almost 2-fold what it was reported for ofatumumab.

Duvelisib
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Duvelisib
Availability	Prescription only
Generic	Duvelisib
Duvelisib Other Names	Duvelisib
Related Drugs	Venclexta, rituximab, Rituxan, cyclophosphamide, Imbruvica, Calquence
Weight	15mg, 25mg
Type	Oral capsule
Formula	C₂₂H₁₇ClN₆O
Weight	Average: 416.87 Monoisotopic: 416.1152369
Protein binding	The protein binding of duvelisib is greater than 98% and this level is not dependent on serum concentration. It is reported that duvelisib is a substrate of P-gp and BCRP.
Groups	Approved, Investigational
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Duvelisib is an inhibitor of phosphatidylinositol 3-kinase delta and gamma used to treat relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

Duvelisib is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies.

The CLL is a cancer of the blood stem cells which are the blood cells that can develop into different types of cells. In leukemia, there is an overproduction of cells that are abnormal and do not mature into blood cells and thus, they just crowd out normal cells and impair their normal function. In lymphocyte leukemia, the abnormal cell growth is observed in the lymphoid cells which are the type of blood cells that mature into lymphocytes. The CLL is the type of lymphocytic leukemia that develops slowly over months or years. The SLL is a very similar disease to the CLL and these terms are usually referred interchangeably. The only difference between these two diseases is that in CLL the cells are found mostly in the blood and bone marrow while in SLL, the cells are mainly found in the lymph nodes.

As well, duvelisib obtained an accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies. This approval is still under the status of continued approval and it is restrained to confirmatory trials.

The follicular lymphoma is a B-cell lymphoma that clusters in the lymph nodes or other tissues.

Duvelisib is also used to associated treatment for these conditions: Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL), Relapsed or Refractory Follicular Lymphoma, Refractory, relapsed small lymphocytic lymphoma

How Duvelisib works

Duvelisib acts as a strong reversible inhibitor of the isoform gamma and delta of the phosphoinositide3-kinase (PI3K). PI3K plays a very important role in innate and adaptative immunity and the inhibition of the form delta and gamma has been very important for the suppression of immunity.

The activity of PI3K gamma and delta is restricted to hematopoietic cells and it is necessary for normal B cell development. In lymphomas, the activation of PI3K is enlarged to promote unlimited growth and survival. Hence, inhibition of PI3K can provide an inhibition of the signaling from BCR, inhibition of a cytokine signaling from the microenvironment and enhancement of anti-tumor immunity. The specific mechanism of this PI3K inhibitors are further described as follows:

-BCR activates signaling pathways after antigen engagement and it is also critical for the physiologic life of the lymphocytes and neoplastic lymphomas. In CLL, BCR reacts to auto- and exo-antigens to promote clonal expansion. This sustained presence of BCR activates delta PI3K producing a pro-survival pathway of the neoplastic cells which already present a higher activity of PI3K. Thus, the blockade of PI3K will limit the activity of BCR and the driven physiology of the lymphoma.

-The inhibition of PI3K can also inhibit paracrine and autocrine pro-survival signals mediated by adhesion molecules, chemokines and soluble factors. This activity is attained due to the fact that several downstream signals convey on PI3K.

-It has been reported that inactivation of PI3K produces a significant resistance to tumorigenesis. This data suggests that inhibition of PI3K can facilitate recognition and elimination of tumor cells.

In summary, duvelisib inhibits the isoform delta of PI3K which is necessary for cell proliferation and survival and the isoform gamma which is critical for cytokine signaling and the pro-inflammatory response.

Toxicity

Carcinogenic studies have not been performed and duvelisib did not produce any genetic damage in vitro or in vivo. In the case of fertility studies, there was found some histological abnormalities in male and female rats such as seminiferous epithelial atrophy, decreased testes weight, soft testes, small epididymis, oligo/aspermia, decreased ovary weight, and uterine atrophy.

Food Interaction

Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of duvelisib.
Take with or without food.

Duvelisib Disease Interaction

Major: colitis, infectionsModerate: hepatotoxicity, neutropenia

Volume of Distribution

The volume of distribution of duvelisib ranges from 26 to 102 L.

Elimination Route

Duvelisib is rapidly absorbed and its peak plasma concentration is reached 1-2 hours after initial administration with a bioavailability of 42% and with a minimal accumulation whose rate ranges between 1.5 and 2.9. The maximal plasma concentration is reported to range in between 471 to 3294 ng/ml with a systemic exposure ranging from 2001 to 19059 ng.h/ml. Changes in the administered dose produce correspondent changes in all absorption parameters indicating a dose-response profile.

Half Life

The reported half-life of duvelisib is in the range of 5.2 to 10.9 hours.

Clearance

Duvelisib clearance rate is reported to be in the range of 3.6 to 11.2 L/h.

Elimination Route

Duvelisib is eliminated after 3.5-9.5 hours when administered as a single dose and after 6.5-11.7 hours when given in multiple doses. From the administered dose, 79% os excreted in feces and 14% in urine. About 10% of the total administered dose is secreted unchanged.