Indications
Idelalisib is approved for use in specific hematological malignancies. It is indicated for the management of chronic lymphocytic leukemia (CLL), relapsed follicular B-cell non-Hodgkin lymphoma (FL), and relapsed small lymphocytic lymphoma (SLL). In patients with relapsed CLL, idelalisib is prescribed as a second-line treatment in combination with rituximab, especially for those who are suitable for rituximab monotherapy due to other health conditions. For treating FL and SLL, idelalisib is recommended for patients who have undergone at least two prior systemic treatments.
Absorption
Idelalisib is administered orally, and its absorption kinetics reveal that the median time to reach maximum plasma concentration (Tmax) is approximately 1.5 hours. This rapid absorption underscores the importance of timing in therapeutic monitoring and scheduling doses for maximal efficacy.
Metabolism
The metabolism of idelalisib is primarily facilitated by aldehyde oxidase and the cytochrome P450 enzyme CYP3A, resulting in the conversion to its main metabolite, GS-563117. This metabolite, however, does not exhibit activity against the P110δ protein, indicating the specificity of metabolism pathways. Idelalisib is also metabolized to a lesser extent by the enzyme UGT1A4, contributing to its metabolic profile and elimination.
Mechanism of Action
Idelalisib acts as a targeted therapeutic agent by inhibiting P110δ, the delta isoform of the enzyme phosphatidylinositol-4,5-bisphosphate 3-kinase (PI-3K). PI-3Ks, a group of enzymes, are critical regulators in numerous cellular processes, including growth, proliferation, differentiation, motility, survival, and intracellular trafficking - pathways often implicated in cancer development. Uniquely, the P110δ isoform is predominantly found in leukocytes, where it plays a vital role in the function of various immune cells such as T cells, B cells, mast cells, and neutrophils. By selectively inhibiting this enzyme, idelalisib triggers apoptosis in malignant cells and impedes several key signaling pathways, notably those related to the B-cell receptor (BCR) and C-X-C chemokine receptors types 5 and 4. These pathways are crucial for the movement and localization of B-cells to the lymphatic system and bone marrow. In the context of lymphoma, idelalisib has demonstrated efficacy in reducing chemotaxis and adhesion, thereby diminishing cell viability and contributing to its therapeutic effect.
