Clinical Pharmacology and Drug-Drug Interactions in HIV-Associated Malignancy

Division Of Basic Sciences - Nci

Investigators

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Abstract

Our laboratory is interested in studying the pharmacokinetics (PK) of therapeutic agents in the absence and presence of concomitant HIV drugs to better understand if there are clinically meaningful changes in drug exposure of either the HIV or non-HIV therapeutic, such that dose adjustments would be warranted. We have previously evaluated the safety and drug-drug interactions between sorafenib and ritonavir, an HIV medication with strong CYP3A4 inhibitory activity. We also evaluated the PK of tocilizumab, a humanized anti-IL-6 receptor (gp80) antibody, in patients with Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease. In a separate study, the PK of pomalidomide and liposomal doxorubicin were analyzed to assess for any potential drug interactions in patients with KSHV. Furthermore, we have investigated the role of polypharmacy in Sub-Saharan African to understand drug-drug interactions between antiretroviral and anti-cancer drugs. Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor, caused by Kaposi sarcoma-associated herpesvirus, that most frequently involves the skin, but may also involve lymph nodes, lungs, bone and gastrointestinal tract. It is most common in people with HIV but may also occur in patients without a diagnosis of HIV. Patients with HIV associated KS have worse survival than HIV-infected patients without KS. As it is a relapsing and remitting condition, patients with KS often require prolonged courses of cytotoxic chemotherapy and improved approaches for refractory and recurrent KS are needed to decrease morbidity among patients with KS. Cell cycle dysregulation is one of the hallmarks of cancer and has been developed as a therapeutic target in patients with metastatic breast cancer. Cell cycle is controlled by several proteins, including cyclin D kinases (CDKs), cyclins and retinoblastoma (Rb)-E2F signaling pathway. Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1. KS is an endothelial tumor, and KSHV-infected endothelial cells serve as the best current model for KS as there are no good animal models for this disease. Abemaciclib was found to inhibit proliferation of KSHV-infected and uninfected human umbilical vein endothelial cells (HUVEC) at doses as low as 0.1 uM. The CPP will be involved in determining the PK of abemaciclib in a phase I/II study of patients with HIV-associated and HIV-negative KS. In addition, current antiretroviral therapy (ART) has greatly improved the prognosis for HIV-infected individuals. However, because ART is not curative, life-long therapy is required. This long-term therapy is associated with a variety of adverse effects, and resistance to available drugs is likely to limit future treatment options for many patients. New antiviral drugs, targeting novel steps in the HIV replication cycle, are therefore required for the long-term care of HIV-infected individuals. We have played a key role in the development of a new class of anti-HIV compounds known as maturation inhibitors (MIs). With our collaborators we are involved in the preclinical development of second-generation bevirimat and analogs that are active against the strains of HIV-1 that are insensitive to the parent compound. We have identified a series of compounds that are highly potent against a wide range of HIV-1 isolates across multiple subtypes.