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

Division Of Basic Sciences - Nci

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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. We have recently completed evaluating the safety and drug-drug interaction between rivaroxaban, cobicistat, and cobicistat with darunavir in healthy volunteers with the results of this study forthcoming. We also evaluated the drug-drug interaction of tenofovir alafenamide (TAF) and a rifapentine-based tuberculosis regimen in healthy volunteers. In particular, the intracellular concentration of the active metabolite, tenofovir-diphosphate, at the site of action, peripheral blood mononuclear cells (PBMC), was further investigated. Kaposi Sarcoma (KS) is a multicentric angio-proliferative 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 µM. 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. Bioanalytical measurements of abemaciclib will be conducted on a validated ultra HPLC-MS/MS assay and the measured exposure for abemaciclib will be used to correlate to pharmacodynamic endpoints, clinical response, toxicity, and pharmacogenetic analyses. Relevant to abemaciclib are the genes encoding the drug metabolizing enzyme CYP3A4 and the transporters ABCB1 and ABCB2. KSHV-associated inflammatory cytokine syndrome (KICS) and KSHV-multicentric Castleman disease (MCD) occur in people living with HIV. These diseases cause severe inflammation that can be fatal if not treated. Pacritinib, is a JAK2/tyrosine kinase 3 inhibitor with negligible activity against JAK1 that also suppresses the interleukin-1 (IL-1) directed inflammatory pathway via inhibition of interleukin 1 receptor associated kinase. Pacritinib blocks signaling through the interleukin 6 receptor (IL-6R). Given the overlapping cytokine profile between KSHV-MCD and KICS and elevated levels of IL6, pacritinib is hypothesized to have therapeutic effect in this disorder that is associated with excess inflammation. We will be involved with characterizing the PK and PG of pacritinib in this phase II clinical trial. Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma caused by KSHV with clinicopathologic and molecular profiles distinct from other HIV-related lymphomas. KSHV-MCD is a rare lymphoproliferative disorder that develops predominantly in people with HIV with inflammatory symptoms associated with high levels of interleukin-6 (IL-6), KSHV-encoded viral IL-6 (vIL-6), and other cytokines. Daratumumab is a human monoclonal antibody that binds to a unique region on CD38 and induces killing of CD38-expressing cells via antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis. In this phase II study, we will evaluate the PK and PG of daratumumab in patients with PEL and KSHV-MCD.