Clinical Pharmacology 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. Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a lymphoproliferative disorder driven by cytokine excess, particularly human and viral interleukin 6. Tocilizumab, a humanized anti-IL-6 receptor (gp80) antibody, has demonstrated benefit in KSHV-negative MCD, although its utility in patients with KSHV-MCD is unknown. Tocilizumab was administered every two weeks (q2wk) at a dose of 8 mg/kg over a 1-hr infusion to patients with KSHV-MCD. Patients were randomized to either tocilizumab alone or with zidovudine and valganciclovir, agents that target KSHV replication. Eight patients with KSHV-MCD were given tocilizumab 8 mg/kg every two weeks and serum levels measured via ELISA. Using these serum concentrations, the PK data was modeled and compared with published literature and were found to be in good agreement. This suggests that tocilizumab PK is similar in this KSHV population as with other patient populations. Additionally, IL-6 is a regulator of CYP3A4, and in diseases where IL-6 levels are elevated, CYP3A4 function is reduced, leading often times to dose adjustments in concomitant drugs that are metabolized by CYP3A4. Upon treatment with the anti-IL-6 agent tocilizumab, CYP3A4 function can be restored to baseline activity and if doses of the concomitant drugs aren't lowered, then significant toxicity could be experienced. It was a later objective of this study to assess this phenomenon, but there was insufficient PK sampling of the concomitant CYP3A4 drugs to properly study this. In conclusion, tocilizumab is safe and has activity among patients with a diagnosis of KSHV-MCD and HIV. However, unlike treatment with rituximab, which can yield sustained responses, the PFS in this study was short, and tocilizumab did not alter KSHV-VL, IL-10, or IL-1beta levels. Incomplete responses may occur because tocilizumab does not block signaling by vIL-6, which binds directly to the gp130 subunit without requiring gp80. Nonetheless, tocilizumab may be useful in the management of KSHV-MCD as part of a multiagent regimen. In a separate study in patients with KSHV (16-C-0047), the pharmacokinetics of pomalidomide and liposomal doxorubicin were analyzed to assess any potential drug interactions in 34 male patients with KSHV. The CPP measured plasma concentrations of both drugs in all 34 patients and assessed their PK using noncompartmental methods. No clinically-relevant drug interactions were observed in these patients on the doses administered of pomalidomide and liposomal doxorubicin. Further, each agent demonstrated PK that was comparable with published single agent studies. We investigated the role of polypharmacy in Sub-Saharan Africa. The cancer burden in this region is predicted to increase by 85% by 2030, the largest increase worldwide. This region also has a large HIV positive population. Drug-drug interactions (DDIs) from concomitant use of multiple drugs increases the risk of drug toxicities, sub-optimal therapy, and drug resistance. With the increase in polypharmacy, involving antiretroviral (ARV) and anti-cancer drugs, there is a greater need for an appreciation of clinically relevant DDIs. Anti-cancer and ARV drugs studied in this review were from The World Health Organization's Model List of Essential Medicines 2017. We reviewed drug package inserts, www.drugbank.ca and www.UpToDate.com, to evaluate pharmacokinetic interactions with CYP450 and ABCB1. The DDIs between drugs, were assessed using the University Of Liverpool, UK HIV Drug Interactions Checker, and the LexiComp Drug Interaction tool of www.UpToDate.com. 70% of ARVs studied interact with CYP450, all involve CYP3A4, and 55% interact with ABCB1. 65% of anti-cancer drugs interact with CYP450, 44% of which do so via CYP3A4. 75% of anti-cancer drugs interact with ARV drugs, with 9 absolute contraindications to concomitant therapy. There exist a substantial number of DDIs between ARV and anti-cancer drugs, primarily mediated through CYP450 enzymes. Dolutegravir based regimens offer the safest DDI profile for concurrent use with anti-cancer drugs. However, there are substantial holes in our knowledge, and this study serves to highlight the need for additional research to better define these interactions and their effect on drug exposure, as attention to these DDIs is a relatively simple intervention that could lead to optimizing disease treatment. Abemaciclib in Kaposi Sarcoma (KS): 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 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.