| Abstract |
Tenofovir disoproxil fumarate (Tdf, Viread) is a licensed, nucleotide reverse transcriptase inhibitor (RTI) commonly used in highly active antiretroviral therapy (HAART) in combination with a nucleoside RTI, low dose ritonavir and a protease inhibitor. Low dose ritonavir is used to boost HIV protease inhibitor drug levels, as it provides potent inhibition of the CYP450 3A4 enzymes that metabolize these agents. Tenofovir containing HAART has an excellent record of durable antiviral benefit, and an excellent patient safety profile with few short term adverse effects documented. However, recent tenofovir safety reports have confirmed pre-clinical concerns for 1) bone thinning, particularly in women; and 2) nephrotoxicity, Two independent lines of research--- clinical study data, and in vitro data-- offer significant warning that Tdf adverse effects may be linked to the concurrent use of tenofovir with ritonavir. We now propose a pharmacokinetic study in healthy volunteers that offers a mechanism of connecting in vitro evidence of ritonavir's inhibition of drug efflux pumps, with potential tenofovir intracellular accumulation and toxicity.
This proposal represents a new collaboration between established Tufts investigators working in HIV metabolics and pharmacologic issues-- Dr. Wanke and Dr. Greenblatt, with Dr. Hellinger, an experienced HIV clinical researcher, who has recently moved to the Tufts Division of Infectious Diseases. This study will establish a novel arena of study at Tufts, and will provide clinically relevant data that may generate additional study of: 1) the in vitro impact of ritonavir on the transport of tenofovir in target cell lines, 2) the mechanism of tenofovir associated renal and bone toxicities in HIV+ patients, and 3) interventional approaches designed to prevent these toxicities. Preliminary data will provide important grounding for future NIH submissions regarding toxicities of these important antiretroviral agents, and will provide an opportunity to establish the intracellular nucleotide quantitation by HPLC methodology. These will be important components of future case-control and prospective studies of tenofovir renal and bone toxicities in HIV+ patients.
Tenofovir is eliminated unchanged in urine via glomerular filtration and active tubular secretion, with terminal elimination half life of 17 hours and intracellular half life up to 50 hours. In vitro, ritonavir may influence other enzymes and transporter proteins critical to maintaining intracellular drug concentrations of nucleosides and nucleotides, including p-glycoprotein and multidrug resistance proteins (MRP1, MRP2, and MRP4). Although not of sufficient magnitude to mandate dose adjustment based on plasma concentrations, one study of tenofovir with coformulated lopinavir/ritonavir has shown a 33% increase in tenofovir plasma AUC, and a 51% increase in plasma Cmin. Tenofovir intracellular concentrations have not been studied in ritonavir interaction studies.
The study is designed as a randomized, cross-over, with single dose tenofovir plus ritonavir or placebo given to 12 HIV-negative, healthy volunteers who will have pharmacokinetic monitoring at the Tufts General Clinical Research Center. Concurrent evaluation of plasma, urine and intracellular tenofovir diphosphate concentrations will offer insight into the contribution of ritonavir to tenofovir associated toxicities. This study will provide clinical data relevant to understanding the impact of ritonavir's in vitro findings regarding transporter proteins involved in nucleotide cellular influx and efflux.
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