Measurement of Intracellular Didanosine and Tenofovir Phosphorylated Metabolites and Possible Interaction of the Two Drugs in Human Immunodeficiency Virus-Infected Patients

Abstract

Recent work has demonstrated the existence of a systemic interaction between didanosine (ddI) and tenofovir disoproxyl fumarate (TDF) that leads to a significant increase in plasma ddI levels when coadministered with TDF (40 to 50% increase). These two drugs are, respectively, nucleoside and nucleotide analogues of adenosine and efficiently inhibit the human immunodeficiency virus (HIV) reverse transcriptase when transformed to their triphosphate moieties in the intracellular (IC) medium (ddA-TP and TFV-DP, respectively). Since ddI and TDF partly share the same IC metabolic pathway leading to the active triphosphates, we investigated a putative IC interaction. We used high-performance liquid chromatography-tandem mass spectrometry techniques to determine ddA-TP and TFV-DP IC levels in HIV-infected patients cotreated with both drugs, in comparison with patients treated with just one of the two drugs. These measurements revealed no significant differences in IC levels of the corresponding triphosphates when ddI (250 mg, once a day [QD]) was coadministered with TDF (300 mg, QD) compared to ddI 400 mg (QD) administered without TDF, thus supporting the dose adaptation proposed for this combination. However, we observed that both ddA-TP and TFV-DP have very long IC half-lives, resulting in unusual IC pharmacokinetic profiles with no significant changes in triphosphate concentrations between two dosings. In the case of TFV-DP, this t 1/2 of elimination was roughly estimated to be 180 h (7.5 days). This characteristic is certainly interesting in terms of efficacy but could have some drawbacks in terms of virus resistance for patients discontinuing these drugs.Nucleoside reverse transcriptase inhibitors (NRTIs) were the first antiretroviral class shown to be effective against human immunodeficiency virus (HIV) infection and still play a critical role as major components of highly active antiretroviral therapy. The first generation of NRTIs comprised 2Ј,3Ј-dideoxynucleosides which have to undergo three phosphorylation reactions within cells and work both as competitive inhibitors and as chain terminators with regards to HIV reverse transcriptase.Closely related drugs, i.e., acyclic phosphonate analogues of nucleotides (NtRTIs), have recently been approved for clinical applications and are now given as part of combination antiretroviral regimens. This new strategy consists of directly providing the cell with the monophosphate analogue, thus bypassing the first phosphorylation step, which proved to be rate limiting for many NRTIs. The first approved drug of this category is tenofovir disoproxyl fumarate (TDF), which provides high intracellular (IC) levels of tenofovir diphosphate (TFV-DP, equivalent to NRTI triphosphate) with very low mitochondrial toxicity (7).However, the issue of drug-drug interactions between NRTIs and also between NRTIs and NtRTIs is of major concern and should be addressed with all the analytical and chemical tools available. NRTIs and NtRTIs might interact not only at the systemic level (absorption, ...

AIDS Vaccines and Preexposure Prophylaxis: Is Synergy Possible?

“…[16][17][18][19][20][21][22] Furthermore, in some experiments, animals that became infected despite receiving TDF as PrEP or PEP showed delayed onset of viremia and delayed seroconversion, 18,20,23 demonstrating that even in the case of incomplete protection against infection, PrEP or PEP may lead to attenuated acute infection (perhaps by allowing the immune system to gain some control of the virus). The demonstrated efficacy of TDF in the treatment of HIV infection, the lack of reported serious safety problems associated with its use, 24 its long halflife, [25][26][27][28] and its relatively high threshold to drug resistance 29 make this antiretroviral agent an attractive candidate for systemic or topical prophylactic use. Tenofovir and related drugs have high concentrations in genital tissues, [30][31][32] so repeated exposure with locally aborted HIV infection is theoretically possible and, if it occurs, may lead to the development of HIVspecific cellular immune responses.…”

Double Oral Administration of Emtricitabine/Tenofovir Prior to Virus Exposure Protects against Highly Pathogenic Simian/Human Immunodeficiency Virus Infection in Macaques

“…Thus, we could not conclude that the single administration of FTC/TDF 2 weeks before virus challenge had no preventive effect. The median intracellular half-life of TDF was estimated to be approximately 150 to 180 h, and TDF was still detectable in some patients 14 and 28 days after the administration of the last dose (28,29). The long half-life of TDF might account for the results seen in group 2.…”

The Future of HIV Prevention: Prospects for an Effective Anti-HIV Microbicide

“…NRTIs require three phosphorylations, and this process is influenced by a number of cellular factors including cell type, cell cycle, and the activation and infection status of the cell in which they occur [45]. In particular, the initial phosphorylation by nucleoside kinases is believed to be rate-limiting [46]. In contrast, NtRTIs undergo only two phosphorylation steps and it is the initial rate-limiting step of the NRTI activation process that is not required [46].…”

“…In particular, the initial phosphorylation by nucleoside kinases is believed to be rate-limiting [46]. In contrast, NtRTIs undergo only two phosphorylation steps and it is the initial rate-limiting step of the NRTI activation process that is not required [46]. Consequently, NtRTIs are more suitable for development as microbicides than the NRTIs.…”