Relationship Between Plasma Concentrations Of 3'-Deoxy-3'-Fluorothymidine (Alovudine) And Antiretroviral Activity In Two Concentration-Controlled Trials

Flexner, Charles; Horst, Charles van der; Jacobson, Mark A.; Powderly, William G.; Duncanson, Frederick P.; Ganes, Derek; Barditch‐Crovo, Patricia; Petty, Brent G.; Baron, Penny; Armstrong, Donald; Bricmont, Patricia; Kuye, Olatunde; Yacobi, Avraham; Desjardins, Robert E.; Polsky, Bruce

doi:10.1093/infdis/170.6.1394

Cited by 74 publications

(44 citation statements)

References 26 publications

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“…The development of FLT, the parental drug of fosalvudine tidoxil, was stopped despite promising clinical efficacy (7,9) after adverse events had been observed. The toxicity and severe adverse events in earlier studies affected mainly the bone marrow and the liver (1, 7).…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial DNA Depletion in Rat Liver Induced by Fosalvudine Tidoxil, a Novel Nucleoside Reverse Transcriptase Inhibitor Prodrug

Venhoff

Lebrecht

Reuss

et al. 2009

Antimicrob Agents Chemother

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Fosalvudine tidoxil is a prodrug derived from the nucleoside reverse transcriptase inhibitor 3-deoxy-3-fluorothymidine (FLT; alovudine). FLT effectively inhibits resistant human immunodeficiency virus type 1, but its clinical development was stopped due to bone marrow and liver toxicity. In this study, we examined the long-term in vivo effects of fosalvudine tidoxil on the mitochondrial DNA (mtDNA) contents in rats. SpragueDawley rats received fosalvudine tidoxil (15, 40, or 100 mg/kg of body weight/day) by oral gavage during a period of 8 weeks. Didanosine (100 mg/kg/day) was used as a positive control for mitochondrial toxicity. mtDNA levels in liver, gastrocnemius muscle, sciatic nerve, and inguinal fat pad tissues were quantified by real-time PCR. In hepatic mitochondria, fosalvudine tidoxil induced significant mtDNA depletion. At doses of 15, 40, and 100 mg/kg, the mean hepatic mtDNA values were 62, 64, and 47% of control values, respectively. Rats exposed to 100 mg/kg of fosalvudine tidoxil, unlike all other groups, had slightly elevated levels of glutamate pyruvate transaminase in sera. Didanosine induced a loss of mtDNA (to 48% of the control level) similar to that induced by fosalvudine tidoxil. mtDNA levels in skeletal, neural, and adipose tissues in the negative control and treatment groups were similar. Our results suggest that fosalvudine tidoxil induces mitochondrial hepatotoxicity and that this effect warrants scrutiny in clinical trials.Fosalvudine tidoxil (Heidelberg Pharma, Germany) is a prodrug derived from 3-deoxy-3-fluorothymidine (FLT; alovudine) by covalent linkage to a carrier lipid moiety. Fosalvudine tidoxil is currently in clinical development as a new deoxythymidine analogue nucleoside reverse transcriptase inhibitor (NRTI) for the treatment of human immunodeficiency virus (HIV) infection. Fosalvudine tidoxil was given once daily to 43 HIV-infected patients without prior antiretroviral therapy in a 2-week clinical dose-finding phase II trial (3). Oral doses between 5 and 40 mg of fosalvudine tidoxil induced dose-dependent suppression of the HIV load and were well tolerated (3).NRTIs are, however, associated with long-term toxic effects which are related to the abilities of some active metabolites to interfere with the replication of mitochondrial DNA (mtDNA) (8,19). The mitochondrial toxicity may affect many organs, but the liver, peripheral nerves, subcutaneous fat, and skeletal muscle appear to be the most frequent targets (4, 14).Currently, only a little information about the long-term mitochondrial toxicity of fosalvudine tidoxil in vivo is available. Data from clinical trials have, however, suggested that FLT, the parent compound of fosalvudine tidoxil, may induce side effects compatible with a mitochondrial mechanism, such as anemia (1) and hepatic failure and hyperlactatemia (7). Data from in vitro studies corroborate the severe toxicity of FLT observed in vivo. FLT has significant effects on the viability of and mtDNA contents in cultured human HepG2 cells (5). Consistent with...

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Section: Discussionmentioning

confidence: 99%

“…Data from clinical trials have, however, suggested that FLT, the parent compound of fosalvudine tidoxil, may induce side effects compatible with a mitochondrial mechanism, such as anemia (1) and hepatic failure and hyperlactatemia (7). Data from in vitro studies corroborate the severe toxicity of FLT observed in vivo.…”

mentioning

confidence: 92%

Mitochondrial DNA Depletion in Rat Liver Induced by Fosalvudine Tidoxil, a Novel Nucleoside Reverse Transcriptase Inhibitor Prodrug

Venhoff

Lebrecht

Reuss

et al. 2009

Antimicrob Agents Chemother

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“…The nucleoside analogue alovudine, close in structure to AZT, has reached phase II clinical trials. Alovudine is very potent against HIV variants highly resistant to AZT [234,235]. In vitro, alovudine demonstrated good activity against NRTI multi-resistant HIV strains [236].…”

Section: Nucleoside Rt Inhibitors In Clinical Developmentmentioning

confidence: 99%

Nucleoside and nucleotide inhibitors of HIV-1 replication

Vivet-Boudou

Didierjean

Isel

et al. 2006

Cell. Mol. Life Sci.

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HIV-1 reverse transcriptase (RT) is one of the main targets for antiviral therapy. Two classes of RT inhibitors can be distinguished: those that are nucleoside or nucleotide analogues (sharing the common NRTIs abbreviation) and those that are not. This review focuses on the NRTIs, which are highly efficient in slowing down viral replication and are used in combination regimens. Unfortunately, the current inhibitors do not completely suppress viral replication and due to the high capacity of adaptation of HIV, allow the selection of drug-resistant viruses. Resistance mechanisms to NRTIs have been extensively investigated and can be divided into two types: improved discrimination of a nucleotide analogue relative to the natural substrate or increased phosphorolytic cleavage of an analogue-blocked primer. This knowledge is important both for the development of new drugs designed to target resistant strains and for the development of new antiviral strategies. The NRTIs currently in clinical trials and new developments in this area are also reviewed.

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“…However, FLT-treated rats experienced mitochondrial DNA depletion (Venhoff et al, 2009). Patient toxicity, including two deaths that resulted from hepatic failure, halted clinical trials in phase II (Flexner et al, 1994). Interest in FLT was renewed somewhat with reports that FLT is effective at lower, less toxic doses (De Clercq, 2010).…”

Section: Introductionmentioning

confidence: 99%

Balancing Antiviral Potency and Host Toxicity: Identifying a Nucleotide Inhibitor with an Optimal Kinetic Phenotype for HIV-1 Reverse Transcriptase

et al. 2012

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Two novel thymidine analogs, 3Ј-fluoro-3Ј-deoxythymidine (FLT) and 2Ј,3Ј-didehydro-3Ј-deoxy-4Ј-ethynylthymidine (Ed4T), have been investigated as nucleoside reverse transcriptase inhibitors (NRTIs) for treatment of HIV infection. Ed4T seems very promising in phase II clinical trials, whereas toxicity halted FLT development during this phase. To understand these different molecular mechanisms of toxicity, pre-steadystate kinetic studies were used to examine the interactions of FLT and Ed4T with wild-type (WT) human mitochondrial DNA polymerase ␥ (pol ␥), which is often associated with NRTI toxicity, as well as the viral target protein, WT HIV-1 reverse transcriptase (RT). We report that Ed4T-triphosphate (TP) is the first analog to be preferred over native nucleotides by RT but to experience negligible incorporation by WT pol ␥, with an ideal balance between high antiretroviral efficacy and minimal host toxicity. WT pol ␥ could discriminate Ed4T-TP from dTTP 12,000-fold better than RT, with only an 8.3-fold difference in discrimination being seen for FLT-TP. A structurally related NRTI, 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxythymidine, is the only other analog favored by RT over native nucleotides, but it exhibits only a 13-fold difference (compared with 12,000-fold for Ed4T) in discrimination between the two enzymes. We propose that the 4Ј-ethynyl group of Ed4T serves as an enzyme selectivity moiety, critical for discernment between RT and WT pol ␥. We also show that the pol ␥ mutation R964C, which predisposes patients to mitochondrial toxicity when receiving 2Ј,3Ј-didehydro-2Ј,3Ј-dideoxythymidine to treat HIV, produced some loss of discrimination for FLT-TP and Ed4T-TP. These molecular mechanisms of analog incorporation, which are critical for understanding pol ␥-related toxicity, shed light on the unique toxicity profiles observed during clinical trials.

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Relationship Between Plasma Concentrations Of 3'-Deoxy-3'-Fluorothymidine (Alovudine) And Antiretroviral Activity In Two Concentration-Controlled Trials

Cited by 74 publications

References 26 publications

Mitochondrial DNA Depletion in Rat Liver Induced by Fosalvudine Tidoxil, a Novel Nucleoside Reverse Transcriptase Inhibitor Prodrug

Mitochondrial DNA Depletion in Rat Liver Induced by Fosalvudine Tidoxil, a Novel Nucleoside Reverse Transcriptase Inhibitor Prodrug

Nucleoside and nucleotide inhibitors of HIV-1 replication

Balancing Antiviral Potency and Host Toxicity: Identifying a Nucleotide Inhibitor with an Optimal Kinetic Phenotype for HIV-1 Reverse Transcriptase

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