Association of Thymidylate Synthase Gene Polymorphisms with Stavudine Triphosphate Intracellular Levels and Lipodystrophy

Domingo, Peré; Cabeza, M. Carmen; Pruvost, Alain; Salazar, Juliana; Gutierrez, María del Mar; Mateo, María; Fontanet, Angels; Fernández, Irene; Domingo, Joan Carles; Villarroya, Francesc; Vidal, Francesc; Baiget, Montserrat

doi:10.1128/aac.01589-10

Cited by 11 publications

(16 citation statements)

References 40 publications

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“…In a later study, Domingo et al showed that a thymidylate synthetase genetic polymorphism was associated with d4T-TP intracellular levels [32]. Among the low-expressing thymidylate synthetase genotypes, those that were associated with higher propensity for toxicity had higher intracellular d4T-TP levels, similar to those found in adults taking 40 mg b.i.d.…”

Section: Discussionmentioning

confidence: 82%

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Effect of reducing the paediatric stavudine dose by half: A physiologically-based pharmacokinetic model

Malmberg

Matsushima

et al. 2015

International Journal of Antimicrobial Agents

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Owing to significant dose-related toxicity, the adult stavudine dose was reduced in 2007. The paediatric dose, however, has not been reduced. Although the intended paediatric dose is 1 mg/kg twice daily (b.i.d.), the current weight-band dosing approach results in a mean actual dose of 1.23 ± 0.47 mg/kg. Both efficacy and mitochondrial toxicity depend on the concentration of the intracellular metabolite stavudine triphosphate (d4T-TP). We simulated the effect of reducing the paediatric dose to 0.5 mg/kg. A physiologically-based pharmacokinetic model consisting of 13 tissue compartments plus a full ADAM model was used to describe the elimination of stavudine. The volume of distribution at steady-state and apparent oral clearance were simulated and the resulting AUC profile was compared with literature data in adult and paediatric populations. A biochemical reaction model was utilised to simulate intracellular d4T-TP levels for both the standard and proposed reduced paediatric doses. Simulated and observed exposure after oral dosing showed adequate agreement. Mean steady-state d4T-TP for 1.23 mg/kg b.i.d. was 27.9 (90% CI 27.0–28.9) fmol/106 cells, 25% higher than that achieved by the 40 mg adult dose. The 0.5 mg/kg dose resulted in d4T-TP of 13.2 (12.7–13.7) fmol/106 cells, slightly higher than the adult dose of 20 mg b.i.d. [11.5 (11.2–11.9) fmol/106 cells], which has excellent antiviral efficacy and substantially less toxicity. Current paediatric dosing may result in even higher d4T-TP than the original 40 mg adult dose. Halving the paediatric dose would significantly reduce the risk of mitochondrial toxicity without compromising antiviral efficacy.

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Section: Discussionmentioning

confidence: 82%

“…Among the low-expressing thymidylate synthetase genotypes, those that were associated with higher propensity for toxicity had higher intracellular d4T-TP levels, similar to those found in adults taking 40 mg b.i.d. [32]. The same polymorphism has also been associated with peripheral neuropathy in patients on stavudine-based therapy [33].…”

Section: Discussionmentioning

confidence: 99%

Effect of reducing the paediatric stavudine dose by half: A physiologically-based pharmacokinetic model

Malmberg

Matsushima

et al. 2015

International Journal of Antimicrobial Agents

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“…Recently, the association of HLA-B*40∶01 with HALS has been reported in a South East Asian population treated with d4T [6]. We have showed the association of thymidylate synthase (TS) polymorphisms with HALS in a limited sample of patients [7], [8].…”

Section: Introductionmentioning

confidence: 82%

Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients

et al. 2013

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PurposeTo assess in a cohort of Caucasian patients exposed to stavudine (d4T) the association of polymorphisms in pyrimidine pathway enzymes and HLA-B*40∶01 carriage with HIV/Highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome (HALS).MethodsThree-hundred and thirty-six patients, 187 with HALS and 149 without HALS, and 72 uninfected subjects were recruited. The diagnosis of HALS was performed following the criteria of the Lipodystrophy Severity Grading Scale. Polymorphisms in the thymidylate synthase (TS) and methylene-tetrahydrofolate reductase (MTHFR) genes were determined by direct sequencing, HLA-B genotyping by PCR-SSOr Luminex Technology, and intracellular levels of stavudine triphosphate (d4T-TP) by a LC-MS/MS assay method.ResultsHALS was associated with the presence of a low expression TS genotype polymorphism (64.7% vs. 42.9%, OR = 2.43; 95%CI: 1.53–3.88, P<0.0001). MTHFR gene polymorphisms and HLA-B*40∶01 carriage were not associated with HALS or d4T-TP intracellular levels. Low and high expression TS polymorphisms had different d4T-TP intracellular levels (25.60 vs. 13.60 fmol/106 cells, P<0.0001). Independent factors associated with HALS were(OR [95%CI]: (a) Combined TS and MTHFR genotypes (p = 0.006, reference category (ref.): ‘A+A’; OR for ‘A+B’ vs. ref.: 1.39 [0.69–2.80]; OR for ‘B+A’ vs. ref.: 2.16 [1.22–3.83]; OR for ‘B+B’ vs. ref.: 3.13, 95%CI: 1.54–6.35), (b) maximum viral load ≥5 log10 (OR: 2.55, 95%CI: 1.56–4.14, P = 0.001), (c) use of EFV (1.10 [1.00–1.21], P = 0.008, per year of use).ConclusionHALS is associated with combined low-expression TS and MTHFR associated with high activity polymorphisms but not with HLA-B*40∶01 carriage in Caucasian patients with long-term exposure to stavudine.

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“…Low expression TS genotype was associated with the development of HIV-1/cART-associated lipodystrophy syndrome (OR = 14.0; 95%CI: 2.09 --108, p = 0.0032). Our preliminary data show that polymorphisms in the thymidylate synthase gene are strongly associated with d4T-TP intracellular levels and with the development of lipodystrophy [95].…”

Section: Polymorphism In Other Genesmentioning

confidence: 98%

“…Therefore, modifications at intracellular levels of d4T-TP may change the toxicity profile of d4T. We determined d4T-TP intracellular levels in peripheral blood mononuclear cells using a prominence liquid chromatograph connected to a triple-quadruple mass spectrometer [95]. Also, polymorphisms in the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), reduced folate carrier 1 (RFC1, SLC19A1) and Cyclin D1 (CCND1) genes were determined by direct sequence analysis.…”

Section: Polymorphism In Other Genesmentioning

confidence: 99%

Pharmacogenetics of the lipodystrophy syndrome associated with HIV infection and combination antiretroviral therapy

Vidal

Domingo

Viladés

et al. 2011

Expert Opinion on Drug Metabolism & Toxicology

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Association of Thymidylate Synthase Gene Polymorphisms with Stavudine Triphosphate Intracellular Levels and Lipodystrophy

Cited by 11 publications

References 40 publications

Effect of reducing the paediatric stavudine dose by half: A physiologically-based pharmacokinetic model

Effect of reducing the paediatric stavudine dose by half: A physiologically-based pharmacokinetic model

Polymorphisms of Pyrimidine Pathway Enzymes Encoding Genes and HLA-B*40∶01 Carriage in Stavudine-Associated Lipodystrophy in HIV-Infected Patients

Pharmacogenetics of the lipodystrophy syndrome associated with HIV infection and combination antiretroviral therapy

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