High Levels of Zidovudine (AZT) and Its Intracellular Phosphate Metabolites in AZT- and AZT-Lamivudine-Treated Newborns of Human Immunodeficiency Virus-Infected Mothers

Durand-Gasselin, Lucie; Pruvost, Alain; Dehée, Axelle; Vaudre, G.; Tabone, Marie‐Dominique; Grassi, Jacques; Leverger, G; Garbarg‐Chenon, Antoine; Bénech, Henri; Dollfus, Catherine

doi:10.1128/aac.01130-07

Cited by 26 publications

(25 citation statements)

References 55 publications

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“…Indeed, high levels of AZT/AZT monophosphate (AZ-MP)/AZT-TP, and 3TC-TP were consistent with short-term hematological disturbance observed in clinics (7,11). If, as suggested by the literature (10), this overexposure was related to a more efficient phosphorylation due to a higher activation in the peripheral blood mononuclear cells (PBMCs) of the neonates than in adults, it could be the same for TFV-DP and could cause toxicity problems. It is important with this background to verify that neonatal intracellular TFV-DP concentrations in PBMCs are not too high following PMTCT exposure.…”

mentioning

confidence: 51%

“…Newborns are likely to be overexposed to intracellular phosphorylated nucleoside reverse transcriptase inhibitors (NRTIs), as was shown for lamivudine triphosphate (3TC-TP) and zidovudine triphosphate (AZT-TP) during the first 2 weeks of life (10). Indeed, high levels of AZT/AZT monophosphate (AZ-MP)/AZT-TP, and 3TC-TP were consistent with short-term hematological disturbance observed in clinics (7,11).…”

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confidence: 74%

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Plasma and Intracellular Tenofovir Pharmacokinetics in the Neonate (ANRS 12109 Trial, Step 2)

Hirt

Ekouévi

Pruvost

et al. 2011

Antimicrob Agents Chemother

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The objective of this study was to investigate for the first time tenofovir (TFV) pharmacokinetics in plasma and peripheral blood mononuclear cells (PBMCs) of the neonate. HIV-1-infected pregnant women received two tablets of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) at onset of labor and then one tablet daily for 7 days postpartum. A single dose of 13 mg/kg of body weight of TDF was administered to 36 neonates within 12 h of life after the HIV-1-infected mothers had been administered two tablets of TDF-emtricitabine at delivery. A total of 626 samples collected within the 2 days after the drug administration were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed by a population approach. In the neonate, the median TFV plasma area under the curve and minimal and maximal concentrations, respectively, were 3.73 mg/liter ⅐ h and 0.076 and 0.29 mg/liter. In PBMCs, TFV concentrations were detectable in all fetuses, whereas tenofovir diphosphate (TFV-DP) was quantifiable in only two fetuses, suggesting a lag in appearance of TFV-DP. The median TFV-DP neonatal concentration was 146 fmol/10 6 cells (interquartile range [IQR], 53 to 430 fmol/10 6 cells); two neonates had very high TFV-DP concentrations (1,530 and 2963 fmol/10 6 cells). The 13-mg/kg TDF dose given to neonates produced plasma TFV and intracellular active TFV-DP concentrations similar to those in adults. This dose should be given immediately after birth to reduce the delay before the active compound TFV-DP appears in cells.The combination tenofovir (TFV) disoproxil fumarate (TDF)-emtricitabine (FTC) has been considered during the perinatal period to prevent mother-to-child transmission (PMTCT) and/or to reduce viral resistance to nevirapine (NVP) (3, 8); its administration to pregnant women at the onset of labor followed by a single dose to the neonate was thus proposed. The TEmAA (Tenofovir/Emtricitabine in Africa and Asia) ANRS 12109 Trial study was an open, phase I/II trial built in two steps. In the first step, the TDF-FTC combination was administered to HIV-infected pregnant women, and the pharmacokinetics, safety, and toxicity were evaluated for mothers and their newborns (2). After estimation of the maternal and fetal FTC-tenofovir (TFV) pharmacokinetic profiles, the mother was proposed to renew the dose after 12 h if she had not delivered yet in order to maintain effective TFV fetal concentrations. Then, a 13-mg/kg of body weight TDF dose (at birth) was proposed for neonates to obtain similar exposure to that in adults (16). In the second step of the TEmAA study, the TDF-FTC combination was administered to HIV-infected pregnant women and to their newborns, allowing evaluation of these dose propositions based on the results obtained in the first step of the study. Tolerance and virological results have been reported elsewhere (24).TFV, like other nucleoside analogues, undergoes intracellular phosphorylation by various cellular kinases to an active diphosphate (TFV-DP), which competiti...

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confidence: 51%

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confidence: 74%

Plasma and Intracellular Tenofovir Pharmacokinetics in the Neonate (ANRS 12109 Trial, Step 2)

Hirt

Ekouévi

Pruvost

et al. 2011

Antimicrob Agents Chemother

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“…69 Another study also found higher ZDV phosphates (MP plus DP plus TP) among 5 women versus 16 men (1.4-fold; P < 0.01), and a third study found higher 3TC-TP in female compared with male infants despite similar plasma concentrations (1.8-fold; P = 0.04). 61,81 However, a separate study found lower ZDV-triphosphates in female compared with male adults although plasma concentrations were similar. 82 An in vitro study evaluated the effects of progesterone, estrogen, and testosterone on conversion of ZDV and 3TC to ZDV-TP and 3TC-TP in PBMCs and found no major effects, but some minor lowering on 3TC-TP for progesterone and testosterone (all differences were below 50% versus control).…”

Section: Clinical Pharmacokineticsmentioning

confidence: 98%

“…61,[69][70][71] The half-life of ZDV-TP is about 7 hours and that for 3TC-TP is about 22 hours. 69 These half-lives for the pharmacologically active moieties are several-fold longer than the parent drug in plasma, and form the pharmacokinetic rationale for the dosing frequencies used in patients today (twice daily for ZDV and once-or twice-daily for 3TC).…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

“…59 In utero and breast milk concentrations of 3TC elicit measurable concentrations in the feeding infant, which may be relevant for HIV prophylaxis during breastfeeding or the development of drug resistance should the infant become HIV-infected. 58,61 Like ZDV, there are few drug-drug interaction concerns with 3TC. It too has potential antagonistic phosphorylation issues with other deoxycytidine analogs such as with emtricitabine and the investigational agent, apricitabine.…”

Section: Clinical Pharmacokineticsmentioning

confidence: 99%

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Zidovudine and Lamivudine for HIV Infection

Anderson

Rower²

2010

Clinical Medicine Reviews in Therapeutics

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Zidovudine and lamivudine (ZDV and 3TC) are long-standing nucleoside analog-reverse transcriptase inhibitors (NRTIs) with extensive clinical experience in a wide spectrum of patients from in utero through childhood and adult ages. The safety profiles of both drugs are well-known and side effects for ZDV most commonly include nausea/vomiting, fatigue, anemia/neutopenia, and lipoatrophy; while 3TC is well-tolerated. ZDV-3TC is currently a viable alternative NRTI backbone for initial three-drug therapy of HIV infection when tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) cannot be used because of a relative or absolute contraindication. ZDV-3TC continue to be viable alternatives for children, pregnant women and in resource limited settings where other recommended options are not readily available. ZDV-3TC penetrate the Central Nervous System (CNS) well, which makes ZDV-3TC attractive for use in patients with HIV-associated neurological deficits. Additional benefits of these drugs may include the use of ZDV in combination with certain NRTIs to exert selective pressure to prevent particular drug resistance mutations from developing, and giving a short course of ZDV-3TC to prevent resistance after prophylactic single dose nevirapine.

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Sample Preparation for LC‐MS Bioanalysis of Peripheral Blood Mononuclear Cells

Fu¹,

Li²

2019

Sample Preparation in LC‐MS Bioanalysis

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High Levels of Zidovudine (AZT) and Its Intracellular Phosphate Metabolites in AZT- and AZT-Lamivudine-Treated Newborns of Human Immunodeficiency Virus-Infected Mothers

Cited by 26 publications

References 55 publications

Plasma and Intracellular Tenofovir Pharmacokinetics in the Neonate (ANRS 12109 Trial, Step 2)

Plasma and Intracellular Tenofovir Pharmacokinetics in the Neonate (ANRS 12109 Trial, Step 2)

Zidovudine and Lamivudine for HIV Infection

Sample Preparation for LC‐MS Bioanalysis of Peripheral Blood Mononuclear Cells

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