Objective: To determine the concentrations of intracellular active anabolites of stavudine (d4T) and didanosine (DDI) and their interpatient variability in HIV-infected patients and to explore relationships between plasma and intracellular forms.
Methods: This pilot study included 28 antiretroviral-naive HIV-infected patients who received d4T (40/30 mg twice daily), ddI (400/250 mg daily) and efavirenz (600 mg daily). After 6 months of therapy, 7 ml of blood was collected between 0.5 and 16.2 h and 2.5 and 28.5 h after the last dose of d4T and ddI, respectively. Plasma samples were obtained for the determination of d4T and ddI concentrations. Peripheral blood mononuclear cells were prepared for measuring intracellular d4T and ddI triphosphates (d4T-TP and ddA-TP, respectively).
Results: d4T-TP and ddA-TP concentrations were above the limit of quantification in 25 of 26 compliant patients: median d4T-TP was 31 fmol/106 cells (range, 0–99) and median ddA-TP was 8 fmol/106 cells (range, 0–23). The half-life of d4T-TP was calculated as 7 h. Interpatient variability in d4T-TP and ddA-TP concentrations was 48% and 58%, respectively. A significant relationship was observed between plasma d4T and intracellular d4T-TP. No relation was found between ddI and ddA-TP. A linear relation was observed between the intracellular concentrations of d4T-TP and ddA-TP.
Conclusion: This is the first time that data have been obtained on intracellular concentrations of d4T-TP and ddA-TP, their intracellular pharmacokinetics and interpatient variability. Other similar studies with more patients are needed to enhance knowledge of the intracellular pharmacology of the nucleoside reverse transcriptase inhibitors.
From aCEA, Pharmacology and Immunology Unit, DSV/DRM, Gif-Sur-Yvette, bIMEA, Bichat-Claude Bernard Hospital, Paris, cIRD, University of Montpellier, Montpellier, dINSERM SC4, Saint Antoine Hospital, and eBristol-Myers Squibb, Infectiology–Immunology, Rueil-Malmaison France and fPLNS-Dakar, Senegal.
Requests for reprints to: H. Benech, Service de Pharmacologie et d'Immunologie, CEA/Saclay, 91191 Gif-sur-Yvette Cedex, France.
Received: 29 November 2002; revised: 24 March 2003; accepted: 1 July 2003.