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The Clinical Pharmacology of Nucleoside Reverse Transcriptase Inhibitors 291tolerated and has many desirable pharmacokinetic properties including a sufficientlylong plasma and intracellular half-life to allow for once daily dosing. Tenofovir isan acyclic nucleotide. Structurally, it is similar to adefovir and cidofovir. Nephrotoxicity,which manifests as changes in laboratory markers of renal tubular function,is the main clinical toxicity of these drugs. Tenofovir, however, does notinhibit renal cell growth and epithelium integrity to the same extent as adefovirand cidofovir in vitro, and clinical trials have shown a very low incidence of renaltoxicities with tenofovir (38–40). Nevertheless, there are case reports of tenofovirinducedrenal dysfunction (41) and retrospective cohorts have shown greaterdeclines in renal function with NRTI regimens including tenofovir compared toother NRTI-based regimens (42). Use of other nephrotoxic drugs and underlyingrenal dysfunction appear to predispose patients to tenofovir-induced renal dysfunction,but other risk factors have not been definitively linked to the toxicity. In manyof the case reports, tenofovir plasma concentrations were elevated, so it is likelythat this is a concentration-dependent toxicity, but further studies are needed todetermine the exact mechanisms for this toxicity and the patients at risk. There areno studies to date evaluating associations between plasma and intracellular tenofovirconcentrations and the development of renal toxicity.Optimal use of antiretroviral agents means finding an acceptable balancebetween maximizing therapeutic benefits and reducing adverse effects. Furtherstudies of the associations between NRTI intracellular concentrations and clinicaloutcomes are desperately needed.THERAPEUTIC USES, FDA-APPROVED INDICATIONS,AND DOSING REGIMENSThere are eight commercially available, Food and Drug Administration (FDA)-approved NRTIs, though zalcitabine is rarely used. Table 2 highlights the FDAapproveddosing regimens for these drugs. Five NRTIs are approved for use inchildren including abacavir, didanosine, lamivudine, stavudine, and zidovudine,though the approved age groups and dosing strategies (weight vs. body surfacearea) vary widely. Dose finding, efficacy, and safety studies of tenofovir andemtricitabine in children are ongoing. With the exception of abacavir and zidovudine,the NRTIs are predominately renally eliminated and thus require doseadjustments for impaired renal function. Abacavir and zidovudine are metabolizedin the liver, and therefore may require dose adjustments in patients withhepatic impairment. Drug-specific adverse effects for the NRTIs are also listed inTable 2. The Department of Health and Human Services Guidelines for the Use ofAntiretroviral Agents in HIV-1 Infected Adults and Adolescents is a frequentlyupdated resource for information on the treatment of HIV (9).REFERENCES1. Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differencesof zidovudine and lamivudine triphosphate concentrations in HIV-infectedindividuals. Aids 2003; 17(15):2159–2168.2. Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-inducedmitochondrial toxicity. Clin Ther 2000; 22(6):685–708.3. Lewis W, Simpson JF, Meyer RR. Cardiac mitochondrial DNA polymerase-g isinhibited competitively and noncompetitively by phosphorylated zidovudine. Circ ResFeb 1994; 74(2):344–348.