What are the pharmacokinetics of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) in antiretroviral therapy of HIV infection?

Updated: Apr 18, 2019
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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Answer

NRTIs are prodrugs and must undergo phosphorylation by intracellular kinases to exert their activity. Collectively, the oral bioavailability of NRTIs ranges from 25%-93%, with tenofovir and didanosine on the lower end of the spectrum. Food does not significantly affect absorption of any of the NRTIs except didanosine, which must be taken on an empty stomach to achieve optimal absorption and drug levels.

Although serum half-lives of NRTIs are relatively short, intracellular drug levels are the best indicator for drug activity and determine the dose administered for each NRTI. [13] Most NRTIs are renally eliminated and require dosage adjustments in patients with renal insufficiency; the exception is abacavir, which is given at the normal dose regardless of creatinine clearance.

NRTIs are not metabolized by the cytochrome P450 system; therefore, minimal drug-drug interactions occur. Interactions that have been found to be clinically significant involve didanosine. When given in combination with tenofovir, didanosine levels are higher than expected, and lower doses must be given to avoid potentially serious adverse effects. A similar scenario has been demonstrated when didanosine is combined with ribavirin in the treatment of patients with HIV and hepatitis C virus (HCV) coinfection. This combination should be avoided. [8]

Tenofovir alafenamide (AF) is a prodrug of tenofovir that has high antiviral efficacy similar at a dose less than one-tenth that of the original formulation of tenofovir prodrug (i.e., tenofovir disoproxil fumarate [DF]). Tenofovir AF provides lower blood levels but higher intracellular levels compared with tenofovir DF. [14, 15]  Tenofovir AF is a substrate for p-glycoprotein and can be given at a lower dose (10 mg) when coadministered with strong p-glycoprotein inhibitors (e.g., ritonavir, cobicistat). [16, 17]


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