Intracellular Pharmacokinetics of Antiretroviral Drugs in HIV-Infected Patients, and their Correlation with Drug Action.
Level 5 - mechanism / opinion, no new human data
Narrative review of pharmacokinetic studies without systematic review or meta-analysis methodology
PubMed 20000887 · doi:10.2165/11318110-000000000-00000
What was done
The authors reviewed 31 published studies measuring intracellular concentrations of antiretroviral drugs (NRTIs, NNRTIs, and protease inhibitors) in HIV-infected patients. They assessed findings concerning the relationships between intracellular concentrations, plasma drug levels, virological or immunological efficacy (evaluated in 8 studies), and drug toxicity (evaluated in 4 studies).
What was found
The abstract reports no pooled numerical data or specific effect sizes. For NRTIs, most studies failed to show a significant relationship between plasma and intracellular triphosphate concentrations. In well-designed prospective studies, virological efficacy correlated significantly with intracellular concentrations of NRTIs but not with plasma concentrations. For protease inhibitors, one prospective study of lopinavir found efficacy was influenced by both trough plasma and intracellular levels. Evidence regarding toxicity (zidovudine-associated hemoglobin reduction and efavirenz-related neuropsychiatric disorders) was inconclusive due to few studies and methodological heterogeneity.
Why it matters
Because antiretrovirals act intracellularly, cellular drug concentrations may be more clinically relevant than plasma concentrations for predicting therapeutic efficacy and certain toxicities.
Limits
Technical challenges persist in isolating/counting peripheral blood mononuclear cells and standardizing intracellular assays. Existing assays cannot differentiate between active free drug and membrane- or protein-bound drug. The overall evidence base is small (only 8 efficacy and 4 toxicity studies), with most studies limited by small sample sizes and non-standardized designs.
Cited by
- supports Inside cells, AZT is phosphorylated into AZT triphosphate, which acts as an inhibitor of reverse transcriptase.