Recent developments in the clinical pharmacology of anti-HIV nucleoside analogs.

PURPOSE OF REVIEW: This review summarizes recent developments regarding the unique clinical pharmacologic profile of nucleoside analog reverse transcriptase inhibitors for management of HIV. RECENT
FINDINGS: First, intracellular data in patients suggest that nucleoside reverse transcriptase inhibitor-triphosphates are compartmentalized in different cell types. Additionally, intracellular drug-drug interactions were identified, which were undetectable in plasma. Second, extracellular data illustrate multiple bidirectional plasma drug-drug interactions between renally eliminated tenofovir and liver-metabolized drugs. Definitive mechanistic details for these interactions are lacking but they appear to involve renal and/or enteric drug transporters. Furthermore, the plasma versus female genital tract disposition of these agents was recently elucidated, which is important for currently investigated indications for pre-exposure and post-exposure prophylaxis. Finally, tenofovir/emtricitabine and abacavir (using a promising human leukocyte antigen-B*5701 genetic test for hypersensitivity)/lamivudine have emerged as common first-line nucleoside analog reverse transcriptase inhibitors because of co-formulations, once-daily dosing, and favorable tolerability and adverse effect profiles. Nevertheless, elucidating the long-term safety profile for all nucleoside analog reverse transcriptase inhibitors remains a priority.
SUMMARY: Knowledge of nucleoside analog reverse transcriptase inhibitor disposition intracellularly and extracellularly has expanded. This provides a basis for rational use of these agents clinically and adds new perspectives for future research.