Possible Causes of Early Treatment Failure With a Novel ARV Regimen

Peter J. Ruane, MB, BCh, MRCPI, Andrew D. Luber, PharmD


September 11, 2003

In This Article

Insufficient Pharmacokinetics of Once-Daily ABC and/or 3TC

It has been suggested that the early treatment failures observed in these studies could be due to insufficient intracellular concentrations of ABC (which is not approved for once-daily dosing) and/or 3TC when dosed once daily. If insufficient intracellular concentrations of either or both ABC and 3TC were present at the end of a once-daily dosing interval, viral replication and subsequent resistance might ensue.[1] However, pharmacokinetic analyses suggest that this should not occur.[13,14,15,16,17] Following once-daily dosing, the intracellular half-life of the active moiety of ABC, carbavir-triphosphate (CBV-TP), is 20 hours with levels in excess of the IC50 for wild-type viral isolates.[16,17] Likewise, similarly dosed 3TC-triphosphate (3TC-TP) has an intracellular half-life of greater than 15 hours and median 3TC-TP levels above the threshold are required to inhibit wild-type virus. In addition, 3TC-TP concentrations appear comparable in both once- and twice-daily dosing.[13,14,15]

While the above intracellular kinetics are reassuring, the interpatient variability of 3TC-TP concentrations has not been adequately studied. Consequently, it is possible that a subgroup of patients might have suboptimal 3TC-TP levels upon once-daily dosing, which would facilitate the development of resistance. This concern is substantiated by the observation of the M184V mutation upon treatment failure in the 2 clinical trials at hand. Further data will be required to determine whether this is a consequence of interpatient pharmacokinetic variability of 3TC-TP.

However, clinical data from the ESS30009 trial, which compared TDF plus 3TC/ABC with EFV plus 3TC/ABC, with both regimens being administered once daily, suggest that putative suboptimal intracellular concentrations of ABC-TP and/or 3TC-TP cannot be linked to virologic failure for all regimens. Few failures were observed in the EFV arm despite the once-daily dosing scheme.[2] If therapeutic intracellular trough concentrations of ABC and 3TC were not achieved, selection of EFV-resistant mutants and subsequent resistance would be expected. Further support for once-daily dosing of both 3TC and ABC is provided by clinical trials demonstrating similar virologic response rates with ABC and 3TC when dosed either once or twice daily.[18,19]

Pharmacokinetic evaluations of ABC and TDF in plasma have been performed and no negative drug-drug interactions have been identified.[20] However, intracellular pharmacokinetic analyses of the disposition of CBV-TP and TDF-diphosphate (the active moiety of TDF) when ABC and TDF are administered concurrently have not been performed. Potential intracellular interactions include:

  • Decreased cellular uptake or upregulation of efflux pumps. If active pumps on the cell wall are needed for ABC or TDF to enter the cell and 1 or both agents inhibit these pumps or upregulate efflux pump activity, a decrease in intracellular concentrations, and a subsequent decrease in conversion to the active phosphate moiety, could occur.

  • Competitive antagonism for phosphorylation. The conversion of ABC to CBV-TP and TDF to TDF-DP occurs through 2 separate enzyme systems, therefore the likelihood of competition for phosphorylation between these 2 agents is minimal. One theoretical concern involves a potential interaction with adenosine phosphotransferase (the enzyme required to convert abacavir to abacavir monophosphate) and TDF. TDF-DP competes with naturally occurring adenosine for incorporation into the growing DNA chain. If TDF-DP somehow interacts with adenosine phosphotransferase in a negative manner, a decrease in CBV-TP concentrations could occur.

  • Competitive antagonism for incorporation into the growing DNA chain. Unlike the interaction between zidovudine and stavudine, in which both agents compete for thymidine in the growing DNA chain, CBV-TP competes for naturally occurring guanosine-TP and TDF-DP competes for adenosine-TP. Consequently, an interaction through this mechanism appears unlikely.


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