In silico study supports the efficacy of a reduced dose regimen for stavudine

Stavudine (d4T) is used extensively as part of HAART in resource poor settings, despite its toxicities. The revised WHO guidelines specify replacement of d4T with less toxic but more expensive drugs when feasible, and that d4T doses be standardized to 30 mg twice daily (bid) (irrespective of body-weight), from the approved 40 mg bid in adults (body-weight ⩾60 kg). Therefore, an in silico population pharmacokinetic and biochemical model was utilized to compare relative efficacies of the two doses in humans. Assessment of predicted quartile ranges of simulated concentrations of the triphosphate of d4T suggested sufficient trough concentrations to inhibit wild type HIV-1 reverse transcriptase at the reduced dose, lending support to the revised WHO recommendations.

► Stavudine (d4T) is widely used in resource poor settings despite toxicity.
► WHO recommended reducing d4T dose from 40 to 30 mg bid when replacement is not feasible.
► A population PK/biochemical model was used to simulate cellular d4T-TP versus dose.
► d4T-TP concentrations for 30 mg bid exceeded wt HIV-1 EC50 in most virtual subjects.
► This suggests that this low dose could maintain antiviral efficacy.