Pharmacokinetics (PK) of atazanavir/ritonavir (ATV/r) once daily (OD) and lopinavir/ritonavir (LPV/r) twice daily (BD) and OD over 72 hours following drug intake cessation.
Objectives: Drug persistence in plasma beyond the next due dose impacts on forgiveness around dose timing accuracy. We investigated the plasma decay following drug cessation of ATV/r OD and LPV/r BD and OD over 72h from steady-state to examine the fall of concentrations over time.
Methods: Healthy volunteers each received ATV/r 300/100 mg OD, LPV/r 400/100 mg BD, and LPV/r 800/200 mg OD for 10 days. All drug intake phases were followed by a 7-day wash-out period. Steady-state full PK profiles were assessed for each phase from day 10 over 72h. ATV and LPV concentrations were measured by hplc-MS/MS. Half-life (t1/2) over the normal dosing interval and terminal t1/2 to the last measurable concentration were determined by non-compartmental methods (WinNonLin).
Results: 16 subjects (6 females) completed all 3 PK phases. The geometric mean terminal half-life of ATV was 8.77h and was not different from the 0 to 24 h half-life. The terminal half-life of LPV was 2.33h following BD dosing and 2.44h following OD dosing and these values were significantly reduced compared to the t1/2 over the respective dosing intervals [7.15h (0-12h), 4.88h (0-24h)]. No subject on ATV had concentrations below the proposed MEC of 150ng/mL at 24h. 44% of the subjects on LPV OD had concentrations below the proposed MEC of 1000ng/mL at 24h. If dosing were delayed by an additional 12h, 100% of subjects on LPV OD, 81% of subjects on LPV BD and 31% on ATV OD were below the proposed MEC.
Conclusions: This study has investigated the PK forgiveness of 2 boosted protease inhibitor regimens. Whereas the decline in LPV concentrations occurs rapidly as the boosting effect of ritonavir diminishes, ATV declines at a slower rate. Advice regarding delayed doses of protease inhibitors should be provided.