We have shown that low-dose ritonavir caused weak increases in the Cmax and AUC of oral AMD070, during both the acute and steady-state phases of ritonavir treatment. In addition, the combination of single-dose AMD070 with low-dose ritonavir in our study appeared safe, as the subjects tolerated the study regimen well and no adverse events of grade 3 or 4 were reported. The exclusion of female subjects is a limitation of this study in that the study results may not be generalizable to females.
The common mechanisms contributing to the increase of the AUC of oral drugs include increasing oral bioavailability (by increasing either absorption or decreasing presystemic clearance or both) and decreasing elimination (by inhibiting metabolism and/or excretion). The apparent decrease of Tmax and Vz/F and the increase of Cmax in our study were consistent with an increase in oral bioavailability. Thus, ritonavir may inhibit P-gp (thus increasing AMD070 absorption) and intestinal CYP3A4 (thus decreasing presystemic clearance). The inhibition of the hepatic CYP3A4 enzyme may also be involved. Alteration of renal clearance is unlikely since less than 1% of AMD070 is excreted unchanged in the urine (AnorMED, Inc., data on file).
In our study, ritonavir was given for 14 days at a low dose. In a study with HIV-infected subjects (11
), ritonavir (given as a single agent) was administered in dosing regimens of 200 mg to 500 mg twice daily; the trough ritonavir concentration decreased from day 8 to day 16, whereas the AUC and Cmax
were relatively time invariant. One of the proposed mechanisms was the induction of CYP3A4. Based on the model of the time course, the authors concluded that the half-life of the potential ritonavir-mediated CYP3A4 induction was ~3.5 days. Their data show that the trough concentrations of ritonavir tended to stabilize by the end of a 2-week dosing period. Apparently, ritonavir in our study reached steady state and the ritonavir pharmacokinetic parameters were similar to those reported by Aarnoutse et al. (1
). Since ritonavir induces CYP3A4 enzyme activity, we had expected slightly higher CYP3A4 activity after 2 weeks of ritonavir treatment. Although the geometric mean ratio of AMD070 Cmax
with both acute (day 3) and chronic (day 17) ritonavir dosing to that with no ritonavir dosing showed the lack of bioequivalence of AMD070, it is still not clear whether the impacts of acute and chronic ritonavir treatment on AMD070 are different. An in vitro study has shown that AMD070 weakly inhibits CYP2D6, CYP3A4, and CYP1A2 (AnorMED, Inc., data on file), which can metabolize ritonavir and add to the complexity of the AMD070-ritonavir drug interaction.
Single-dose rather than steady-state pharmacokinetics of AMD070 were studied because dosing once or twice daily as anticipated in future efficacy studies would yield an accumulation less than or equal to two times the single-dose concentrations only during the terminal elimination phase, with little or no detectable difference in peak concentration and AUC (19
). Furthermore, concentrations achieved with single 200-mg doses are near the range expected to be clinically relevant (19
). The AMD070 dose chosen (200 mg) was based on demonstrated safety in the study of up to 400 mg twice daily (AIDS Clinical Trials Group study A5191) (19
AMD070 has modest antiretroviral activity in some patients with dosing of 200 mg every 12 h (17
); the doses used in the antiretroviral studies are also below the concentrations associated with maximal leukocyte mobilization (19
). The pharmacokinetic interaction we report here may provide a way to increase concentrations of AMD070, and perhaps the antiviral activity, without increasing the AMD070 dose, as occurs for numerous other antiretroviral drugs, primarily protease inhibitors. However, after the clinical phase of this study was completed, the FDA placed AMD070 on clinical hold due to liver histology changes observed in longer-term preclinical toxicity experiments. Currently, AMD070 is still on clinical hold. However, it has been reported that disrupting the CXCR4 receptor-mediated trafficking of hematopoietic progenitor cells produces a stem cell mobilization effect (5
). Therefore, the favorable ritonavir interaction may also have relevance in another clinical setting, as AMD070 has leukocyte-mobilizing activity similar to that of AMD3100, another CXCR4 inhibitor which is in advanced clinical development as a stem-cell-mobilizing drug (2
). AMD070, however, has the significant advantage of being orally bioavailable (19
In conclusion, the coadministration of ritonavir with AMD070 weakly increased the Cmax and AUC of AMD070 in blood plasma. The increased Cmax and AUC of AMD070 due to concomitant ritonavir dosing may result in clinically beneficial effects.