Pharmacokinetics of Indinavir/Ritonavir
Pharmacokinetics of Indinavir/Ritonavir
Background: Addition of efavirenz (600 mg) to indinavir/ritonavir (800/100 mg) results in significant decreases in indinavir levels in healthy volunteers. This study evaluated the steady-state pharmacokinetics of indinavir/ritonavir at 800/100 mg twice daily (bid) in combination with efavirenz at 600 mg once daily (qd) in HIV-infected Thai subjects who used this nucleoside-sparing combination in The HIV Netherlands Australia Thailand Research Collaboration 009 study.
Methods: At week 4 of the study, 12-hour pharmacokinetic profiles for indinavir/ritonavir were obtained for 20 HIV-infected subjects. For efavirenz, the concentrations at 12 hours and 24 hours (Cmin) after dosing were assessed.
Results: All subjects (10 males and 10 females) completed the study. The geometric mean area under the concentration versus time curve, Cmin, and maximum plasma concentration of indinavir were 45.7 mg/(L · h) (95% confidence interval [CI], 39.8-52.5), 0.32 mg/L (95% CI, 0.24-0.44), and 11.1 mg/L (95% CI, 9.4-13.0), respectively. A >10-fold variation in indinavir Cmin was observed. All subjects had an indinavir Cmin that was at least comparable with the reported mean population Cmin of indinavir at 800 mg thrice daily without ritonavir (0.15 mg/L). The geometric mean concentration at 12 hours and Cmin of efavirenz were 3.1 mg/L (95% CI, 2.5-3.7) and 2.1 mg/L (95% CI, 1.6-2.6), respectively.
Conclusions: Despite the known pharmacokinetic interaction between efavirenz and indinavir/ritonavir, the combination of indinavir/ritonavir at 800/100 mg bid and efavirenz at 600 mg qd results in adequate minimum concentrations of both indinavir and efavirenz for treatment-naive patients.
The combination of efavirenz and indinavir given with nucleoside analogues has demonstrated a potent and durable antiretroviral effect in nucleoside-experienced patients. The same combination of efavirenz and indinavir when given in the absence of nucleoside analogues has demonstrated efficacy similar to that achieved with the regimen of indinavir, zidovudine, and lamivudine.
Efavirenz has the advantage of once-daily (qd) dosing with three 200-mg capsules or, more recently, one 600-mg tablet (available in the United States and Europe). In contrast, indinavir must be taken three times daily (tid). The pharmacokinetic profile of indinavir can be improved by combining it with a low dose (100 mg) of ritonavir. The combination of indinavir with low-dose ritonavir allows for more convenient twice daily (bid) administration (800/100 mg bid) and permits concurrent intake with food. This indinavir/ritonavir drug combination is widely used, and available data suggest that its virologic efficacy is comparable with that of indinavir at 800 mg tid without ritonavir.
The combination of efavirenz and indinavir given with ritonavir has the potential to be a potent compact combination regimen that should offer ease of adherence. However, mutual drug interactions between these agents may alter the pharmacokinetic properties of indinavir, ritonavir, or efavirenz, potentially resulting in subtherapeutic drug levels. A study including healthy volunteers demonstrated that the addition of efavirenz to indinavir/ritonavir at 800/100 mg bid resulted in significant decreases in indinavir levels. However, all individual trough levels (Cmin) of indinavir remained equivalent to or greater than the mean Cmin described for the 800-mg tid regimen of indinavir without ritonavir. Therefore, it may be argued that dose modifications are not necessary for protease inhibitor-naive patients who use the combination of indinavir/ritonavir at 800/100 mg and efavirenz at 600 mg qd.
These pharmacokinetic findings have yet to be confirmed for HIV-1-infected subjects, and it cannot be excluded that differences may exist between HIV-infected subjects and non-HIV-infected healthy volunteers with respect to the pharmacokinetics of these antiretroviral drugs. For instance, it has been demonstrated that inflammation and infection can affect the activity of the cytochrome p450 isoenzymes involved in the metabolism of both the protease inhibitor and the nonnucleoside analogue reverse transcriptase inhibitor classes of antiretroviral drugs. Therefore, we undertook this study to evaluate the pharmacokinetics of indinavir, low-dose ritonavir, and efavirenz in an open-label, single-arm, nonrandomized trial (the HIV Netherlands Australia Thailand Research Collaboration [HIV-NAT] 009 study) designed to evaluate the efficacy, safety, and tolerability of indinavir/ritonavir at 800/100 mg bid in combination with efavirenz at 600 mg qd.
Background: Addition of efavirenz (600 mg) to indinavir/ritonavir (800/100 mg) results in significant decreases in indinavir levels in healthy volunteers. This study evaluated the steady-state pharmacokinetics of indinavir/ritonavir at 800/100 mg twice daily (bid) in combination with efavirenz at 600 mg once daily (qd) in HIV-infected Thai subjects who used this nucleoside-sparing combination in The HIV Netherlands Australia Thailand Research Collaboration 009 study.
Methods: At week 4 of the study, 12-hour pharmacokinetic profiles for indinavir/ritonavir were obtained for 20 HIV-infected subjects. For efavirenz, the concentrations at 12 hours and 24 hours (Cmin) after dosing were assessed.
Results: All subjects (10 males and 10 females) completed the study. The geometric mean area under the concentration versus time curve, Cmin, and maximum plasma concentration of indinavir were 45.7 mg/(L · h) (95% confidence interval [CI], 39.8-52.5), 0.32 mg/L (95% CI, 0.24-0.44), and 11.1 mg/L (95% CI, 9.4-13.0), respectively. A >10-fold variation in indinavir Cmin was observed. All subjects had an indinavir Cmin that was at least comparable with the reported mean population Cmin of indinavir at 800 mg thrice daily without ritonavir (0.15 mg/L). The geometric mean concentration at 12 hours and Cmin of efavirenz were 3.1 mg/L (95% CI, 2.5-3.7) and 2.1 mg/L (95% CI, 1.6-2.6), respectively.
Conclusions: Despite the known pharmacokinetic interaction between efavirenz and indinavir/ritonavir, the combination of indinavir/ritonavir at 800/100 mg bid and efavirenz at 600 mg qd results in adequate minimum concentrations of both indinavir and efavirenz for treatment-naive patients.
The combination of efavirenz and indinavir given with nucleoside analogues has demonstrated a potent and durable antiretroviral effect in nucleoside-experienced patients. The same combination of efavirenz and indinavir when given in the absence of nucleoside analogues has demonstrated efficacy similar to that achieved with the regimen of indinavir, zidovudine, and lamivudine.
Efavirenz has the advantage of once-daily (qd) dosing with three 200-mg capsules or, more recently, one 600-mg tablet (available in the United States and Europe). In contrast, indinavir must be taken three times daily (tid). The pharmacokinetic profile of indinavir can be improved by combining it with a low dose (100 mg) of ritonavir. The combination of indinavir with low-dose ritonavir allows for more convenient twice daily (bid) administration (800/100 mg bid) and permits concurrent intake with food. This indinavir/ritonavir drug combination is widely used, and available data suggest that its virologic efficacy is comparable with that of indinavir at 800 mg tid without ritonavir.
The combination of efavirenz and indinavir given with ritonavir has the potential to be a potent compact combination regimen that should offer ease of adherence. However, mutual drug interactions between these agents may alter the pharmacokinetic properties of indinavir, ritonavir, or efavirenz, potentially resulting in subtherapeutic drug levels. A study including healthy volunteers demonstrated that the addition of efavirenz to indinavir/ritonavir at 800/100 mg bid resulted in significant decreases in indinavir levels. However, all individual trough levels (Cmin) of indinavir remained equivalent to or greater than the mean Cmin described for the 800-mg tid regimen of indinavir without ritonavir. Therefore, it may be argued that dose modifications are not necessary for protease inhibitor-naive patients who use the combination of indinavir/ritonavir at 800/100 mg and efavirenz at 600 mg qd.
These pharmacokinetic findings have yet to be confirmed for HIV-1-infected subjects, and it cannot be excluded that differences may exist between HIV-infected subjects and non-HIV-infected healthy volunteers with respect to the pharmacokinetics of these antiretroviral drugs. For instance, it has been demonstrated that inflammation and infection can affect the activity of the cytochrome p450 isoenzymes involved in the metabolism of both the protease inhibitor and the nonnucleoside analogue reverse transcriptase inhibitor classes of antiretroviral drugs. Therefore, we undertook this study to evaluate the pharmacokinetics of indinavir, low-dose ritonavir, and efavirenz in an open-label, single-arm, nonrandomized trial (the HIV Netherlands Australia Thailand Research Collaboration [HIV-NAT] 009 study) designed to evaluate the efficacy, safety, and tolerability of indinavir/ritonavir at 800/100 mg bid in combination with efavirenz at 600 mg qd.