LHPG Comment: Pharmacoenhancement of indinavir by ritonavir is currently being investigated to allow once or twice daily dosing of indinavir. Several such regimens are in clinical practice. Ritonavir decreases hepatic clearance of indinavir increasing the half life and results in an increase in indinavir trough concentrations with a small effect on Cmax. Where possible therapeutic drug monitoring should be used to ensure appropriate plasma concentrations of indinavir.

Coadministration of indinavir (800 mg twice daily) and ritonavir (100 mg twice daily) increased indinavir AUC by 178%, based on cross-study comparison to indinavir alone (800 mg three times daily); ritonavir AUC increased by 72%. Coadministration of indinavir (400 mg twice daily) and ritonavir (400 mg twice daily) had no effect on indinavir AUC but increased Cmin by 4-fold (based on cross-study comparison to indinavir alone (800 mg three daily); ritonavir AUC and Cmin were unchanged. Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition. Appropriate doses for this combination, with respect to efficacy and safety, have not been established. Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher than 100 mg twice daily. In cases of co-administration of ritonavir (100 mg twice daily) and indinavir (800 mg twice daily) caution is warranted as the risk of nephrolithiasis may be increased.
Norvir Summary of Product Characteristics, AbbVie Ltd, September 2016.

Coadministration of ritonavir (400 mg twice daily for 15 days) and indinavir (400 mg twice daily for 15 days) with food was studied in 10 subjects. Effects were assessed relative to indinavir alone (800 mg every 8 hours) given under fasting conditions. On day 15, indinavir AUC decreased by 7%, Cmax decreased by 62%, and Cmin increased 4-fold. Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
Norvir Prescribing Information, AbbVie Inc, December 2016.

The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Preliminary clinical data suggest that indinavir 400 mg in combination with ritonavir 100 mg, both administered orally twice daily, may be an alternative dosing regimen. A boosted dose of 800 mg indinavir/100 mg ritonavir twice daily results in increased risk of adverse events. Coadministration of indinavir (800 mg twice daily) was studied with different doses of ritonavir (100-400 mg twice daily) and compared to historical data from indinavir alone (800 mg three times daily). Coadministration with ritonavir 100 mg increased indinavir AUC by 178% and Cmin by 11-fold; ritonavir AUC increased by 72% and Cmin increased by 62%. Coadministration with ritonavir 200 mg increased indinavir AUC by 266% and Cmin by 24-fold; ritonavir AUC increased by 96% and Cmin increased by 371%. Coadministration with ritonavir 400 mg increased indinavir AUC by 220% and Cmin by 24-fold; ritonavir AUC was unchanged. Coadministration of a lower dose of indinavir (400 mg twice daily) and ritonavir (400 or 100 mg twice daily) was also compared to historical data from indinavir alone (800 mg three times daily). Coadministration with ritonavir 400 mg increased indinavir AUC by 68% and Cmin by 10-fold; there was no effect on ritonavir concentrations. Coadministration with ritonavir 100 mg resulted in AUC and Cmin values for indinavir that were comparable to the reference regimen. Indinavir should not be given with ritonavir to patients with decompensated liver disease as ritonavir is principally metabolised and eliminated by the liver.
Crixivan Summary of Product Characteristics, Merck Sharp & Dohme Ltd, October 2018.

Compared to historical data in patients who received indinavir 800 mg every 8 hours alone, twice-daily coadministration to volunteers of indinavir 800 mg and ritonavir with food for two weeks resulted in an 2.7-fold increase of indinavir AUC, a 1.6-fold increase in Cmax, and an 11-fold increase in Cmin for a 100-mg ritonavir dose and a 3.6-fold increase of indinavir AUC24h, a 1.8-fold increase in indinavir Cmax, and a 24-fold increase in indinavir Cmin for a 200-mg ritonavir dose. In the same study, twice-daily coadministration of indinavir (800 mg) and ritonavir (100 mg) resulted in increases in ritonavir Cmax, AUC and Cmin of 61%, 72% and 62% respectively; increases following a 200 mg ritonavir dose were 19%, 96% and 4.7-fold for ritonavir Cmax, AUC and Cmin respectively. The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Preliminary clinical data suggest that the incidence of nephrolithiasis is higher in patients receiving indinavir in combination with ritonavir than those receiving indinavir 800 mg every 8 h.
Crixivan Prescribing Information, Merck & Co Inc, May 2018.

Indinavir (400 mg twice daily) and ritonavir (100 mg twice daily) was administered to 40 HIV+ subjects. Indinavir Cmin were determined in 34 subjects at week 4; 91% (31/34) were found to have adequate trough concentrations (Cmin >150 ng/ml). 96% of subjects with adequate Cmin at week 4 had viral loads <50 copies/ml at week 48.
Efficacy and safety of ritonavir/indinavir 100/400 mg twice daily in combination with two nucleoside analogues in antiretroviral treatment-naïve HIV-infected individuals. Duvivier C, Astriti M, Marcelin AG, et al. Antiviral Ther, 2003, 8: 603-609.

Coadministration of indinavir (667 mg twice daily) and ritonavir (100 mg twice daily) was evaluated in 24 HIV+ subjects and compared to indinavir alone (800 mg three times daily). Indinavir Cmin increased 6-fold (from 250 to 1511 nM), AUC increased in 1.5 fold (from 77034 to 119557 nM.h) and there was no change in Cmax (10407 vs 10428 nM).
Pharmacokinetics of indinavir and ritonavir administered at 667 and 100 mg respectively, every 12 hours compared with indinavir administered at 800 mg every 8 hours in human immunodeficiency virus-infected patients. Rhame F, Rawlins S, Petruschke R, et al. Antimicrob Agents Chemother, 2004, 48: 4200-4208.

Coadministration of indinavir/ritonavir (400/100 mg twice daily) to 19 HIV+ subjects resulted in Cmin, AUC and Cmax values that were 24%, 37% and 39% of those obtained following indinavir/ritonavir 800/100 mg twice daily. Indinavir Cmin was below target (100 ng/ml) in three subjects, one of whom had virological failure. Of the 16 subjects with Cmin above target, one also had virological failure.
Pharmacokinetics of reduced-dose indinavir/ritonavir 400/100 mg every 12 h in HIV-1 infected Thai patients. Boyd M, Burger D, Mootsikapun P, et al. 11th Conference on Retroviruses and Opportunistic Infections, San Francisco, February 2004, abstract 616.

Indinavir + Efavirenz + Ritonavir

The effect of efavirenz (600 mg once daily) on a indinavir/ritonavir (800/100 mg twice daily) regimen was investigated in 14 healthy volunteers. Addition of efavirenz decreased both indinavir and ritonavir plasma concentrations. This resulted in a 19% decrease in indinavir AUC, a 48% decrease in indinavir Cmin and a 13% decrease in indinavir Cmax. However, the Cmin remained above the presumed therapeutic threshold of 100 ng/ml.
A pharmacokinetic study to investigate the influence of efavirenz on a bid indinavir/ritonavir regimen (800/100 mg) in healthy volunteers. Aarnouste RE, Burger DM, Hugen PWH et al. 40th ICAAC, Toronto, September 2000, presentation 423.