LHPG Comment: Pharmacoenhancement of saquinavir by ritonavir is currently being investigated to allow once or twice daily dosing of saquinavir. Several such regimens are in clinical practice. Ritonavir increases saquinavir plasma concentrations by inhibition of first pass metabolism, which raises Cmax, but has only a small effect on plasma half-life. Saquinavir has little or no effect on the pharmacokinetics of ritonavir. Although interindividual variability in saquinavir concentrations is reduced, where possible therapeutic drug monitoring should be used to ensure adequate plasma concentrations of saquinavir. Details of the effect of ritonavir on saquinavir pharmacokinetics in some of the studies are available as a table in the attached document.

Saquinavir has been approved for use with ritonavir as a pharmacokinetic enhancer at the noted doses: saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily. Initiate treatment with saquinavir 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days, then saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily in ART-naïve patients. Doses of ritonavir higher than 100 mg twice daily should not be used. Higher doses of ritonavir have been shown to be associated with an increased incidence of adverse events. Co-administration of saquinavir and ritonavir has led to severe adverse events, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-existing liver disease. Based on cross-study comparison to saquinavir alone (600 mg three daily), coadministration of saquinavir (1000 mg twice daily) and ritonavir (100 mg twice daily) increased saquinavir AUC by 15-fold and Cmin by 5-fold; ritonavir AUC and Cmin were unchanged. Based on cross-study comparison to saquinavir alone (600 mg three daily), coadministration of saquinavir (400 mg twice daily) and ritonavir (400 mg twice daily) increased saquinavir AUC by 17-fold with no change in ritonavir AUC or Cmin. Ritonavir increases the serum levels of saquinavir as a result of CYP3A4 inhibition. Saquinavir should only be given in combination with ritonavir. Ritonavir 100 mg twice daily with saquinavir 1000 mg twice daily provides saquinavir systemic exposure over 24 hours similar to or greater than those achieved with saquinavir 1200 mg three times daily without ritonavir. Saquinavir/ritonavir should not be given together with rifampicin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three medicines are given together. In a clinical study investigating the interaction of rifampicin 600 mg once daily and saquinavir 1000 mg with ritonavir 100 mg twice daily in healthy volunteers, severe hepatocellular toxicity with transaminase elevations up to >20-fold the upper limit of normal after 1 to 5 days of co-administration was noted. Due to the risk of severe hepatoxicity, saquinavir/ritonavir should not be given together with rifampicin.
Norvir Summary of Product Characteristics, AbbVie Ltd, September 2016.

Coadministration is expected to increase saquinavir concentrations. See the complete Prescribing Information for saquinavir for details on co-administration of saquinavir and ritonavir. Saquinavir and ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
Norvir Prescribing Information, AbbVie Inc, December 2016.

The recommended dose of Invirase is 1000 mg (2 x 500 mg film-coated tablets) two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents. For treatment-naive patients initiating treatment with Invirase/ritonavir, the starting recommended dose of Invirase is 500 mg (1 x 500 mg film-coated tablet) two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents for the first 7 days of treatment. After 7 days, the recommended dose of Invirase is 1000 mg two times daily with ritonavir 100 mg two times daily in combination with other antiretroviral agents. Patients switching immediately from treatment with another protease inhibitor taken with ritonavir or from a non-nucleoside reverse transcriptase inhibitor based regimen, without a wash-out period, should however initiate and continue Invirase at the standard recommended dose of 1000 mg two times daily with ritonavir 100 mg two times daily. Invirase film-coated tablets should be swallowed whole and taken at the same time as ritonavir with or after food. In HIV-infected patients, Invirase or saquinavir soft capsules in combination with ritonavir at doses of 1000/100 mg twice daily provide a systemic exposure of saquinavir over a 24 hour period similar to or greater than that achieved with saquinavir soft capsules 1200 mg three times daily.
Invirase Summary of Product Characteristics, Roche Products Ltd, June 2012.

Inivrase (1000 mg twice daily) must be used in combination with ritonavir (100 mg twice daily) because it significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels. When ritonavir (400 mg twice daily for 14 days) was coadministered with saquinavir (soft gel 400 mg twice daily for 14 days), in 8 healthy volunteers, saquinavir AUC and Cmax increased by 121% and 64%, respectively, compared to standard soft gel regimen (1200 mg three times daily, n=33). When ritonavir (100 mg twice daily) was coadministered with saquinavir (hard gel 1000 mg twice daily, steady state), in 24 patients, saquinavir AUC and Cmax were increased by 1124% and 1325%, respectively, compared to standard saquinavir hard gel 600 mg (three times daily) regimen(n=114).
Invirase Prescribing Information, Genentech USA Inc, February 2012.