LHPG Comment: Note the difference in SPC (European) and Prescribing Information (USA). In this case the charts reflect the use of low dose ritonavir as a pharmacokinetic enhancer to boost plasma concentrations of other protease inhibitors. There is also a difference in pharmacokinetics when rifabutin is given daily compared to once or twice weekly.

Due to the large increase in rifabutin AUC, the concomitant use of rifabutin with ritonavir dosed as an antiretroviral agent is contraindicated due to an increase of rifabutin serum concentrations and risk of adverse events including uveitis. Based on parallel group comparison, coadministration of rifabutin (150 mg daily) and ritonavir (500 mg twice daily) increased rifabutin AUC by 4-fold and Cmin by 2.5-fold. AUC and Cmin of 25-o-desacetyl rifabutin metabolite were increased by 38-fold and 16-fold respectively. The reduction of the rifabutin dose to 150 mg 3 times per week may be indicated for select PIs when co-administered with ritonavir as a pharmacokinetic enhancer. The Summary of Product Characteristics of the co-administered protease inhibitor should be consulted for specific recommendations. Consideration should be given to official guidance on the appropriate treatment of tuberculosis in HIV-infected patients.
Norvir Summary of Product Characteristics, AbbVie Ltd, September 2016.

The coadministration of ritonavir (500 mg every 12 hours for 10 days) with rifabutin (150 mg daily for 16 days) was investigated using a study with parallel group design. Rifabutin AUC, Cmax and Cmin were increased by 4-, 2.5-and 6-fold, respectively. The 25-O-desacetyl rifabutin metabolite AUC, Cmax and Cmin were increased by 35-, 16-and 181-fold, respectively. Dosage reduction by at least three quarters of the usual dose of 300 mg/day is recommended (e.g. 150 mg every other day or three times a week). Further dosage adjustment may be necessary.
Norvir Prescribing Information, AbbVie Inc, December 2016.

Nineteen patients (group 1 n=10, group 2 n=9) took part in a study to evaluate plasma exposures and safety of rifabutin and its active metabolite with a combination of ritonavir (400 mg twice daily) and saquinavir (400 mg twice daily). Group 1 received 300 mg rifabutin every 7 days and group 2 150 mg every 3 days for 8 weeks. Rifabutin exposures were similar at 4 and 8 weeks and had minimal effect on ritonavir and saquinavir. It is safe to use ritonavir and saquinavir with rifabutin on intermittent dosing over 8 weeks.
A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with Human Immunodeficiency Virus. Gallicano K, Khaliq Y, Carignan G, et al. Clin Pharmacol Ther, 2001, 70:149–58.

Coadministration of ritonavir (500 mg 12 hourly) and rifabutin (150 mg once daily) was studied in five healthy volunteers. There was a 4-fold increase in rifabutin AUC (0–24h) and a 35-fold increase in 25-O-desacetyl rifabutin. Rifabutin Cmax and Cmin increased by 2.5 and 6-fold, respectively. Cmax and Cmin of 25-O-desacetyl rifabutin increased by 16- and 200-fold, respectively. As both parent drug and metabolite have similar activities, the combined mean AUC increased nearly 7-fold in the presence of ritonavir. If ritonavir is to be administered concurrently with an antimycobacterial, an alternative to rifabutin (e.g. clarithromycin) is recommended.
The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin. Cato A, Cavanaugh J, Shi H, et al. Clin Pharmacol Ther, 1998, 63:414–21.