Liverpool HIV Interactions

Do Not Coadminister

Lopinavir/ritonavir (LPV/r)

Rifampicin

Quality of Evidence: High

Summary:

Coadministration of lopinavir/ritonavir with rifampicin is not recommended as it causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higher dose of lopinavir/ritonavir (400/400 mg twice daily) is used but this is associated with a higher risk of liver and gastrointestinal toxicity. Therefore, this coadministration should be avoided unless judged strictly necessary.

Description:

Coadministration of Kaletra with rifampicin is not recommended. Rifampicin administered with Kaletra causes large decreases in lopinavir concentrations due to CYP3A induction by rifampicin. The decrease in lopinavir concentrations may in turn significantly decrease the lopinavir therapeutic effect. A dose adjustment of Kaletra 400 mg/400 mg twice daily has allowed compensating for the CYP 3A4 inducer effect of rifampicin. However, such a dose adjustment might be associated with ALT/AST elevations and with increase in gastrointestinal disorders. Therefore, this coadministration should be avoided unless judged strictly necessary. If this coadministration is judged unavoidable, increased dose of Kaletra at 400 mg/400 mg twice daily may be administered with rifampicin under close safety and therapeutic drug monitoring. The Kaletra dose should be titrated upward only after rifampicin has been initiated.
Kaletra Summary of Product Characteristics, AbbVie Ltd, January 2021.

Coadministration of rifampicin and Kaletra is contraindicated as it may lead to loss of virologic response and possible resistance to Kaletra or to the class of protease inhibitors or to other coadministered antiretroviral agents. Kaletra is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. Coadministration of rifampicin (600 mg once daily) and lopinavir/ritonavir (400/100 mg twice daily) to 22 HIV- subjects results in decreases in lopinavir Cmax, AUC and Cmin of 55%, 75% and 99% respectively. Data from 10 subjects receiving rifampicin and lopinavir/ritonavir (800/200 mg twice daily) showed a 2% increase in lopinavir Cmax, but decreases of 16% and 57% for AUC and Cmin, when compared to lopinavir/ritonavir 400/100 mg twice daily alone. Coadministration of rifampicin with lopinavir/ritonavir (400/400 mg twice daily) to 9 HIV- subjects resulted in decreases of 7% and 2% for lopinavir Cmax and AUC and an increase of 3% for Cmin, when compared to 400/100 mg alone.
Kaletra Prescribing Information, AbbVie Ltd, October 2020.

The steady-state pharmacokinetics of lopinavir were evaluated in HIV-infected adults stable on LPV/r tablets (400/100 mg twice daily) who were given rifampicin (600 mg daily), and the dose of the LPV/r gradually increased over a period of two weeks ( first to 600/150 twice daily and then to 800/200 mg twice daily). Twenty one subjects started the study, but two were withdrawn due to grade 3/4 transaminitis. The median [IQR) pre-dose LPV concentrations were 8.1 (6.2 to 9.8) mg/L at baseline, 1.7 (0.3 to 3.0) mg/L after 7 days of rifampicin, 5.9 (2.1 to 9.9) mg/L with 1.5 times the dose of LPV/r, and 10.8 (7.0 to 13.1) mg/L with double-dose LPV/r. There were no significant differences in the LPV AUC, Cmax, pre-dose concentrations, 12 h concentration, or half-life between the baseline and double-dose LPV/r time points. Doubling the dose of the tablet formulation of LPV/r overcame induction by rifampicin, with less hepatotoxicity occurring in this cohort of HIV-infected participants than reported in healthy-volunteer studies. The cohort consisted of HIV-infected patients who were virologically suppress with high CD4 counts – the risk of hepatotoxicity may be different in HIV-infected individuals with TB and/or with different CD4 counts.
Pharmacokinetics of lopinavir in HIV-infected adults receiving rifampin with adjusted doses of lopinavir-ritonavir tablets. Decloedt EH, McIlleron H, Smith P, et al. Antimicrob Agents Chemother, 2011, 55(7): 3195-3200.

A study looking at the interaction between rifampicin (600 mg once daily) and LPV/RTV (600/150 or 800/200 mg twice daily) in 11 HIV- subjects had to be terminated early due to severe nausea, vomiting and elevated AST/ALT. No major complaints or laboratory abnormalities were noted during the first phase of the study (rifampicin alone), but 10/11 subjects suffered from nausea and/or vomiting following the addition of LPV/RTV. No LPV was detected in trough samples from 5/11 subjects (due to either no drug intake or vomiting); trough concentrations in 3 subjects receiving 600/150 mg were 6.7, 7.2 and 10.3 µg/ml and in 3 subjects receiving 800/200 mg were 8.3, 11.5 and 13.8 µg/ml. The reasons for the adverse events may be related to a) the sequence of drug administration, b) non-linear pharmacokinetics of LPV/RTV after intake of higher doses, or c) unknown factors which make healthy volunteers more susceptible to adverse events.
Unexpected high incidence of nausea, vomiting and asymptomatic elevations of AST/ALT enzymes in healthy volunteers receiving rifampin and adjusted doses of lopinavir/ritonavir tablets. Nijland H, et al. 8th International Workshop on Clinical Pharmacology of HIV Therapy, Budapest, April 2007, abstract 51.

Two twice-daily adjusted-dose regimens of lopinavir/ritonavir were tested in combination with rifampicin in healthy subjects. All subjects were treated with LPV/r 400/100 mg from days 1-15. From days 16-24 half the subjects were given LPV/r 800/200 mg (Arm 1) in dose titration and half LPV/r 400/400 mg (Arm 2) in dose titration. Rifampicin was given to all subjects between days 11-24. PK data was available from 19 subjects. The geometric mean ratio for lopinavir AUC12, Cmin and Cmax were 0.84, 0.43 and 1.02 respectively in arm 1 (800/200 mg) were 0.98, 1.03 and 0.93 respectively in arm 2 (400/400 mg). There was toxicity observed with the higher dose of LPV/r and rifampicin with discontinuation in 9/29 subjects (31%). The treatment of HIV-infected patients with TB with these agents must be approached with caution and close monitoring of liver function is essential. Judicious use of TDM will aid ensuring LPV levels are above the minimum required.
Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. la Porte CJ, Colbers EP, Bertz R, et al. Antimicrob Agents Chemother, 2004, 48: 1553-1560.

View all available interactions with Lopinavir/ritonavir (LPV/r) by clicking here.