Liverpool HIV Interactions

Do Not Coadminister

Cabotegravir/rilpivirine [long acting] (CAB/RPV LA)

Rifampicin

Quality of Evidence: Very Low

Summary:

Coadministration with intramuscular cabotegravir and rilpivirine has not been studied and is contraindicated due to the risk of sub-therapeutic concentrations and the related risk of the development of resistance. Coadministration of rifampicin (600 mg once daily) and oral cabotegravir (30 mg once daily) decreased cabotegravir Cmax, AUC and C24 by 6%, 59% and 50%, respectively. Similarly to oral cabotegravir, concomitant administration with rifampicin is not recommended with intramuscular cabotegravir. Furthermore, significant decreases in rilpivirine plasma concentrations are expected. Coadministration of rilpivirine (150 mg once daily) and rifampicin (600 mg once daily) decreased rilpivirine Cmax, AUC and Cmin by 69%, 80% and 89%, respectively. There was no significant effect on rifampicin. Coadministration is contraindicated due to the potential for loss of therapeutic effect and development of resistance. Using PBPK modelling, rifampicin was predicted to reduce the exposure of long-acting intramuscular cabotegravir by 61% and rilpivirine by 38%. The interaction with rifampicin was not overcome by shortening the dosing interval of intramuscular cabotegravir and rilpivirine.

Description:

Coadministration of rifampicin and oral cabotegravir decreased cabotegravir AUC and Cmax by 59% and 6%. Rifampicin significantly decreased cabotegravir plasma concentration which is likely to result in loss of therapeutic effect. Dosing recommendations for co-administration of Vocabria with rifampicin have not been established and co-administration of Vocabria with rifampicin is contraindicated.

Vocabria (cabotegravir oral and injection) European Summary of Product Characteristics, ViiV Healthcare, January 2021.

Coadministration of oral rilpivirine and rifampicin (600 mg once daily) had no effect on rifampicin AUC or Cmax; 25-desacetyl-rifampicin AUC decreased by 9% and there was no change in Cmax. Rilpivirine AUC, Cmin and Cmax decreased by 80%, 89% and 69%, respectively. Rilpivirine must not be used in combination with rifampicin as co-administration is likely to result in loss of therapeutic effect of rilpivirine. [This interaction study has been performed with a dose higher than the recommended dose for rilpivirine assessing the maximal effect on the co-administered medicinal product. The dosing recommendation is applicable to the recommended dose of rilpivirine of 25 mg once daily.]

Rekambys (rilpivirine prolonged release injection) European Summary of Product Characteristics, Janssen-Cilag, January 2021.

Coadministration is predicted to decrease concentrations of cabotegravir and rilpivirine. Coadministration is contraindicated with Cabenuva due to potential for loss of virologic response and development of resistance. Coadministration of rifampicin (600 mg once daily) and oral cabotegravir (30 mg single dose) was studied in 15 subjects. Cabotegravir Cmax, AUC and Ctau decreased by 6%, 59% and 50%, respectively. Coadministration of rifampin (600 mg once daily) and oral rilpivirine (150 mg once daily) was studied in 16 subjects. Rilpivirine Cmax, AUC and Cmin decreased by 69%, 80% and 89%, respectively. Rifampin Cmax increased by 2% and AUC decreased by 1%; there was no change in Cmax of 25-desacetylrifampin, but AUC decreased by 9%. [This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug.]

Cabenuva (cabotegravir/rilpivirine extended release injection) US Prescribing Information, ViiV Healthcare, January 2021.

Coadministration of oral cabotegravir (30 mg once daily) and rifampicin (600 mg once daily) was studied in 15 subjects and was found to decrease cabotegravir AUC, Cmax and C24 by 21%, 17% and 26%, respectively. Rifampicin decreased cabotegravir AUC and Cmax by 59% and 6%. Half-life decreased by 57% and oral clearance was increased by 2.4-fold. Concomitant administration of rifampicin with oral and long-acting formulations of cabotegravir is not recommended currently without further study.

Effect of rifampin on the single-dose pharmacokinetics of oral cabotegravir in healthy subjects. Ford SL, Sutton K, Lou Y, et al. Antimicrob Agents Chemother. 2017;61(10):e00487-17.

PBPK modelling was used to simulate the interaction between long-acting (LA) intramuscular cabotegravir/rilpivirine and the strong inducer rifampicin. At steady-state, rifampicin was predicted to reduce the exposure of LA cabotegravir by 61% and rilpivirine by 38% with a large proportion of individuals predicted to have concentrations below 664 ng/mL (i.e., 4x PA-IC90) for cabotegravir and below 50 ng/mL for rilpivirine at the end of the dosing interval. An increase in the dosing frequency did not overcome the interaction with rifampicin. Increasing the dosing frequency of cabotegravir to 4 weeks or to 3 weeks did not significantly improve cabotegravir exposure. Similarly, an increase in the dosing frequency of rilpivirine was not able to overcome the interaction with rifampicin. Therefore, coadministration of long-acting intramuscular cabotegravir and rilpivirine should be avoided with strong inducers.

Management of drug-drug interactions between long-acting cabotegravir and rilpivirine and comedications with inducing properties: a modelling study. Bettonte S, Berton M, Stader F, et al. Clin Infect Dis, 2022, online ahead of print.

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