Liverpool COVID-19 Interactions

Do Not Coadminister

Nirmatrelvir/ritonavir (5 days)

Acalabrutinib

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied and is not recommended. Acalabrutinib is metabolised by CYP3A4 and concentrations are expected to increase due to strong inhibition of CYP3A4 by nirmatrelvir/ritonavir. Itraconazole (a strong CYP3A4 inhibitor) increased acalabrutinib AUC by 5-fold. A similar effect is expected with nirmatrelvir/ritonavir and coadministration is not recommended. When short course treatment with strong inhibitors (such as nirmatrelvir/ritonavir) is required, the product label for acalabrutinib advises to stop temporarily acalabrutinib treatment. Restart acalabrutinib 3 days after completing nirmatrelvir/ritonavir treatment given that CYP3A4 inhibition takes several days to resolve. Of interest, a PBPK modelling study predicted ritonavir (100 mg twice daily for 5 days) to increase acalabrutinib Cmax and AUC by 3.85- and 6.54-fold and suggests that the interaction with nirmatrelvir/ritonavir can be overcome by administering acalabrutinib at a reduced dose of 25 mg twice daily.

Description:

PBPK models were developed to predict the drug interactions of Bruton’s tyrosine kinase inhibitors (ibrutinib, zanubrutinib and acalabrutinib) with ritonavir (100 mg twice daily for 5 days). Ritonavir was predicted to increase ibrutinib Cmax and AUC by 33- and 53.88-fold, to increase zanubrutinib Cmax and AUC 2.57- and 3.18-fold, and to increase acalabrutinib Cmax and AUC 3.85- and 6.54-fold. Based on these simulations, dose-adjustment strategies may consist of ibrutinib at 25 mg every 48 h, zanubrutinib at 80 mg twice daily and acalabrutinib at 25 mg twice daily with nirmatrelvir/ritonavir.

Drug-drug interactions and dose management of BTK inhibitors when initiating nirmatrelvir/ritonavir (Paxlovid) based on physiologically-based pharmacokinetic models. Li C, Chen L, Li L, Chen W. Eur J Pharm Sci. 2023, 189: epub ahead of print.