Effects of nirmatrelvir/ritonavir on midazolam and dabigatran pharmacokinetics in healthy participants

Abstract

Aims To evaluate pharmacokinetics (PK) and safety after coadministration of nirmatrelvir/ritonavir or ritonavir alone with midazolam (a cytochrome P450 3A4 substrate) and dabigatran (a P‐glycoprotein substrate). Methods PK was studied in 2 phase 1, open‐label, fixed‐sequence studies in healthy adults. Single oral doses of midazolam 2 mg ( n = 12) or dabigatran 75 mg ( n = 24) were administered alone and after steady state (i.e. ≥2 days) of nirmatrelvir/ritonavir 300 mg/100 mg and ritonavir 100 mg. Midazolam and dabigatran plasma concentrations and adverse events were analysed for each treatment. Results After administration of midazolam with nirmatrelvir/ritonavir (test) or alone (reference), midazolam geometric mean area under the concentration–time curve extrapolated to infinity (AUC inf ) and maximum plasma concentration (C max ) increased 14.3‐fold and 3.7‐fold, respectively. Midazolam coadministered with ritonavir (test) or alone (reference) resulted in 16.5‐fold and 3.9‐fold increases in midazolam geometric mean AUC inf and C max , respectively. After administration of dabigatran with nirmatrelvir/ritonavir (test) or alone (reference), dabigatran geometric mean AUC inf and C max increased 1.9‐fold and 2.3‐fold, respectively. Dabigatran coadministered with ritonavir (test) or alone (reference) resulted in a 1.7‐fold increase in dabigatran geometric mean AUC inf and C max . Midazolam or dabigatran exposures were generally comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, with a slightly higher dabigatran C max with nirmatrelvir/ritonavir vs . ritonavir alone. Nirmatrelvir/ritonavir was generally safe when administered with or without midazolam or dabigatran. No serious or severe adverse events were reported. Conclusion Coadministration of midazolam or dabigatran with nirmatrelvir/ritonavir increased systemic exposure of midazolam or dabigatran. Midazolam exposures were comparable when coadministered with nirmatrelvir/ritonavir or ritonavir alone, suggesting no incremental effect of nirmatrelvir. Dabigatran C max was slightly higher when coadministered with nirmatrelvir/ritonavir compared with of ritonavir alone, suggesting a minor incremental effect of nirmatrelvir.