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. 2023 Sep;89(9):2867-2876.
doi: 10.1111/bcp.15788. Epub 2023 May 31.

Effects of itraconazole and carbamazepine on the pharmacokinetics of nirmatrelvir/ritonavir in healthy adults

Donna S Cox  1 , Lien Van Eyck  2 , Sylvester Pawlak  3 , Bruce Beckerman  4 , Carlos Linn  5 , Katherine Ginman  6 , Youliny Thay Cha  6 , Robert R LaBadie  6 , Haihong Shi  6 , Bharat Damle  7
Affiliations
Free article

Effects of itraconazole and carbamazepine on the pharmacokinetics of nirmatrelvir/ritonavir in healthy adults

Donna S Cox et al. Br J Clin Pharmacol. 2023 Sep.
Free article

Abstract

Aims: The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir.

Methods: Pharmacokinetics were measured in two phase 1, open-label, fixed-sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed.

Results: Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUCtau and Cmax were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUCinf and Cmax were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported.

Conclusions: Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe.

Keywords: drug interactions; drug safety; infectious diseases; medication safety; pharmacokinetics; virology.

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References

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