Amenamevir (formerly ASP2151) is a helicase-primase inhibitor being developed for the treatment of herpesvirus infection. Amenamevir is both a substrate and inducer of cytochrome P450 (CYP) 3A4. Three studies were done in healthy volunteers to investigate potential CYP3A pharmacokinetic interactions with the following drugs: (1) Midazolam (probe substrate for CYP3A): After 10 days' pretreatment with amenamevir 400 mg daily, geometric mean maximum concentration of drug in blood plasma (C ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC ) of midazolam 7.5 mg were about 68% and 51%, respectively, of those after midazolam alone. (2) Cyclosporine (substrate and inhibitor of CYP3A): After 5 days' pretreatment with cyclosporine 100 mg twice daily, geometric mean C of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 66% and 69%, and AUC about 82% and 79%, of those after amenamevir alone. (3) Ritonavir (inhibitor of CYP3A): When given with single doses of ritonavir 600 mg, geometric mean C of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 1.4 and 1.6 times higher, and geometric mean AUC about 2.6 and 3.3 times higher, than after amenamevir alone. Amenamevir has the potential to be involved in CYP3A-mediated pharmacokinetic interactions in clinical practice.

NCT02588521.

Background A knowledge of the biology of colorectal liver metastases would be invaluable to inform clinical decision making; however, deriving this information from metastatic lesions is not feasible until after resection. We aimed to use proteomic analysis to establish the degree of biological similarity across disease sites and identify and validate biomarkers in the primary tumour that predict response to neoadjuvant chemotherapy in liver metastases.Methods Tissue from primary colorectal tumour and liver metastases (n=16) were subjected to proteomic analysis with isobaric tagging for relative quantifi cation. Data were analysed with ProteinPilot software (Ab Sciex, Framingham, MA USA) with stratifi cation of patients into low or high response to chemotherapy. These biomarkers were investigated by immunohistochemistry on a tissue microarray of 56 patients. Their therapeutic potential was investigated by dosing of SW480 cells with irinotecan or fl uorouracil with or without inhibition by small interfering RNA (siRNA) or a competitive inhibitor (dicoumarol).Findings We identifi ed 5766 discrete proteins, of which 2•54% were diff erentially expressed between primary and metastatic tumours. There were 170 potential response biomarkers in the primary tumour and 27 in the metastases. Lambda-crystallin homolog and NQO1 were common to both tissue types and showed consistent dysregulation. Immunostaining of NQO1 in metastatic tissue was lower in patients responding than in those not responding to chemotherapy (p=0•041), with a signifi cant correlation between primary and metastatic disease sites (r=0•44, p=0•001). Knockdown of NQO1 with siRNA followed by treatment with irinotecan or fl uorouracil reduced the IC50 from 100•1 to 49•8 μM and from 200•1 to 25•0 μM, respectively. Treatment of cells with dicoumarol before incubation in irinotecan or fl uorouracil reduced the IC50 from 100•0 μM to 50•0 μM and from 183•7 μM to 49•9 μM, respectively.Interpretation We show that proteomic sequencing of matched metastatic colorectal cancer samples is feasible with high coverage. The high degree of similarity between the primary and secondary tumours suggests that the primary tissue is predictive of the metastatic phenotype. NQO1 expression in the primary tumour predicts response to neoadjuvant chemotherapy in liver metastases, and inhibition of this protein at both genetic and functional levels improves chemosensitivity.