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Amenamevir: Studies of Potential CYP3A-Mediated Pharmacokinetic Interactions With Midazolam, Cyclosporine, and Ritonavir in Healthy Volunteers.

ABSTRACT: 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_max ) and area under the plasma drug concentration-time curve from time zero to infinity (AUC_0-∞ ) 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_max of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 66% and 69%, and AUC_0-∞ 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_max of amenamevir after 400-mg and 1200-mg single doses was, respectively, about 1.4 and 1.6 times higher, and geometric mean AUC_0-∞ 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.

SUBMITTER: Adeloye T

PROVIDER: S-EPMC6585933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n?=?10) and the potential two-way pharmacokinetic interactions of elbasvir (n?=?30) or grazoprevir (n?=?39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24?h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.

Project description:Background and objectiveTrilaciclib is a cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression in patients with extensive-stage small-cell lung cancer. Trilaciclib is a substrate and time-dependent inhibitor of cytochrome P450 3A4 and an inhibitor of multidrug and toxin extrusion 1, multidrug and toxin extrusion 2-K, organic cation transporter 1, and organic cation transporter 2. Here, we investigate the pharmacokinetic drug-drug interaction potential of trilaciclib.MethodsTwo phase I studies were conducted as prospective, open-label, fixed-sequence drug-drug interaction studies in healthy subjects (n = 57, n = 20) to investigate potential interactions between intravenously administered trilaciclib (200 or 240 mg/m2) and orally administered midazolam (5 mg), metformin (1000 mg), itraconazole (200 mg), and rifampin (600 mg). A population pharmacokinetic model was fit to phase Ib/IIa data in patients with extensive-stage small-cell lung cancer (n = 114) to assess the impact of trilaciclib dose and exposure (area under the plasma concentration-time curve) on topotecan clearance.ResultsCoadministration with trilaciclib had minimal effects on the exposure (area under the plasma concentration-time curve from time 0 to infinity) of midazolam (geometric least-square mean ratio [GMR] vs midazolam alone 1.065; 90% confidence interval [CI] 0.984-1.154) but statistically significantly increased plasma exposure (GMR 1.654; 90% CI 1.472-1.858) and decreased renal clearance (GMR 0.633; 90% CI 0.572-0.701) of metformin. Coadministration of trilaciclib with rifampin or itraconazole decreased trilaciclib area under the plasma concentration-time curve from time 0 to infinity by 17.3% (GMR 0.827; 90% CI 0.785-0.871) and 14.0% (GMR 0.860; 0.820-0.902), respectively, vs trilaciclib alone. Population pharmacokinetic modeling showed no significant effect of trilaciclib on topotecan clearance.ConclusionsOverall, the drug-drug interaction and safety profiles of trilaciclib in these studies support its continued use in patients with extensive-stage small-cell lung cancer.Clinical trial registrationStudy 106: EudraCT number: 2019-002303-18; Study 114: not applicable; Study 03: Clinicaltrials.org: NCT02514447; August 2015.

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Amenamevir: Studies of Potential CYP3A-Mediated Pharmacokinetic Interactions With Midazolam, Cyclosporine, and Ritonavir in Healthy Volunteers.

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