title: Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of ABT-493: A First-In-Human Study.
abstract: ABT-493 is a hepatitis C virus nonstructural protein 3/4A protease inhibitor with pangenotypic antiviral activity. This study investigated the pharmacokinetics, safety, and tolerability of single and multiple ascending doses of ABT-493 and the effect of food and ritonavir coadministration on ABT-493 pharmacokinetics in healthy adults. In the blinded, randomized, placebo-controlled phase 1 single- and multiple-dose portions of the study, ABT-493 25-800 mg were evaluated as single doses, and 200, 400, and 800 mg were evaluated as multiple doses. The effect of food and ritonavir was assessed in a crossover unblinded fashion. ABT-493 pharmacokinetic parameters were estimated using noncompartmental methods. ABT-493 25-800 mg showed a greater than dose-proportional increase in exposures. Minimal accumulation (≤15%) was observed after ABT-493 200- and 400-mg multiple dosing; higher accumulations (approximately 80%) were observed after the 800-mg dose. ABT-493 harmonic mean half-life was 6-9 hours. Food had a minimal effect on ABT-493 exposures. All adverse events were assessed by the investigator as mild to moderate in severity, no serious adverse events were reported, and no subjects discontinued from the study. No clinically significant laboratory tests, vital signs, or electrocardiogram values were reported. A maximum tolerated dose was not reached.
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois 60064.
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois 60064.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Infectious Diseases, AbbVie Inc., North Chicago, Illinois 60064.
authors.forename: Armen
authors.initials: A
authors.lastname: Asatryan
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois 60064.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chiu
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois 60064.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois 60064.
authors.forename: Jack
authors.initials: J
authors.lastname: Clifton
authors.affiliation: Infectious Diseases, AbbVie Inc., North Chicago, Illinois 60064.
authors.forename: Andrew
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois 60064. Electronic address: wei.liu@abbvie.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
mesh_terms: D000328:Adult; D000621:Aminoisobutyric Acids; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood*; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D018565:Food-Drug Interactions; D006505:Hepatitis / Q000188:drug therapy; D006801:Humans; D047029:Lactams, Macrocyclic; D007930:Leucine / Q000031:analogs & derivatives; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D011392:Proline / Q000031:analogs & derivatives; D011810:Quinoxalines / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood*
chemical_list: D000621:Aminoisobutyric Acids; D000998:Antiviral Agents; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D011810:Quinoxalines; D013449:Sulfonamides; D011392:Proline; D007930:Leucine; C000612853:glecaprevir
keywords: bioavailability; clinical pharmacokinetics; cytochrome P450; food effects