title: Phase 1 single dose studies to optimize the pharmacokinetics of DG17, a novel HIV-protease inhibitor pro-drug, using sodium bicarbonate and ritonavir.
abstract: DG17 is an orally available prodrug of DG35 (a novel HIV protease inhibitor with variable pharmacokinetics). These studies aimed to optimize DG17 pharmacokinetics by gastric acid neutralization and ritonavir pharmacoenhancement. Both studies were conducted using a randomized, cross-over design in which 6 healthy individuals were administered a single dose of 100mg or 200mg DG17, half with the study intervention (sodium bicarbonate solution in the first study, low dose ritonavir in the second). After a one week washout period, each subject was then administered a second dose of DG17, with the study intervention only administered to the other half. Cmax and AUC increases with gastric acid neutralization were greatest in those with the lowest absorption of DG17 alone. All doses were subsequently given with sodium bicarbonate solution in the second study. Low-dose ritonavir co-administration with DG17 increased DG35 C(max) (median 1437 versus 100 ng/ml, p=0.028) and AUC (median 6975 versus 154ng/ml*hr, p=0.028) compared with DG17 without ritonavir. Plasma DG35 exceeded the IC(90) for HIV for > or = 12 hours following a single DG17/ritonavir dose. No significant adverse events occurred. Single dose DG17 is safe and best administered in a manner preventing gastric acid degradation and with low-dose ritonavir.
authors.affiliation: Burnet Institute, Melbourne, Australia. kcherry@burnet.edu.au
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Cherry
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Hoy
authors.forename: James S
authors.initials: JS
authors.lastname: Rowe
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: John
authors.initials: J
authors.lastname: Mills
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005744:Gastric Acid / Q000378:metabolism; D006678:HIV / Q000254:growth & development*; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017693:Sodium Bicarbonate / Q000627:therapeutic use*
chemical_list: C530654:DG17 compound; D017320:HIV Protease Inhibitors; D011355:Prodrugs; D017693:Sodium Bicarbonate; D019438:Ritonavir