title: Pharmaceutical approach to HIV protease inhibitor atazanavir for bioavailability enhancement based on solid dispersion system.
abstract: Atazanavir (ATV) is a low oral bioavailability (BA) compound and, clinically, is generally coadministrated with ritonavir (RTV), which boosts the oral BA of ATV by inhibiting cytochrome P450 (CYP) 3A, and P-glycoprotein (Pgp) via the same metabolic pathway. However, depending on pharmacokinetic interaction, RTV-boosted ATV has great potential for other comedication. In this study we demonstrated the pharmaceutical approach to BA improvement of ATV without RTV in rats, based on the solid dispersion system using sodium lauryl sulfate (SLS) as a carrier and Gelucire 50/13 as an absorption enhancer. ATV solid dispersions in SLS were prepared by a conventional solvent method and, at ratios of ATV to SLS of 1 : 2 and 1 : 3, were demonstrated to form an amorphous state in powder X-ray diffraction (PXRD) analysis and exhibited 2.26- and 2.36-fold improvement in a dissolution test in comparison to bulk ATV, respectively. After oral administration to rats, ATV solid dispersion in SLS at a ratio of 1 : 2 showed a 3.5-fold increase in BA compared with bulk ATV. Moreover, the addition of Gelucire 50/13 to ATV solid dispersion, at a total ratio of Gelucire 50/13, ATV and SLS 1 : 1 : 2 gave 7.0- and 4.7-fold increase in Cmax and BA compared with bulk ATV, respectively, when the relative BA to RTV-boosted ATV reached 93%. The results in this study proved that a pharmaceutical approach could improve the bioavailability of ATV without pharmacokinetic interaction with RTV.
authors.affiliation: Department of Pharmacokinetics, Kyoto Pharmaceutical University, Japan.
authors.forename: Keizo
authors.initials: K
authors.lastname: Fukushima
authors.forename: Shuichi
authors.initials: S
authors.lastname: Terasaka
authors.forename: Kenta
authors.initials: K
authors.lastname: Haraya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kodera
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Seki
authors.forename: Ayako
authors.initials: A
authors.lastname: Wada
authors.forename: Yukako
authors.initials: Y
authors.lastname: Ito
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Shibata
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sugioka
authors.forename: Kanji
authors.initials: K
authors.lastname: Takada
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000069446:Atazanavir Sulfate; D001682:Biological Availability; D004337:Drug Carriers / Q000737:chemistry*; D005079:Excipients / Q000737:chemistry*; D005223:Fats / Q000737:chemistry*; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D009821:Oils / Q000737:chemistry*; D009842:Oligopeptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011208:Powders; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D004337:Drug Carriers; D005079:Excipients; D005223:Fats; D017320:HIV Protease Inhibitors; D009821:Oils; D009842:Oligopeptides; D011208:Powders; D011725:Pyridines; C071184:Gelucire 50-13; D012967:Sodium Dodecyl Sulfate; D000069446:Atazanavir Sulfate