title: Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption.
abstract: Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria.
  
  
  
  In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule.
  
  
  
  Pretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax(p < 0.01) and AUC0-last(p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmaxand AUClast(p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmaxand 12% of AUClastlost due to rabeprazole.
  
  
  
  The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Ave., Room U-68, San Francisco, CA, 94143-0912, USA.
authors.forename: Kathleen Panter
authors.initials: KP
authors.lastname: Faber
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Ave., Room U-68, San Francisco, CA, 94143-0912, USA.
authors.forename: Hsin-Fang
authors.initials: HF
authors.lastname: Wu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Ave., Room U-68, San Francisco, CA, 94143-0912, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Yago
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xu
authors.affiliation: Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, New Jersey, USA.
authors.forename: Pathanjali
authors.initials: P
authors.lastname: Kadiyala
authors.affiliation: Department of Medicine University of California San Francisco, San Francisco, California, USA.|Clinical Research Center, University of California San Francisco, San Francisco, California, USA.
authors.forename: Lynda A
authors.initials: LA
authors.lastname: Frassetto
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Ave., Room U-68, San Francisco, CA, 94143-0912, USA. leslie.benet@ucsf.edu.
authors.forename: Leslie Z
authors.initials: LZ
authors.lastname: Benet
mesh_terms: D065567:Absorption, Physiological; D000126:Achlorhydria / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D000284:Administration, Oral; D000328:Adult; D000069446:Atazanavir Sulfate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001622:Betaine / Q000008:administration & dosage; D018592:Cross-Over Studies; D004347:Drug Interactions; D005260:Female; D018565:Food-Drug Interactions; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D064750:Rabeprazole / Q000009:adverse effects / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D001622:Betaine; D000069446:Atazanavir Sulfate; D019438:Ritonavir
keywords: PPIs; absorption; atazanavir; food effects; weakly basic drugs