Kathleen Panter Faber1, Hsin-Fang Wu1, Marc R Yago1, Xiaohui Xu2, Pathanjali Kadiyala2, Lynda A Frassetto3,4, Leslie Z Benet5. 1. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, 533 Parnassus Ave., Room U-68, San Francisco, CA, 94143-0912, USA. 2. Bioanalytical Sciences, Bristol-Myers Squibb, Princeton, New Jersey, USA. 3. Department of Medicine University of California San Francisco, San Francisco, California, USA. 4. Clinical Research Center, University of California San Francisco, San Francisco, California, USA. 5. 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.
Abstract
PURPOSE: 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. METHODS: 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. RESULTS: 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 Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole. CONCLUSIONS: 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.
RCT Entities:
PURPOSE: 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. METHODS: 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. RESULTS: Pretreatment with rabeprazole resulted in significant reductions in atazanavirCmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavirCmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATVCmax and 12% of AUClast lost due to rabeprazole. CONCLUSIONS: 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: Gillian S Smelick; Timothy P Heffron; Laura Chu; Brian Dean; David A West; Scott L Duvall; Bert L Lum; Nageshwar Budha; Scott N Holden; Leslie Z Benet; Adam Frymoyer; Mark J Dresser; Joseph A Ware Journal: Mol Pharm Date: 2013-10-24 Impact factor: 4.939
Authors: Marc R Yago; Adam R Frymoyer; Gillian S Smelick; Lynda A Frassetto; Nageshwar R Budha; Mark J Dresser; Joseph A Ware; Leslie Z Benet Journal: Mol Pharm Date: 2013-09-10 Impact factor: 4.939