K. P. Faber,1 H. F. Wu,2 M. R. Yago,2 L. Frassetto,2 L. Z. Benet2; 1Genentech, South San Francisco, CA, 2University of California, San Francisco, San Francisco, CA
BACKGROUND: Significant pharmacokinetic (PK) interactions exist between gastric acid-reducing agents and certain protease inhibitors, most notably atazanavir (ATV), which rely on acidic environments for optimal oral absorption. Under fasting conditions, betaine hydrochloride (BHCl) effectively restored the exposure of dasatinib, a weakly basic drug with pH-dependent solubility, in healthy subjects pretreated with rabeprazole (RAB). Here we examined if BHCl administration during fed conditions could mitigate reductions in ATV exposure observed during pharmacologically-induced hypochlorhydria.
METHODS: In this 3 period, crossover study, 8 healthy subjects received ritonavir-boosted ATV (ATV/RTV 300/100 mg): (A) alone, (B) after pretreatment with RAB (20mg BID x 3 d), and (C) 5 min following BHCl (1500 mg), after RAB pretreatment. ATV was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule. ATV and RTV plasma concentrations were measured over 22 hr and PK parameters were determined by non-compartmental analysis.
RESULTS: Pretreatment with RAB resulted in significant decreases in ATV Cmax (p<0.01) and AUC0-22 (p<0.001) (mean % change±SD) (71±30% and 70±23%, respectively), and modest decreases in RTV Cmax and AUC0-22 (p<0.01) (40±59% and 41±20%, respectively), relative to ATV/RTV alone. Addition of BHCl restored 13% of ATV Cmax and 12% of AUC0-22 lost due to RAB pretreatment.
CONCLUSION: Co-administration of RAB with ATV/RTV resulted in significant decreases in ATV exposure. Addition of BHCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Analyses of pH and concentration data suggest further time separation of BHCl and ATV administration may result in more substantial gains in exposure.