title: Pharmacokinetics and pharmacodynamics of aliskiren/hydrochlorothiazide single-pill combination tablets and free combination of aliskiren and hydrochlorothiazide.
abstract: Single-pill combinations (SPCs) of complementary antihypertensive agents provide patients with a simple and effective treatment regimen. To ensure that the efficacy and safety of an SPC is the same as that for the individual drugs administered together (free combination), SPC and free-combination formulations must be shown to be bioequivalent. Three open-label, randomized studies compared the pharmacokinetics of SPC tablets of the direct renin inhibitor aliskiren and hydrochlorothiazide (HCT), at doses of 150/25, 300/12.5, and 300/25 mg, with the corresponding free combinations in healthy volunteers. Data from 2 randomized, double-blinded studies of patients with hypertension were used to assess inhibition of plasma renin activity (PRA) by the aliskiren/HCT 300/25 mg SPC and the free combination. At all dose combinations, aliskiren and HCT systemic drug exposure was similar when administered as an SPC or free combination, indicating bioequivalence. Aliskiren/HCT 300/25 mg SPC inhibited PRA to the same extent as the free combination. HCT alone increased PRA through activation of the renin-angiotensin system; aliskiren prevented this diuretic-induced increase to the same extent when administered as the free combination or as the SPC. In conclusion, aliskiren/HCT SPCs are pharmacokinetically and pharmacodynamically bioequivalent to aliskiren and HCT in free combination.
authors.affiliation: Novartis Institutes for BioMedical Research, Inc, Cambridge, MA 02139, USA.
authors.forename: Jing-He
authors.initials: JH
authors.lastname: Yan
authors.forename: Venkateswar
authors.initials: V
authors.lastname: Jarugula
authors.forename: Ron
authors.initials: R
authors.lastname: Sabo
authors.forename: Cheraz Cherif
authors.initials: CC
authors.lastname: Papst
authors.forename: Jack
authors.initials: J
authors.lastname: Zhang
authors.forename: William P
authors.initials: WP
authors.lastname: Dole
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000577:Amides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D016018:Least-Squares Analysis; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D012083:Renin / Q000378:metabolism; D013607:Tablets; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D055815:Young Adult; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D004232:Diuretics; D004338:Drug Combinations; D005650:Fumarates; D006852:Hydrochlorothiazide; D012083:Renin; D013607:Tablets; D000092502:Renin Inhibitors; C446481:aliskiren