title: Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non-peptide AVP antagonist in healthy subjects.
abstract: BACKGROUND
  Before these trials were done, the effects of CYP3A4 inhibition and induction on the pharmacokinetics (PK) and pharmacodynamics (PD) of tolvaptan in healthy subjects were unknown. As tolvaptan is a CYP3A4 substrate, knowing the effects of inhibition and induction on CYP3A4-mediated metabolism was important for dosing recommendations.
  
  
  CONCLUSIONS
  This paper describes the changes in tolvaptan PK and PD following inhibition or induction of CYP3A4 and explores the mechanisms behind the disparity seen between tolvaptan PK and effects on urine output. It also discusses the concentrations at which tolvaptan produces its maximal response on urine output and the timing of the onset and offset of this response. AIMS In vitro studies indicated CYP3A4 alone was responsible for tolvaptan metabolism. To determine the effect of a CYP3A4 inhibitor (ketoconazole) and a CYP3A4 inducer (rifampicin) on tolvaptan pharmacokinetics (PK) and pharmacodynamics (PD), two clinical trials were performed.
  
  
  METHODS
  For CYP3A4 inhibition, a double-blind, randomized (5:1), placebo-controlled trial was conducted in 24 healthy subjects given either a single 30 mg dose of tolvaptan (n= 19) or matching placebo (n= 5) on day 1 with a 72 h washout followed by a 3 day regimen of 200 mg ketoconazole, once daily with 30 mg tolvaptan or placebo also given on day 5. For CYP3A4 induction, 14 healthy subjects were given a single dose of 240 mg tolvaptan with 48 h washout followed by a 7 day regimen of 600 mg rifampicin, once daily, with 240 mg tolvaptan also given on the seventh day.
  
  
  RESULTS
  When co-administered with ketoconazole, mean C(max) and AUC(0,∞) of tolvaptan were increased 3.48- and 5.40-fold, respectively. Twenty-four hour urine volume increased from 5.9 to 7.7 l. Erythromycin breath testing showed no difference following a single dose of tolvaptan. With rifampicin, tolvaptan mean C(max) and AUC were reduced to 0.13- and 0.17-fold of tolvaptan administered alone. Twenty-four hour urine volume decreased from 12.3 to 8.8 l.
  
  
  CONCLUSIONS
  Tolvaptan is a sensitive CYP3A4 substrate with no inhibitory activity. Due to the saturable nature of tolvaptan's effect on urine excretion rate, changes in the pharmacokinetic profile of tolvaptan do not produce proportional changes in urine output.
authors: Otsuka Pharmaceutical Development & Commercialization, Inc., 2440 Research Blvd, Rockville, MD 20850, USA. susan.shoaf@otsuka-us.com
authors: Susan E
authors: SE
authors: Shoaf
authors: Patricia
authors: P
authors: Bricmont
authors: Suresh
authors: S
authors: Mallikaarjun
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D065092:Antidiuretic Hormone Receptor Antagonists; D019540:Area Under Curve; D001552:Benzazepines / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000652:urine; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D012293:Rifampin / Q000494:pharmacology; D000077602:Tolvaptan; D014554:Urination / Q000187:drug effects; D055815:Young Adult
chemical_list: D058888:14-alpha Demethylase Inhibitors; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D000077602:Tolvaptan; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole; D012293:Rifampin