title: Pharmacokinetics and food interaction of a novel prodrug of tenofovir, tenofovir dipivoxil fumarate, in healthy volunteers.
abstract: OBJECTIVE
  Tenofovir dipivoxil fumarate is a novel ester prodrug of tenofovir, a specific anti-hepatitis B virus (HBV) drug candidate. The pharmacokinetic properties and the effects of food intake on tenofovir dipivoxil have not yet been reported in healthy adults. The aim of this study was to evaluate the pharmacokinetic properties and food interaction of tenofovir dipivoxil in healthy Chinese volunteers.
  
  
  METHODS
  Pharmacokinetic studies included an ascending single dose of 150, 300, 600 mg and multiple doses of 300 mg. Food interaction was evaluated following a single oral dose of tenofovir dipivoxil fumarate 300 mg administered with a high-fat and high-energy standard breakfast or after a 12-h fast. Pharmacokinetic parameters of tenofovir given in each treatment period were calculated using non-compartmental analysis.
  
  
  RESULTS
  After a single dose of 150, 300 and 600 mg, the main pharmacokinetic parameters for tenofovir were as follows: Cmax 209·6, 456·7, 989·8 ng/mL; AUClast 1744·9, 2663·5, 6010·2 ng h/mL, respectively. After multiple doses of 300 mg, the main pharmacokinetic parameters for tenofovir were Cmax 523·4 ng/mL, AUClast 4152·4 ng h/mL. After a single dose of 300 mg with a high-fat and high-energy standard breakfast, the main pharmacokinetic parameters for tenofovir were Cmax 448·5 ng/mL, AUClast 3286·8 ng h/mL. The plasma Cmax and AUC of tenofovir showed significance difference between a single dose of 300 mg and the accordingly multiple doses (P < 0·05). A standard high-fat meal enhanced mean AUClast values of tenofovir (relative AUClast  = 125·8%; 90% CI 114·5, 136·2); however, food did not show any significant on Cmax (relative Cmax  = 103·4%; 90% CI 94·6, 112·6).
  
  
  CONCLUSIONS
  Oral tenofovir dipivoxil fumarate produced predictable and dose-proportional plasma tenofovir pharmacokinetics. The accumulation ratio was 1·51, suggesting tenofovir dipivoxil fumarate displayed accumulation after repeated administration. The bioavailability of tenofovir dipivoxil fumarate was increased by approximately 25% as measured by AUClast after a single dose when taken with food, compared with fasting.
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: C
authors.initials: C
authors.lastname: Lu
authors.forename: Y
authors.initials: Y
authors.lastname: Jia
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Song
authors.forename: X
authors.initials: X
authors.lastname: Sun
authors.forename: A
authors.initials: A
authors.lastname: Wen
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004435:Eating; D005215:Fasting / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008297:Male; D063065:Organophosphonates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D010757:Phosphorous Acids / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics*; D000068698:Tenofovir
chemical_list: C574165:9-(2-((bis(pivaloyloxymethoxy)phosphinoyl)methoxy)propyl)adenine; D063065:Organophosphonates; D010757:Phosphorous Acids; D011355:Prodrugs; D000068698:Tenofovir; D000225:Adenine