title: Pharmacokinetics of nifedipine slow-release during sustained tocolysis.
abstract: OBJECTIVE
  The pharmacokinetics of nifedipine as a tocolytic agent has not been studied in great detail in pregnant women and has instead focused on immediate release tablets and gastrointestinal therapeutic system (GITS) tablets. The aim of this study was to determine nifedipine slow-release half-life and distribution volume in pregnant women and to compare these with pharmacokinetic parameters of nifedipine in non-pregnant subjects described in the literature.
  
  
  METHODS
  This is a study parallel to a trial studying women with threatened preterm labor between 26 + 0 and 32 + 2 weeks after initial tocolysis and a completed course of corticosteroids, who were randomly allocated to maintenance nifedipine (slow-release tablets 20 mg 4 times daily) or placebo. Exclusion criteria for the pharmacokinetic study were contra-indications for nifedipine, impaired liver function, and concomitant intake of inhibitors or inducers of the cytochrome P450 3A4 isoenzyme. Blood samples for measuring nifedipine plasma concentrations were drawn at t = 0, t = 12 hours, t = 24 hours, t = 48 hours, t = 72 hours, t = 7 days, and t = 9 days.
  
  
  METHODS
  Pharmacokinetic parameters were estimated using iterative two-stage Bayesian population pharmacokinetic analysis by MWPharm© software. The study was designed to establish a correlation between body weight and nifedipine plasma level.
  
  
  RESULTS
  The pharmacokinetic parameters of nifedipine slow-release tablets were determined from the data of 8 pregnant women. Nifedipine slow-release had a half-life of 2 - 5 hours, a mean distribution volume of 6.2 ± 1.9 L/kg (calculated while using a fixed biological availability of 0.45 taken from the literature due to lack of intravenous data in this population) compared to a half-life of 6 - 11 hours, and a distribution volume of 1.2 - 1.3 L/kg described in non-pregnant subjects in the literature. None of the women delivered during study medication. Study medication was continued for the duration of the pharmacokinetic study (9 days) in all women. A correlation between nifedipine plasma levels and maternal body weight was not demonstrated. This may have been caused by lack of power.
  
  
  CONCLUSIONS
  Pregnant subjects in this study, using nifedipine slow-release tablets, showed a larger volume of distribution and a shorter elimination half-life than for non-pregnant subjects as published in the literature.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: ter Laak
authors.forename: Carolien
authors.initials: C
authors.lastname: Roos
authors.forename: Daan J
authors.initials: DJ
authors.lastname: Touw
authors.forename: Paul R M
authors.initials: PR
authors.lastname: van Hattum
authors.forename: Anneke
authors.initials: A
authors.lastname: Kwee
authors.forename: Frederik K
authors.initials: FK
authors.lastname: Lotgering
authors.forename: Ben Willem J
authors.initials: BW
authors.lastname: Mol
authors.forename: Mariëlle G
authors.initials: MG
authors.lastname: van Pampus
authors.forename: Martina M
authors.initials: MM
authors.lastname: Porath
authors.forename: Marc E A
authors.initials: ME
authors.lastname: Spaanderman
authors.forename: Joris A M
authors.initials: JA
authors.lastname: van der Post
authors.forename: Dimitri N M
authors.initials: DN
authors.lastname: Papatsonis
authors.forename: Nils E
authors.initials: NE
authors.lastname: van 't Veer
mesh_terms: D000328:Adult; D001499:Bayes Theorem; D001682:Biological Availability; D001835:Body Weight; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005865:Gestational Age; D006207:Half-Life; D006801:Humans; D008954:Models, Biological; D009426:Netherlands; D009543:Nifedipine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D007752:Obstetric Labor, Premature / Q000517:prevention & control*; D011247:Pregnancy; D015145:Tocolysis / Q000009:adverse effects / Q000379:methods*; D015149:Tocolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D003692:Delayed-Action Preparations; D015149:Tocolytic Agents; D009543:Nifedipine