title: Reduction of saquinavir exposure by coadministration of loperamide: a two-way pharmacokinetic interaction.
abstract: OBJECTIVE
  To assess any pharmacokinetic interactions between loperamide and saquinavir.
  
  
  METHODS
  Double-blind, double-dummy, randomised, placebo-controlled, three-way crossover trial.
  
  
  METHODS
  Twelve healthy male and female volunteers, aged 24-46 years.
  
  
  METHODS
  Saquinavir and loperamide pharmacokinetics were determined over a 72-hour period after single dose administration of saquinavir 600mg and/or loperamide 16mg. Plasma and urine concentrations of loperamide, its metabolites, and saquinavir were analysed using a single liquid chromatography/tandem mass spectrometry method for all compounds.
  
  
  RESULTS
  Saquinavir exposure was reduced by 54% when given with loperamide (median area under the concentration-time curve from zero to infinity [range], 1189 [243-2113] vs 550 [234-1468] pmol . h/mL; p = 0.016) with unchanged renal clearance. In contrast, loperamide concentrations increased and desmethylloperamide concentrations decreased during saquinavir coadministration, resulting in a reduced metabolic clearance of loperamide (median [range], 544 [224-1393] vs 443 [238-692] mL/min; p = 0.016).
  
  
  CONCLUSIONS
  Whereas the effect of saquinavir on loperamide disposition is unlikely to be of clinical relevance, the reduced drug exposure of saquinavir when loperamide is coadministered is worrisome because a relationship between protease inhibitor drug exposure and antiviral response has been reported. Patients receiving saquinavir monotherapy should be advised not to combine these drugs, especially for prolonged periods of time because a reduction in therapeutic efficacy may result.
authors.affiliation: Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. gerd_mikus@med.uni-heidelberg.de
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Laila
authors.initials: L
authors.lastname: Schmidt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Reinhard
authors.initials: R
authors.lastname: Ding
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Yorki
authors.initials: Y
authors.lastname: Tayrouz
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000502:physiology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008139:Loperamide / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D019258:Saquinavir / Q000494:pharmacology*
chemical_list: D008139:Loperamide; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D019258:Saquinavir