title: Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects.
abstract: OBJECTIVE
  Animal and in vitro data suggest that Ginkgo biloba extract (GBE) may modulate CYP3A4 activity. As such, GBE may alter the exposure of HIV protease inhibitors metabolized by CYP3A4. It is also possible that GBE could alter protease inhibitor pharmacokinetics (PK) secondary to modulation of P-glycoprotein (P-gp). The primary objective of the study was to evaluate the effect of GBE on the exposure of lopinavir in healthy volunteers administered lopinavir/ritonavir. Secondary objectives were to compare ritonavir exposure pre- and post-GBE, and assess the effect of GBE on single doses of probe drugs midazolam and fexofenadine.
  
  
  METHODS
  This open-label study evaluated the effect of 2 weeks of standardized GBE administration on the steady-state exposure of lopinavir and ritonavir in 14 healthy volunteers administered lopinavir/ritonavir to steady-state. In addition, single oral doses of probe drugs midazolam and fexofenadine were administered prior to and after 4 weeks of GBE (following washout of lopinavir/ritonavir) to assess the influence of GBE on CYP3A and P-gp activity, respectively.
  
  
  RESULTS
  Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC(0-infinity) and C(max) by 34% (p = 0.03) and 31% (p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin.
  
  
  CONCLUSIONS
  Our results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4. Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively.
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, New Hampshire Ave., Silver Spring, MD 20901, USA. sarah.robertson@fda.hhs.gov
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Robertson
authors.forename: Richard T
authors.initials: RT
authors.lastname: Davey
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Voell
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Formentini
authors.forename: Raul M
authors.initials: RM
authors.lastname: Alfaro
authors.forename: Scott R
authors.initials: SR
authors.lastname: Penzak
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D020441:Ginkgo biloba / Q000009:adverse effects / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D061466:Lopinavir; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D008517:Phytotherapy; D010936:Plant Extracts / Q000009:adverse effects / Q000378:metabolism*; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000493:pharmacokinetics*; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017320:HIV Protease Inhibitors; D010936:Plant Extracts; D011480:Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D016593:Terfenadine; D003577:Cytochrome P-450 Enzyme System; C093230:fexofenadine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019438:Ritonavir; D008874:Midazolam