title: Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK-453,061), in healthy adult subjects.
abstract: OBJECTIVE
  To investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK-453,061), a next generation non-nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co-administration of lersivirine with these inhibitors.
  
  
  METHODS
  Two open-label, randomized, placebo-controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400 mg once daily) on the pharmacokinetics of lersivirine (250 mg once daily). Subjects received ketoconazole 400 mg once daily or placebo on days 1-2 and received lersivirine 250 mg once daily and ketoconazole 400 mg once daily or placebo on days 3-9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000 mg once daily) on the PK of lersivirine (500 mg once daily). On days 1-7, subjects received lersivirine 500 mg once daily plus either VPA 1000 mg or placebo.
  
  
  RESULTS
  Compared with lersivirine alone, co-administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24 h)) and maximum plasma concentration (C(max) ) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24 h) by 25% (90% CI 16%, 35%), with little effect on C(max) (2.5%, 90% CI -9%, 16%). There were no serious adverse events and no treatment-related discontinuations from either study.
  
  
  CONCLUSIONS
  Inhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7-mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co-administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated.
authors: Pfizer Global Research and Development, Sandwich, Kent, UK.
authors: Grant
authors: G
authors: Langdon
authors: John
authors: J
authors: Davis
authors: Gary
authors: G
authors: Layton
authors: Chew-Lan
authors: CL
authors: Chong
authors: Georges
authors: G
authors: Weissgerber
authors: Manoli
authors: M
authors: Vourvahis
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D044466:Asian People; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014635:Valproic Acid / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D009570:Nitriles; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061; D014635:Valproic Acid; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D007654:Ketoconazole