title: Effect of carbamazepine on dolutegravir pharmacokinetics and dosing recommendation.
abstract: OBJECTIVE
  Dolutegravir (DTG) is primarily metabolized by UGT1A1 with CYP3A as a minor route. Carbamazepine (CBZ) is a potent inducer of these enzymes; thus, the effect of oral extended-release CBZ on DTG pharmacokinetics (PK) was evaluated to provide dose recommendation when co-administered.
  
  
  METHODS
  This was a single-center, open-label, fixed-sequence, crossover study in healthy adults. Subjects received three treatments: DTG 50 mg every 24 h (q24h) × 5 days in period 1, followed by CBZ 100 mg every 12 h (q12h) × 3 days, then 200 mg q12h × 3 days, then 300 mg q12h × 10 days in period 2, and DTG 50 mg q24h + CBZ 300 mg q12h × 5 days in period 3. No washout intervals occurred. Each dose was administered with a moderate-fat meal. Serial PK samples for DTG were collected on day 5 of periods 1 and 3. Plasma DTG PK parameters were determined with non-compartmental analysis. Geometric least-squares mean ratios (GMRs) and 90 % confidence intervals (CIs) were generated by the mixed-effect model for within-subject treatment comparisons. Safety assessments were performed throughout the study.
  
  
  RESULTS
  Sixteen subjects enrolled; 14 completed the study. CBZ significantly reduced DTG exposure: GMRs (90 % CI) for DTG + CBZ versus DTG alone were 0.51 (0.48-0.549), 0.67 (0.61-0.73), and 0.27 (0.24-0.31) for area under the curve from time zero to the end of the dosing interval (AUC(0-τ)), maximum observed plasma concentration (Cmax), and plasma concentration at the end of the dosing interval (Cτ), respectively. DTG alone and co-administered with CBZ was well tolerated.
  
  
  CONCLUSIONS
  Integrase strand transfer inhibitor-naive subjects taking CBZ should receive DTG 50 mg twice daily versus once daily, as is recommended with other potent UGT1A/CYP3A inducers. ClinicalTrials.gov: NCT01967771.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, Durham, NC, USA.
authors.forename: Ivy
authors.initials: I
authors.lastname: Song
authors.affiliation: GlaxoSmithKline, Research Triangle Park, Durham, NC, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Weller
authors.affiliation: GlaxoSmithKline, Research Triangle Park, Durham, NC, USA.
authors.forename: Juhin
authors.initials: J
authors.lastname: Patel
authors.affiliation: GlaxoSmithKline, Research Triangle Park, Durham, NC, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Borland
authors.affiliation: GlaxoSmithKline, Research Triangle Park, Durham, NC, USA. brian.r.wynne@viivhealthcare.com.
authors.forename: Brian
authors.initials: B
authors.lastname: Wynne
authors.affiliation: GlaxoSmithKline, Research Triangle Park, Durham, NC, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Choukour
authors.affiliation: GlaxoSmithKline, Research Triangle Park, Durham, NC, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Jerva
authors.affiliation: GlaxoSmithKline, Research Triangle Park, Durham, NC, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Piscitelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002220:Carbamazepine / Q000009:adverse effects / Q000494:pharmacology*; D018592:Cross-Over Studies; D065701:Cytochrome P-450 CYP3A Inducers / Q000009:adverse effects / Q000494:pharmacology*; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D019428:HIV Integrase Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006575:Heterocyclic Compounds, 3-Ring / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D055815:Young Adult; D000099226:Dolutegravir
chemical_list: D002220:Carbamazepine; D065701:Cytochrome P-450 CYP3A Inducers; D003692:Delayed-Action Preparations; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
keywords: Carbamazepine; Dolutegravir; Drug interaction; Healthy subjects