title: Factors influencing efavirenz and nevirapine plasma concentration: effect of ethnicity, weight and co-medication.
abstract: BACKGROUND
  The aim of this study was to examine factors influencing plasma concentration of efavirenz and nevirapine.
  
  
  METHODS
  Data from the Liverpool Therapeutic Drug Monitoring (TDM) registry were linked with the UK Collaborative HIV Cohort (CHIC) Study. For each patient, the first measurement of efavirenz (600 or 800 mg/day) or nevirapine (400 mg/day) plasma concentration was included. Linear regression was used to evaluate the association of dose, gender, age, weight, ethnicity and concomitant antiretroviral drugs or rifampicin with log-transformed drug concentration, adjusted for time since last intake.
  
  
  RESULTS
  Data from 339 patients on efavirenz (34% black, 17% rifampicin) and 179 on nevirapine (27% black, 6% rifampicin) were included. Multivariable models revealed the following predictors for efavirenz concentration: black ethnicity (59% higher; P<0.001), weight (10% lower per additional 10 kg; P=0.002), 800 mg/day (52% higher; P=0.027), rifampicin (35% lower; P=0.039), and zidovudine (25% lower; P=0.010). Notably, without adjustment for other factors, patients on rifampicin had 48% higher efavirenz concentration, as these patients were mostly black and on 800 mg/day. For nevirapine the predictors were black ethnicity (39% higher; P=0.002), rifampicin (40% lower; P=0.002), protease inhibitor (28% higher; P=0.008) and tenofovir (22% higher; P=0.024).
  
  
  CONCLUSIONS
  We observed clear associations between ethnicity and concentrations of nevirapine and efavirenz. Our analyses confirm that concomitant rifampicin substantially decreases concentration of both efavirenz and nevirapine; however, for efavirenz this effect was more than counterbalanced by the effect of ethnicity and increased efavirenz dose. There was also an additional impact of weight, which should be considered when determining optimal dosage. Other associations from our analysis (between tenofovir or protease inhibitor and nevirapine, and zidovudine and efavirenz), require confirmation in formal pharmacokinetic studies.
authors.affiliation: MRC Clinical Trials Unit, London, UK.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stöhr
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.forename: David
authors.initials: D
authors.lastname: Dunn
authors.forename: Caroline
authors.initials: C
authors.lastname: Sabin
authors.forename: Alan
authors.initials: A
authors.lastname: Winston
authors.forename: Richard
authors.initials: R
authors.lastname: Gilson
authors.forename: Deenan
authors.initials: D
authors.lastname: Pillay
authors.forename: Teresa
authors.initials: T
authors.lastname: Hill
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ainsworth
authors.forename: Anton
authors.initials: A
authors.lastname: Pozniak
authors.forename: Clifford
authors.initials: C
authors.lastname: Leen
authors.forename: Loveleen
authors.initials: L
authors.lastname: Bansi
authors.forename: Martin
authors.initials: M
authors.lastname: Fisher
authors.forename: Chloe
authors.initials: C
authors.lastname: Orkin
authors.forename: Jane
authors.initials: J
authors.lastname: Anderson
authors.forename: Margaret
authors.initials: M
authors.lastname: Johnson
authors.forename: Phillippa
authors.initials: P
authors.lastname: Easterbrook
authors.forename: Sara
authors.initials: S
authors.lastname: Gibbons
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000627:therapeutic use; D048588:Benzoxazines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D044383:Black People; D001835:Body Weight / Q000187:drug effects*; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000208:ethnology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019829:Nevirapine / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use; D019562:Viral Load; D044465:White People
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C098320:efavirenz; D012293:Rifampin