title: HIV/AIDS patients display lower relative bioavailability of efavirenz than healthy subjects.
abstract: BACKGROUND
  Pharmacokinetic studies of antiretroviral drugs are often conducted in adult healthy subjects, and the results are extrapolated to HIV/AIDS patients. HIV/AIDS, however, is known to cause morphological and physiological changes that may alter the pharmacokinetics of antiretroviral drugs. We examined the effect of HIV/AIDS on the pharmacokinetics of efavirenz in Ugandans.
  
  
  METHODS
  After a first oral dose of efavirenz 600 mg in treatment-naïve HIV-infected patients, blood samples were collected at nine time points up to 24 hours. The plasma-concentration time data from these patients were merged with previously reported data from adult healthy subjects. Population pharmacokinetic models were fitted to the data, using NONMEM VI software. Covariate analyses were performed to estimate the effects of HIV/AIDS disease, demographic characteristics (sex, bodyweight, age), biochemical variables (serum creatinine, urea, alanine aminotransferase) and pharmacogenetic variation in cytochrome P450 (CYP) 2B6, CYP3A5 and adenosine triphosphate-binding cassette, sub-family B, member 1 (ABCB1) on the population pharmacokinetic parameters.
  
  
  RESULTS
  Efavirenz plasma concentration-time data obtained from 29 HIV-1-infected, treatment-naïve patients were merged with previously reported data from 32 adult healthy subjects. The model identified sex and HIV/AIDS disease as statistically significant categorical predictors of efavirenz pharmacokinetics. Females were predicted to have a 2-fold higher volume of distribution of the peripheral compartment after oral administration (V(2)/F) than males (95% CI 1.53, 2.63), while HIV/AIDS patients were found to have 30% lower relative bioavailability (95% CI 18.7, 40.7) than healthy subjects. The increased V(2)/F in females resulted in a 2-fold longer elimination half-life than in males.
  
  
  CONCLUSIONS
  On the basis of the findings of this analysis, we conclude that, apart from bodyweight-based differences, both HIV/AIDS disease and sex affect efavirenz pharmacokinetics in Ugandans. HIV/AIDS disease is associated with reduced relative bioavailability of efavirenz. We recommend that findings from healthy subject studies be confirmed in HIV/AIDS patients and that caution be applied in direct extrapolation of exposure data to the target patient population.
authors: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors: Jackson K
authors: JK
authors: Mukonzo
authors: Sarah
authors: S
authors: Nanzigu
authors: Dinko
authors: D
authors: Rekić
authors: Paul
authors: P
authors: Waako
authors: Daniel
authors: D
authors: Röshammar
authors: Michael
authors: M
authors: Ashton
authors: Jasper
authors: J
authors: Ogwal-Okeng
authors: Lars L
authors: LL
authors: Gustafsson
authors: Eleni
authors: E
authors: Aklillu
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000493:pharmacokinetics*; D001682:Biological Availability; D001835:Body Weight; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D012737:Sex Factors; D014018:Tissue Distribution; D014454:Uganda; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C098320:efavirenz