title: Pharmacokinetics and pharmacodynamics of low dose mycophenolate mofetil in HIV-infected patients treated with abacavir, efavirenz and nelfinavir.
abstract: BACKGROUND
  The use of mycophenolate mofetil in combination with highly active antiretroviral therapy (HAART) has been proposed in order to inhibit HIV replication. Due to the low doses involved, pharmacokinetic-pharmacodynamic monitoring is recommended.
  
  
  OBJECTIVE
  The aim of this study was to characterise the pharmacokinetic and pharmacodynamic monitoring of low doses of mycophenolate mofetil (0.25 g twice daily) in HIV-infected patients treated with HAART and after programmed discontinuation of HAART, in order to assess whether low doses of this immunosuppressive agent provide a biological effect.
  
  
  METHODS
  Mycophenolic acid (MPA) plasma levels (assessed by high-performance liquid chromatography) and the capacity of patients' sera to inhibit CEM cell line proliferation (assessed by (3)H-thymidine uptake) were measured post-dose at 0, 20, 40 minutes and 1, 2, 4, 6, 8, 10 and 12 hours in nine HIV-infected patients treated with a combination of abacavir, nelfinavir and efavirenz (HAART) and mycophenolate mofetil 0.25 g twice daily at days 7, 28, 120 and 150 (30 days without HAART) after the treatment initiation. A control group of eight patients was treated with HAART alone.
  
  
  RESULTS
  In the 35 post-dose curves analysed, no differences were found in MPA levels between days 7, 28, 120 and 150: area under the plasma concentration-time curve - mean value 15.3 mg . h/L, range 10.4-24.4 mg . h/L; minimum plasma concentration - mean value 0.60 mg/L, range 0.20-4.67 mg/L; maximum plasma concentration mean value 2.60 mg/L, range 0.94-7.98 mg/L. Pretreatment patients' sera did not inhibit CEM proliferation. Post-treatment patients' sera inhibited CEM proliferation to <40% in 25 of 35 curves at 0 hours (six of nine patients), in 34 of 35 curves at 1 hour, in 32 of 35 curves at 2 hours, in 22 of 35 curves at 4 hours, and in 8 of 35 curves at 12 hours. The MPA level versus CEM proliferation inhibition had a concentration that produces 50% of the maximum drug effect (EC(50)) of 0.33 mg/L. Viral load at day 150 was >200 copies/mL in all control patients and in three of nine patients receiving mycophenolate mofetil. These three patients were the only ones repeatedly unable to inhibit pre-dose CEM proliferation to <40%.
  
  
  CONCLUSIONS
  Mycophenolate mofetil pharmacokinetic profiles in HIV patients under HAART are not significantly different from those found in transplant patients. Sera from the majority of patients receiving low doses of mycophenolate mofetil inhibited lymphocyte proliferation during most of the inter-dose interval, despite low MPA plasma levels. For some patients, higher doses may be necessary: the capacity of sera to inhibit CEM proliferation may help to identify these patients.
authors.affiliation: Servei Immunologia, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Millán
authors.forename: Mercè
authors.initials: M
authors.lastname: Brunet
authors.forename: Jaume
authors.initials: J
authors.lastname: Martorell
authors.forename: Felipe
authors.initials: F
authors.lastname: García
authors.forename: Elena
authors.initials: E
authors.lastname: Vidal
authors.forename: Isabel
authors.initials: I
authors.lastname: Rojo
authors.forename: Montserrat
authors.initials: M
authors.lastname: Plana
authors.forename: Teresa
authors.initials: T
authors.lastname: Gallart
authors.forename: Tomas
authors.initials: T
authors.lastname: Pumarola
authors.forename: Jose M
authors.initials: JM
authors.lastname: Miró
authors.forename: Jose M
authors.initials: JM
authors.lastname: Gatell
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D000328:Adult; D000480:Alkynes; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000008:administration & dosage*; D005260:Female; D015497:HIV-1; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D019888:Nelfinavir / Q000008:administration & dosage*; D010078:Oxazines / Q000008:administration & dosage*; D019562:Viral Load; D000099227:Abacavir
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D019888:Nelfinavir; D010078:Oxazines; D000099227:Abacavir; C098320:efavirenz