title: Biphasic elimination of tenofovir diphosphate and nonlinear pharmacokinetics of zidovudine triphosphate in a microdosing study.
abstract: OBJECTIVE
  Phase 0 studies can provide initial pharmacokinetics (PKs) data in humans and help to facilitate early drug development, but their predictive value for standard dosing is controversial. To evaluate the prediction of microdosing for active intracellular drug metabolites, we compared the PK profile of 2 antiretroviral drugs, zidovudine (ZDV) and tenofovir (TFV), in microdose and standard dosing regimens.
  
  
  METHODS
  We administered a microdose (100 μg) of C-labeled drug (ZDV or tenofovir disoproxil fumarate) with or without a standard unlabelled dose (300 mg) to healthy volunteers. Both the parent drug in plasma and the active metabolite, ZDV-triphosphate (ZDV-TP) or TFV-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) and CD4 cells were measured by accelerator mass spectrometry.
  
  
  RESULTS
  The intracellular ZDV-TP concentration increased less than proportionally over the dose range studied (100 μg-300 mg), whereas the intracellular TFV-DP PKs were linear over the same dose range. ZDV-TP concentrations were lower in CD4 cells versus total PBMCs, whereas TFV-DP concentrations were not different in CD4 cells and PBMCs.
  
  
  CONCLUSIONS
  Our data were consistent with a rate-limiting step in the intracellular phosphorylation of ZDV but not TFV. Accelerator mass spectrometry shows promise for predicting the PK of active intracellular metabolites of nucleosides, but nonlinearity of PK may be seen with some drugs.
authors.affiliation: Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Jianmeng
authors.initials: J
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Flexner
authors.forename: Rosa G
authors.initials: RG
authors.lastname: Liberman
authors.forename: Paul L
authors.initials: PL
authors.lastname: Skipper
authors.forename: Nicolette A
authors.initials: NA
authors.lastname: Louissaint
authors.forename: Steven R
authors.initials: SR
authors.lastname: Tannenbaum
authors.forename: Craig W
authors.initials: CW
authors.lastname: Hendrix
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Fuchs
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002250:Carbon Radioisotopes; D054306:Dideoxynucleotides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D000068698:Tenofovir; D013942:Thymine Nucleotides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D015215:Zidovudine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D002250:Carbon Radioisotopes; D054306:Dideoxynucleotides; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; D015215:Zidovudine; C052873:zidovudine triphosphate; D000068698:Tenofovir; D000225:Adenine