Interspecies scaling and pharmacokinetic parameters of 3TC in humans.
3TC is a dideoxy-nucleoside analogue that has demonstrated in-vitro activity against human immunodeficiency virus (HIV). 3TC concentrations in humans were predicted before the initiation of clinical trials by interspecies scaling of pharmacokinetic parameters observed in animal species. Clearance and volume of distribution were estimated for humans using linear regression on a log-log scale of each parameter versus body weight for rats and dogs. The concentration-time profile and the average serum concentration at steady state after various dosage regimens were estimated as a basis for initial dose selection for clinical trials. The predicted parameters (clearance of 16.3 L/hr and volume of distribution of 40 L for a 70-kg man) were compared with that observed (mean clearance of 24 L/hr and mean volume of distribution of 96 L, mean weight of 74 kg) in 20 asymptomatic, HIV positive, volunteers after single intravenous doses of 3TC. Interspecies scaling was applied prospectively as a rationale for dose selection of 3TC in clinical trials.
Hussey
E K
EK
Glaxo Inc. Research Institute, Research Triangle Park, North Carolina 27709.
Donn
K H
KH
Daniel
M J
MJ
Hall
S T
ST
Harker
A J
AJ
Evans
G L
GL
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001835:Body Weight / Q000502:physiology; D018592:Cross-Over Studies; D004285:Dogs; D006679:HIV Seropositivity / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D019259:Lamivudine; D008297:Male; D051381:Rats; D018894:Reverse Transcriptase Inhibitors; D013045:Species Specificity; D016047:Zalcitabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D016047:Zalcitabine