Estimation of serum-free 50-percent inhibitory concentrations for human immunodeficiency virus protease inhibitors lopinavir and ritonavir.
Using measured free fraction and 50% inhibitory concentration (IC50) values for the human immunodeficiency virus protease inhibitors lopinavir (LPV) and ritonavir (RTV) in tissue culture media with various protein concentrations ranging from 5 to 50%, we estimated serum-free IC50 values for each drug. The range of serum-free IC50 values (0.64 to 0.77 ng/ml for LPV and 3.0 to 5.0 ng/ml for RTV) did not exhibit a trend with increasing protein concentrations, despite a 10-fold difference in the free fraction value (0.006 to 0.063) for LPV and a 5-fold difference in the free fraction value (0.013 to 0.057) for RTV. The mean serum-free IC50 by the MTT-MT4 assay (0.69 ng/ml for LPV and 4.0 ng/ml for RTV) may be the most accurate parameter for the estimation of the inhibitory quotient (IQ), a relative measure of in vivo potency defined as the ratio of the minimal free drug concentration in plasma (C(trough,free)) for a specific patient population and the serum-free IC50. Using this approach, we calculated the average IQs for protease inhibitor-naïve patients for LPV and RTV to be 67 and 5.6, respectively.
Hickman
Dean
D
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. dean.x.hickman@abbott.com
Vasavanonda
Sudthida
S
Nequist
George
G
Colletti
Lynn
L
Kati
Warren M
WM
Bertz
Richard
R
Hsu
Ann
A
Kempf
Dale J
DJ
D000465:Algorithms; D000818:Animals; D001681:Biological Assay; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D061466:Lopinavir; D011485:Protein Binding; D011744:Pyrimidinones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000494:pharmacology*
D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D016333:HIV Protease; D019438:Ritonavir