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Antimicrobial Agents and Chemotherapy, August 2004, p. 2911-2917, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2911-2917.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Estimation of Serum-Free 50-Percent Inhibitory Concentrations for Human Immunodeficiency Virus Protease Inhibitors Lopinavir and Ritonavir

Dean Hickman,* Sudthida Vasavanonda, George Nequist, Lynn Colletti, Warren M. Kati, Richard Bertz, Ann Hsu, and Dale J. Kempf

Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

Received 27 May 2003/ Returned for modification 7 August 2003/ Accepted 19 April 2004

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 (Ctrough,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.

* Corresponding author. Mailing address: D-R46V, AP9, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064. Phone: (847) 938-6957. Fax: (847) 937-4349. E-mail: dean.x.hickman{at}abbott.com.

Antimicrobial Agents and Chemotherapy, August 2004, p. 2911-2917, Vol. 48, No. 8
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.8.2911-2917.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Mo, H., King, M. S., King, K., Molla, A., Brun, S., Kempf, D. J. (2005). Selection of Resistance in Protease Inhibitor-Experienced, Human Immunodeficiency Virus Type 1-Infected Subjects Failing Lopinavir- and Ritonavir-Based Therapy: Mutation Patterns and Baseline Correlates. J. Virol. 79: 3329-3338 [Abstract] [Full Text]  


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