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Antimicrobial Agents and Chemotherapy, February 2006, p. 667-673, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.667-673.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of Enfuvirtide in Patients Treated in Typical Routine Clinical Settings

Hartmut Stocker,^1,8* Charlotte Kloft,² Nele Plock,² Antje Breske,³ Guido Kruse,³ Christian Herzmann,¹ Hubert Schulbin,¹ Peter Kreckel,¹ Christoph Weber,¹ Frank Goebel,⁴ Joerg Roeling,⁴ Schlomo Staszewski,⁵ Andreas Plettenberg,⁶ Christiane Moecklinghoff,⁷ Keikawus Arastéh,^1,8 and Michael Kurowski^3,8

Vivantes Auguste Viktoria Klinikum, Berlin, Germany,¹ Clinical Pharmacy, Freie Universitaet Berlin, Berlin, Germany,² HIV-Lab c/o Vivantes Auguste Viktoria Klinikum, Berlin, Germany,³ Ludwig Maximilians Universität München, Munich, Germany,⁴ HIV Center, J. W. Goethe Universität, Frankfurt am Main, Germany,⁵ Institute of Interdisciplinary Infectology and Immunology, Hamburg, Germany,⁶ Hoffmann-La Roche AG, Grenzach, Germany,⁷ Kompetenznetz HIV/AIDS, Berlin, Germany⁸

Received 2 May 2005/ Returned for modification 31 July 2005/ Accepted 4 November 2005

Therapeutic drug monitoring (TDM) is gaining importance for improving the success of antiretroviral treatment in human immunodeficiency virus-infected patients. However, enfuvirtide (ENF) concentrations are not regularly determined. The objective of this work was to study the pharmacokinetics (PK) of ENF in patients treated in routine clinical settings, to develop a population PK model describing the concentration-time profile, and to establish PK reference values. A liquid chromatography-tandem mass spectrometry method was developed and applied to serum samples submitted for TDM. A two-compartment model with linear absorption and elimination was fitted to 329 concentrations from 131 patients. The PK model was used for simulations resulting in percentile curves for ENF levels for the full dosing interval. The model predicted that a median concentration of 1,968 ng/ml would be reached 12 h after administration of 90 mg of ENF, and 23% and 58% of patients are expected to have concentrations below 1,000 ng/ml and 2,200 ng/ml, respectively. Both values have been proposed as cutoffs for virological efficacy. The median maximum concentration of drug in serum (C_max) of 3,943 ng/ml, predicted for 3 h after drug administration, is lower than the C_max reported previously. We found an enormous interpatient variability at every time point, with concentration spectrums covering >1 log and 52% and 123% interindividual variabilities in the typical clearance and volume of distribution, respectively, in contrast to preexisting PK data. In summary, ENF levels are lower and more variable than expected. Many patients may achieve insufficient concentrations. Further covariate analysis in the population PK model might help to identify factors influencing the variability in ENF concentrations.

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* Corresponding author. Mailing address: Vivantes Auguste Viktoria Klinikum, Kompetenznetz HIV/AIDS Deutschland, Rubensstrasse 125, 12157 Berlin, Germany. Phone: 49 30 79033921. Fax: 49 30 79033922. E-mail: hartmut.stocker{at}vivantes.de.

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Antimicrobial Agents and Chemotherapy, February 2006, p. 667-673, Vol. 50, No. 2
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.2.667-673.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.