Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings.

Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings.

Antimicrobial agents and chemotherapy (2006-01-27)

Hartmut Stocker, Charlotte Kloft, Nele Plock, Antje Breske, Guido Kruse, Christian Herzmann, Hubert Schulbin, Peter Kreckel, Christoph Weber, Frank Goebel, Joerg Roeling, Schlomo Staszewski, Andreas Plettenberg, Christiane Moecklinghoff, Keikawus Arastéh, Michael Kurowski

PMID16436725

ABSTRACT

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 (Cmax) of 3,943 ng/ml, predicted for 3 h after drug administration, is lower than the Cmax 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.

MATERIALS

Product Number

Brand

Product Description

EP951031208

Eppendorf^® Deepwell plates, DNA LoBind, 384 wells, white plate, conical bottom, colorless wells, capacity 200 μL, pack of 40 ea (5 bags × 8 plates)

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Eppendorf^® DNA LoBind tubes, capacity 1.5 mL, PCR clean, pkg of 250 ea (5 x 50ea)

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Eppendorf^® Deepwell plates, DNA LoBind, 96 wells, white plate, conical bottom, colorless wells, capacity 500 μL, pkg of 40 ea (5 bags × 8 plates)

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Eppendorf^® Protein LoBind Microplate 384/V-PP, PCR clean, V-bottom clear wells, white border, pack of 240 ea (10 bags × 24 plates)

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Eppendorf^® Deepwell plates, DNA LoBind, 384 wells, white plate, conical bottom, colorless wells, capacity 200 μL, pack of 120 ea (10 bags × 12 plates)

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Eppendorf^® DNA LoBind tubes, capacity 2.0 mL, PCR clean, pkg of 250 ea (5 x 50ea)

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Eppendorf^® Protein LoBind tubes, capacity 0.5 mL, PCR clean, pkg of 100 ea (2 x 50ea)

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Eppendorf^® Protein LoBind tubes, capacity 2.0 mL, PCR clean, pkg of 100 ea (2 x 50ea)

EP951032123

Eppendorf^® Deepwell plates, Protein LoBind, 96 wells, yellow plate, conical bottom, colorless wells, capacity 500 μL, pkg of 40 ea (5 bags × 8 plates)