title: Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings.
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.
authors.affiliation: Vivantes Auguste Viktoria Klinikum, Kompetenznetz HIV/AIDS Deutschland, Rubensstrasse 125, 12157 Berlin, Germany. hartmut.stocker@vivantes.de
authors.forename: Hartmut
authors.initials: H
authors.lastname: Stocker
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kloft
authors.forename: Nele
authors.initials: N
authors.lastname: Plock
authors.forename: Antje
authors.initials: A
authors.lastname: Breske
authors.forename: Guido
authors.initials: G
authors.lastname: Kruse
authors.forename: Christian
authors.initials: C
authors.lastname: Herzmann
authors.forename: Hubert
authors.initials: H
authors.lastname: Schulbin
authors.forename: Peter
authors.initials: P
authors.lastname: Kreckel
authors.forename: Christoph
authors.initials: C
authors.lastname: Weber
authors.forename: Frank
authors.initials: F
authors.lastname: Goebel
authors.forename: Joerg
authors.initials: J
authors.lastname: Roeling
authors.forename: Schlomo
authors.initials: S
authors.lastname: Staszewski
authors.forename: Andreas
authors.initials: A
authors.lastname: Plettenberg
authors.forename: Christiane
authors.initials: C
authors.lastname: Moecklinghoff
authors.forename: Keikawus
authors.initials: K
authors.lastname: Arastéh
authors.forename: Michael
authors.initials: M
authors.lastname: Kurowski
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors / Q000493:pharmacokinetics*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010446:Peptide Fragments / Q000493:pharmacokinetics*; D012016:Reference Values
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide