Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings.
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.
Stocker
Hartmut
H
Vivantes Auguste Viktoria Klinikum, Kompetenznetz HIV/AIDS Deutschland, Rubensstrasse 125, 12157 Berlin, Germany. hartmut.stocker@vivantes.de
Kloft
Charlotte
C
Plock
Nele
N
Breske
Antje
A
Kruse
Guido
G
Herzmann
Christian
C
Schulbin
Hubert
H
Kreckel
Peter
P
Weber
Christoph
C
Goebel
Frank
F
Roeling
Joerg
J
Staszewski
Schlomo
S
Plettenberg
Andreas
A
Moecklinghoff
Christiane
C
Arastéh
Keikawus
K
Kurowski
Michael
M
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
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide