Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings
| Autor: | Christiane Moecklinghoff, Frank D. Goebel, Christoph Weber, Guido Kruse, Schlomo Staszewski, Andreas Plettenberg, Antje Breske, Hubert Schulbin, Nele Plock, Keikawus Arastéh, Joerg Roeling, Peter Kreckel, Christian Herzmann, Hartmut Stocker, Michael Kurowski, Charlotte Kloft |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Adult
Male Efavirenz Population Cmax HIV Infections Pharmacology Enfuvirtide Models Biological chemistry.chemical_compound Pharmacokinetics Indinavir HIV Fusion Inhibitors Reference Values medicine Humans Pharmacology (medical) Drug Interactions education Aged Volume of distribution education.field_of_study medicine.diagnostic_test Dose-Response Relationship Drug business.industry Middle Aged HIV Envelope Protein gp41 Peptide Fragments Infectious Diseases Nelfinavir chemistry Therapeutic drug monitoring Female Drug Monitoring business medicine.drug |
| Zdroj: | Antimicrobial agents and chemotherapy. 50(2) |
| ISSN: | 0066-4804 |
| Popis: | 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. Therapeutic drug monitoring (TDM) of protease inhibitors (PI) and nonnucleoside inhibitors of the reverse transcriptase (NNRTI) is slowly becoming established as an important tool for improving the success of antiretroviral treatment of human immunodeficiency virus (HIV)-infected patients. The ATHENA trial has shown that nelfinavir concentrations below a certain threshold are associated with high rates of virological failure (3, 4). Patients taking efavirenz also have lower chances of sustained viral suppressions when drug concentrations are below 1,000 ng/ml than when they are above this concentration (17). At the other end of the concentration spectrum, TDM may be beneficial for patients with excessive toxic drug effects. Concentration-controlled dose reductions in patients on ritonavir-boosted indinavir who suffer from renal toxicity may alleviate side effects without increasing the risk of therapeutic failure (3). With monitoring of drug levels, individual patients with extremely low or high concentrations can be identified, and a search for the underlying cause can be started, preventing precocious viral failure or unnecessary toxicity. The grow |
| Databáze: | OpenAIRE |
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