Influence of subcutaneous injection site on the steady-state pharmacokinetics of enfuvirtide (T-20) in HIV-1-infected patients.
ABSTRACT Enfuvirtide is the first in a new class of antiretrovirals (ARVs), the fusion inhibitors, and the first ARV to be administered by subcutaneous (s.c.) injection.
The primary objective of this study was to determine the steady-state pharmacokinetics and relative bioavailability of enfuvirtide following sc injection at three separate anatomical sites: abdomen (A), thigh (B) and arm (C).
A single-center, open-label, multiple-dose, three-way randomized, crossover study. Twelve HIV-1-infected adults were recruited from three ongoing Phase II enfuvirtide clinical trials and randomized into three groups. Each group continued to receive s.c. injection of enfuvirtide, at a dose of 90 mg twice daily (bid), according to one of three treatment sequences: ABC, BCA or CAB; over three consecutive periods of approximately 7 days each. Plasma concentrations of enfuvirtide and its metabolite (Ro 50-6343) were measured using a validated liquid chromatography-tandem mass spectrometry method.
The relative bioavailability of enfuvirtide, based on AUC12h and abdomen as a reference site, was 101% for thigh and 117% for arm. The AUC12h of Ro 50-6343 ranged from 14 to 16% of that for enfuvirtide. Although injection site reactions (ISRs) were common, the overall grading (based on pain or discomfort) of all reported ISRs was Grade 1 (mild). The incidence of ISRs varied according to the site of injection, as did the signs and symptoms associated with them. No patient required treatment for an ISR.
Comparability among the three injection sites, in terms of both absorption and the ISR profile, allows HIV-1-infected patients the freedom to choose and to rotate, if necessary, the site of enfuvirtide injection among the three anatomical sites.
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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.Antimicrobial Agents and Chemotherapy 02/2006; 50(2):667-73. · 4.84 Impact Factor
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ABSTRACT: Outpatient subcutaneous therapies are becoming increasingly common. A literature search failed to find produced any studies on application problems pertaining to the self-injection of low-molecular-weight heparins (LMWH) in a heterogeneous outpatient population under daily-life conditions. We therefore designed a study with the aim of recording drug use problems, patient satisfaction, compliance, problems arising from the injection site (abdomen vs. thigh), and residual drug volumes in pre-filled syringes used in self-injection therapy. Patients were recruited in community pharmacies by 95 trained Master's students in pharmacy. Data were collected during recruitment and by means of structured questionnaire-based telephone interviews that were carried out at the beginning and the end of the LMWH treatment. The median age of the 213 patients enrolled in the study was 54 years [interquartile range (IQR) 39-70 years]; of these, 15.5% had their injections administered by a third person. The rate of self-reported non-compliance was 17.1%. At least one relevant problem was recorded in 85.0% of the cases. At the end of the treatment, 38.9% of the patients stated self-administration of the injections required some effort. The preferred injection site was the thigh (68.5%). An overall mean residual drug volume ≥ 10.0% was detected for 3.9% of the patients. If residual drug was present, a median of 11.2% (IQR 8.6-17.6%) of the total drug volume had not been injected. Patients injecting into the thigh showed a higher risk of leaving residual medication (odds ratio 2.16, 95% confidence interval 1.04-4.51). Most patients had drug use problems, whereas no clear factors were associated with non-compliance, the injection site (apart from residual drug), and discomfort or effort required (apart from prior injection use).European Journal of Clinical Pharmacology 02/2011; 67(2):109-20. · 2.85 Impact Factor