To evaluate the possible pharmacokinetic interactions between nevirapine and fluvoxamine or fluoxetine in patients with HIV-1 infection.
Patients who were using fluvoxamine or fluoxetine ...concomitantly were chosen from an unselected cohort (n = 173) of HIV-1-infected individuals using a nevirapine-containing regimen (study group). HIV-1-infected patients using nevirapine without fluvoxamine or fluoxetine and non-HIV-infected individuals who were using fluvoxamine and fluoxetine were included as controls. The influence of fluvoxamine and fluoxetine on the pharmacokinetics of nevirapine was investigated with a previously developed population pharmacokinetic model. Concomitant use of fluvoxamine or fluoxetine was tested independently as covariate for apparent clearance (CL/F) of nevirapine using nonlinear mixed-effect modelling (NONMEM). Furthermore, to explore the influence of nevirapine on the pharmacokinetics of fluvoxamine and fluoxetine, dose-normalised concentrations of fluvoxamine and fluoxetine from the study group were compared with those of the controls.
Of the 173 HIV-1-infected individuals, 14 were using fluoxetine (n = 7) or fluvoxamine (n = 7) simultaneously with nevirapine. In addition, 17 and 29 individuals were identified as controls for the fluoxetine- and fluvoxamine-group, respectively. Concomitant use of fluvoxamine resulted in a significant reduction of 33.7% in CL/F of nevirapine; this reduction in CL/F appeared to be dose-dependent. Concomitant use of fluoxetine had no influence on the pharmacokinetics of nevirapine. Conversely, nevirapine significantly lowered plasma levels of fluoxetine plus norfluoxetine (seproxetine). In contrast, no significant difference was observed in dose-normalised concentrations of fluvoxamine when the controls were compared with the study group.
We advise that special attention is paid to HIV-1-infected indivi-duals using a nevirapine-containing regimen and fluvoxamine or fluoxetine con-comitantly, since pharmacokinetic interactions have been observed.
Objective
The objectives of the study were to develop a population pharmacokinetic model for
11
C‐flumazenil at tracer concentrations, to assess the effects of patient‐related covariates and to ...derive an optimal sampling protocol for clinical use.
Methods
A population pharmacokinetic model was developed using nonlinear mixed effects modelling (NONMEM) with data obtained from 51 patients with either depression or epilepsy. Each patient received ∼370 MBq (1–4 µg) of
11
C‐flumazenil. The effects of selected covariates (gender, weight, type of disease and age) were investigated. The model was validated using a bootstrap method. Finally, an optimal sampling design was established.
Results
The population pharmacokinetics of tracer quantities of
11
C‐flumazenil were best described by a two compartment model. Type of disease and weight were identified as significant covariates (
P
< 0.002). Mean population pharmacokinetic parameters (percent coefficient of variation) were: CL 1530 mL min
−1
(6.6%), V
1
24.8 × 10
3
mL (3.8%), V
2
27.3 × 10
3
mL (5.4%), and Q 2510 mL min
−1
(6.5%). CL was 20% lower in patients with epilepsy, and the influence of weight on V
1
was 0.55% kg
−1
. For the prediction of the AUC, a combination of two time points at
t
= 30 and 60 min post injection was considered optimal (bias −0.7% (95% CI −2.2 to 0.8%), precision 5.7% (95% CI 4.5–6.9%)). The optimal sampling strategy was cross‐validated (observed AUC = 296 MBql
−1
min
−1
(95% CI 102–490), predicted AUC = 288 MBql
−1
min
−1
(95% CI 70–506)).
Conclusions
The population pharmacokinetics of tracer quantities of
11
C‐flumazenil are well described by a two‐compartment model. Inclusion of weight and type of disease as covariates significantly improved the model. Furthermore, an optimal sampling procedure may increase the feasibility and applicability of
11
C‐flumazenil PET.
Everolimus is an orally administered anti-cancer drug that inhibits the mammalian target of rapamycin (mTOR) signal transduction route. Use of everolimus may be associated with insulin resistance, ...manifesting in impaired glucose tolerance or hyperglycaemia.
A 74-year-old female patient with a locally recurrent breast cancer developed hyperglycaemia, which started 2 weeks after the initiation of treatment with everolimus 10 mg once daily. Metformin and insulin were administered to restore normoglycaemia.
At the initiation of treatment with an mTOR inhibitor such as everolimus the treating physician should be aware of the occurrence of hyperglycaemia. Metformin is then the medicine of first choice.
As part of the large international, randomized 2NN trial, the pharmacokinetics of nevirapine in once-daily 400 mg and twice-daily 200 mg dosing regimens were investigated.
Treatment-naive ...HIV-1-infected patients were randomized to receive nevirapine 400 mg once daily or 200 mg twice daily, in combination with lamivudine and stavudine. Blood samples were collected at several time-points (day 3, weeks 1, 2, 4, 24, and 48). Differences in pharmacokinetics between once- versus twice-daily dosing were investigated with nonlinear mixed effects modelling (NONMEM).
In total, 2,899 nevirapine plasma concentrations were available from 578 patients. Dosage and dosing frequency did not influence clearance or volume of distribution of nevirapine, indicating linear pharmacokinetic behavior of nevirapine whether given as a single daily dose or as divided doses over 24 hours. During steady state, the Cmin was lower (3.26 mg/L vs. 4.44 mg/L; p < .001) and the Cmax was higher (7.88 mg/L vs. 6.55 mg/L; p < .001) in the once-daily arm. However, compared to total variability in nevirapine levels for both treatments, these differences were minor. During steady state, total exposure, measured as AUC24h, was comparable for both regimens (133 mg/L*h vs. 133 mg/L*h; p = .084).
The daily exposure to nevirapine (AUC24h) was similar for the 400 mg once-daily and the 200 mg twice-daily dosing regimens. The Cmin of nevirapine is lower and the Cmax of nevirapine is higher for the once-daily regimen as compared to the twice-daily regimen. As a result, 200 mg nevirapine dosed twice daily may be preferred over 400 mg nevirapine dosed once daily.
A simple and selective assay for the determination of the alkylating cyclophosphamide metabolite phosphoramide mustard (PM) in plasma was developed and validated. PM was determined after ...derivatisation by high-performance liquid chromatography (HPLC) with ultraviolet detection at 276 nm. Sample pre-treatment consisted of derivatisation of PM with diethyldithiocarbamate (DDTC) at 70°C for 10 min, followed by extraction with acetonitrile in the presence of 0.7
M sodium chloride. Phase separation occurred due to the high salt content of the aqueous phase. The HPLC system consisted of a C
8 column with acetonitrile–0.025
M potassium phosphate buffer, pH 8.0, (32:68, v/v) as the mobile phase. The entire sample handling procedure, from collection at the clinical ward until analysis in the laboratory, was optimised and validated. Calibration curves were linear from 50 to 10 000 ng/ml. The lower limit of quantification and the limit of detection (using a signal-to-noise ratio of 3) were 50 and 40 ng/ml, respectively, using 500 μl of plasma. Within-day and between-day precisions were below 11% over the entire concentration range and the accuracies were between 100 and 106%. PM was found to be stable at −30°C for at least 10 weeks both in plasma and as a DDTC-derivative in a dry sample. A pharmacokinetic pilot study in two patients receiving 1000 mg/m
2 CP in a 1-h infusion demonstrated the applicability of the assay.
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