Highlights • CYP2D6 genotyping is an oversimplified approach for tamoxifen individualization. • Tamoxifen pharmacokinetics are influenced by many genetic and environmental factors. • There is ...increasing evidence supporting the important role of endoxifen. • TDM is likely to be the optimal strategy for tamoxifen individualization. • Phenotyping strategies may be useful in determining the initial tamoxifen dose.
In view of future pharmacokinetic studies, a highly sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC–MS/MS) method has been developed for the simultaneous ...quantification of tamoxifen and three of its main phase I metabolites in human lithium heparinized plasma. The analytical method has been thoroughly validated in agreement with FDA recommendations. Plasma samples of 200
μl were purified by liquid–liquid extraction with 1
ml
n-hexane/isopropanol, after deproteination through addition of 50
μl acetone and 50
μl deuterated internal standards in acetonitrile. Tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were chromatographically separated on an Acquity UPLC
® BEH C18 1.7
μm 2.1
mm
×
100
mm column eluted at a flow-rate of 0.300
ml/min on a gradient of 0.2
mM ammonium formate and acetonitrile, both acidified with 0.1% formic acid. The overall run time of the method was 10
min, with elution times of 2.9, 3.0, 4.1 and 4.2
min for endoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen and tamoxifen, respectively. Tamoxifen and its metabolites were quantified by triple-quadrupole mass spectrometry in the positive ion electrospray ionization mode. The multiple reaction monitoring transitions were set at 372
>
72 (
m/
z) for tamoxifen, 358
>
58 (
m/
z) for N-desmethyl-tamoxifen, 388
>
72 (
m/
z) for 4-hydroxy-tamoxifen and 374
>
58 (
m/
z) for endoxifen. The analytical method was highly sensitive with the lower limit of quantification validated at 5.00
nM for tamoxifen and N-desmethyl-tamoxifen and 0.500
nM for 4-hydroxy-tamoxifen and endoxifen, which is equivalent to 1.86, 1.78, 0.194 and 0.187
ng/ml for tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen, respectively. The method was also precise and accurate, with within-run and between-run precisions within 12.0% and accuracy ranging from 89.5 to 105.3%. The method has been applied to samples from a clinical study and cross-validated with a validated LC–MS/MS method in serum.
OBJECTIVECurrently, a biosimilar of Remicade is available (CT-P13). Switching patients from Remicade to a biosimilar is still under debate, especially for patients with inflammatory bowel disease ...(IBD). In a retrospective study, we investigated the feasibility and safety of switching patients with IBD from Remicade to a biosimilar infliximab.
PATIENTS AND METHODSAt two large general hospitals in The Netherlands, adult patients with a diagnosis of Crohn’s disease or ulcerative colitis being treated with Remicade were asked to switch to the biosimilar infliximab (CT-P13). After switching, patients were closely monitored by assessing disease activity and evaluating disease-specific measures (serum C-reactive protein and fecal calprotectin). Adverse effects were recorded and serum infliximab concentrations measured. All parameters were assessed at baseline (t=0) and after two infusions with biosimilar infliximab (±week 16).
RESULTSAmong 197 patients with IBD switched to the biosimilar infliximab (∼77%), and no difference in disease activity was observed. Disease-specific measures did not differ between baseline and after two infusions with the biosimilar. Apart from one infusion-related reaction, no serious or unexpected adverse reactions were reported. Serum trough concentrations did not differ between baseline and after switching median4.1 µg/ml (range0.03–22 µg/ml) vs. 4.6 µg/ml (range0.03–22 µg/ml); P=0.08, n=98.
CONCLUSIONThese data suggest that switching patients with IBD to the biosimilar infliximab is safe in clinical practice. After the switch, no clinically relevant differences were observed in disease activity, adverse effects, and serum infliximab concentrations.
Objective
Currently, a biosimilar of Remicade is available (CT-P13). Switching patients from Remicade to a biosimilar is still under debate, especially for patients with inflammatory bowel disease ...(IBD). In a retrospective study, we investigated the feasibility and safety of switching patients with IBD from Remicade to a biosimilar infliximab.
Patients and methods
At two large general hospitals in The Netherlands, adult patients with a diagnosis of Crohn’s disease or ulcerative colitis being treated with Remicade were asked to switch to the biosimilar infliximab (CT-P13). After switching, patients were closely monitored by assessing disease activity and evaluating disease-specific measures (serum C-reactive protein and fecal calprotectin). Adverse effects were recorded and serum infliximab concentrations measured. All parameters were assessed at baseline (
t
=0) and after two infusions with biosimilar infliximab (±week 16).
Results
Among 197 patients with IBD switched to the biosimilar infliximab (∼77%), and no difference in disease activity was observed. Disease-specific measures did not differ between baseline and after two infusions with the biosimilar. Apart from one infusion-related reaction, no serious or unexpected adverse reactions were reported. Serum trough concentrations did not differ between baseline and after switching median: 4.1 µg/ml (range: 0.03–22 µg/ml) vs. 4.6 µg/ml (range: 0.03–22 µg/ml);
P
=0.08,
n
=98.
Conclusion
These data suggest that switching patients with IBD to the biosimilar infliximab is safe in clinical practice. After the switch, no clinically relevant differences were observed in disease activity, adverse effects, and serum infliximab concentrations.
Background and Objective
The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochrome P450 (CYP) enzymes, predominantly CYP2D6. Potent CYP2D6-inhibiting antidepressants can ...seriously disrupt tamoxifen metabolism, probably influencing the efficacy of tamoxifen. For this reason, paroxetine and fluoxetine are recommended not to be used with tamoxifen in breast cancer patients. We investigated the effects of switching potent CYP2D6-inhibiting antidepressants to weak CYP2D6-inhibiting antidepressants on the plasma pharmacokinetics of tamoxifen.
Methods
Ten breast cancer patients who were treated with tamoxifen in combination with a potent CYP2D6-inhibiting antidepressant (paroxetine or fluoxetine) for at least 4 weeks were enrolled. Under close supervision by a psychiatrist, patients were switched to treatment with escitalopram or venlafaxine (weak CYP2D6-inhibiting antidepressants). Before and after the switch, pharmacokinetic blood sampling was performed over 24 h. Pharmacokinetic parameters were estimated using noncompartmental analysis. Adverse effects were recorded during the study.
Results
Endoxifen exposure was ~3-fold higher during escitalopram co-administration than during paroxetine or fluoxetine co-administration (median 387 nM·h range 159–637 nM·h versus 99.2 nM·h range 70.0–210 nM·h;
P
= 0.012; Wilcoxon signed-rank test). The ratio of endoxifen to
N
-desmethyltamoxifen and the ratio of 4-hydroxytamoxifen to tamoxifen increased by 3.3- and ~1.5-fold, reflecting increased CYP2D6 activity. Antidepressant switching did not result in psychiatric problems or antidepressant-related adverse effects.
Conclusion
In this study, switching to the weak CYP2D6 inhibitor escitalopram was safe and feasible and resulted in clinically relevant rises in endoxifen concentrations. We therefore advise switching paroxetine and fluoxetine to escitalopram in patients using tamoxifen. However, switching should always be weighed in individual patients.
Purpose
Antidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of ...the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval.
Methods
Electrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI.
Results
The mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8–23.1 ms;
P
= 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4–33.0 ms;
P
= 0.04), escitalopram (12.5 ms; 95%CI:4.4–20.6 ms;
P
< 0.01) and citalopram (20.7 ms; 95%CI:0.7–40.7 ms;
P
= 0.047), where other agents like venlafaxine did not seem to prolong the QTc-interval. None of the patients had a QTc-interval of >500 ms.
Conclusions
Concomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred.
Background and Objective
Circadian rhythms may influence the pharmacokinetics of drugs. This study aimed to elucidate whether the pharmacokinetics of the orally administered drug sunitinib are ...subject to circadian variation.
Methods
We performed studies in male FVB-mice aged 8–12 weeks, treated with single-dose sunitinib at six dosing times. Plasma and tissue samples were obtained for pharmacokinetic analysis and to monitor messenger RNA (mRNA) expression of metabolizing enzymes and drug transporters. A prospective randomized crossover study was performed in which patients took sunitinib once daily at 8 a.m., 1 p.m., and 6 p.m at three subsequent courses. Patients were blindly randomized into two groups, which determined the sequence of the sunitinib dosing time. The primary endpoint in both studies was the difference in plasma area under the concentration–time curve (AUC) of sunitinib and its active metabolite SU12662 between dosing times.
Results
Sunitinib and SU12662 plasma AUC in mice followed an ~12-h rhythm as a function of administration time (
p
≤ 0.04). The combined AUC from time zero to 10 h (AUC
10
) was 14–27 % higher when sunitinib was administered at 4 a.m. and 4 p.m. than at 8 a.m. and 8 p.m. Twenty-four-hour rhythms were seen in the mRNA levels of drug transporters and metabolizing enzymes. In 12 patients, sunitinib trough concentrations (
C
trough
) were higher when the drug was taken at 1 p.m. or 6 p.m. than when taken at 8 a.m. (
C
trough-1 p.m
. 66.0 ng/mL;
C
trough-6 p.m.
58.9 ng/mL;
C
trough-8 a.m.
50.7 ng/mL;
p
= 0.006). The AUC was not significantly different between dosing times.
Conclusions
Our results indicate that sunitinib pharmacokinetics follow an ~12-h rhythm in mice. In humans, morning dosing resulted in lower
C
trough
values, probably resulting from differences in elimination. This can have implications for therapeutic drug monitoring.
Tamoxifen is a largely inactive pro-drug, requiring metabolism into its most important metabolite endoxifen. Since the cytochrome P450 (CYP) 2D6 enzyme is primarily involved in this metabolism, ...genetic polymorphisms of this enzyme, but also drug-induced CYP2D6 inhibition can result in considerably reduced endoxifen formation and as a consequence may affect the efficacy of tamoxifen treatment. Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) have been effectively used for the treatment of depression and hot flashes, both of which occur frequently in tamoxifen-treated women. Due to the drug–drug interaction considerably reduced endoxifen concentrations by inhibition of CYP2D6 will be the result. Evidence of a significant influence of strong CYP2D6-inhibiting drugs on the pharmacokinetics of tamoxifen has resulted in recommendations to avoid potent CYP2D6-inhibiting antidepressants (e.g., paroxetine, fluoxetine) in patients treated with tamoxifen for breast cancer. Nevertheless, dispensing data for tamoxifen and seven regularly used SSRIs/SNRIs in the period between 2005 and 2010, obtained from a large community pharmacy database in the Netherlands (3,000,000 people), show that the potent CYP2D6-inhibiting drug paroxetine remains one of the most frequently used antidepressants in tamoxifen-treated patients. Moreover, trends in the use of SSRIs/SNRIs in the population of all women were similar with trends in women using tamoxifen. Apparently, the recommendations to avoid paroxetine in tamoxifen-treated women have not been implemented into clinical practice. Several reasons may underlie continued use of this drug–drug combination. Contrary to
CYP2D6
polymorphisms, drug-induced CYP2D6 inhibition can easily be avoided, since alternative drugs are available. In clinical practice, one should strive to avoid potent CYP2D6 inhibitors as much as possible in tamoxifen-treated patients to reduce the risk of compromising the efficacy of the hormonal therapy. Co-medication should be reviewed by both physicians and pharmacists and potent CYP2D6 inhibitors ought to be switched to weaker alternatives.
Aims
Tamoxifen is considered a pro‐drug of its active metabolite endoxifen. The major metabolic enzymes involved in endoxifen formation are CYP2D6 and CYP3A. There is considerable evidence that ...variability in activity of these enzymes influences endoxifen exposure and thereby may influence the clinical outcome of tamoxifen treatment. We aimed to quantify the impact of metabolic phenotype on the pharmacokinetics of tamoxifen and endoxifen.
Methods
We assessed the CYP2D6 and CYP3A metabolic phenotypes in 40 breast cancer patients on tamoxifen treatment with a single dose of dextromethorphan as a dual phenotypic probe for CYP2D6 and CYP3A. The pharmacokinetics of dextromethorphan, tamoxifen and their relevant metabolites were analyzed using non‐linear mixed effects modelling.
Results
Population pharmacokinetic models were developed for dextromethorphan, tamoxifen and their metabolites. In the final model for tamoxifen, the dextromethorphan derived metabolic phenotypes for CYP2D6 as well as CYP3A significantly (P < 0.0001) explained 54% of the observed variability in endoxifen formation (inter‐individual variability reduced from 55% to 25%).
Conclusions
We have shown that not only CYP2D6, but also CYP3A enzyme activity influences the tamoxifen to endoxifen conversion in breast cancer patients. Our developed model may be used to assess separately the impact of CYP2D6 and CYP3A mediated drug–drug interactions with tamoxifen without the necessity of administering this anti‐oestrogenic drug and to support Bayesian guided therapeutic drug monitoring of tamoxifen in routine clinical practice.
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