Open label, three period, single sequence, study of 5, 25, 50 mg sertraline pharmacokinetics in healthy male Korean volunteers
ABSTRACT Sertraline is a naphthalenamine derivative which has the effect of selective serotonin reuptake inhibition. It has been used for major depression, and obsessive compulsive disorder. This study was performed to evaluate the pharmacokinetic (PK) characteristics after the administration of low dose sertraline for the purpose of exploring an application of microdosing methods in PK studies.
An open-label, three-period, single-sequence, dose-escalation study was performed in 6 healthy Korean male volunteers. Subjects were administered a single dose of 5 mg, 25 mg and 50 mg sertraline orally in each period, with 1 week washouts between periods. Blood samples were obtained up to 96 h after drug administration. Plasma concentrations were determined using high performance liquid chromatography-tandem mass spectrometry. PK parameters of sertraline were analyzed using non-compartmental methods.
A total of 6 subjects completed the study. After the administration of sertraline at 5 mg, 25 mg and 50 mg, the median tmax were 6.0, 6.0 and 4.0 h and the mean (SD) elimination half-lives were 31.9 (6.5), 27.2 (6.7) and 28.0 (6.6) h, respectively. The AUC and Cmax increased dose-dependently. The dose-normalized mean (SD) AUC and Cmax were different in each dosing group (p < 0.01) with 2.0 (0.8), 5.3 (1.2) and 6.0 (1.9) mg × hr/l/mg in the 5 mg, 25 mg and 50 mg groups for dose-normalized AUC, and 0.07 (0.01), 0.18 (0.05) and 0.21 (0.08) mg/l/mg in the 5 mg, 25 mg and 50 mg groups for dose-normalized Cmax, respectively, which indicates a lack of dose proportionality.
A lack of dose proportional properties was shown in the 5 mg dose relative to the 25 mg and 50 mg doses of sertraline. This shows that the PK parameters for low-dose sertraline could be different from those in clinical concentrations.
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ABSTRACT: Background: Microdosing is a technique for studying the behavior of compounds in vivo at 1/100th of the dose of a test substance calculated, based on animal data, to yield a pharmacologic effect. In microdosing, use is made of accelerator MS (AMS). In this study, we investigated whether (129)I-labeling of proteins with subsequent AMS measurements is a suitable method to perform microdose studies with therapeutic proteins. We used erythropoietin (EPO) as a case study. Results: In an animal study with (129)I-labeled EPO in Han-Wistar rats, an increase of (129)I-EPO is observed after dose administration. The half-life was found to be 2 and 5.5 h for two different EPOs. These results are in accordance with expected values. Conclusion: Although further research is required, (129)I-labeling of proteins seems a feasible method for AMS microdose studies with peptide and protein drugs, such as biosimilars.Bioanalysis 01/2013; 5(1):53-63. DOI:10.4155/bio.12.297 · 3.03 Impact Factor
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ABSTRACT: Background:Selective serotonin reuptake inhibitors (SSRIs) are often prescribed in patients with postural tachycardia syndrome (POTS), and act at synaptic terminals to increase monoamine neurotransmitters. We hypothesized that they act to increase blood pressure and attenuate reflex tachycardia, thereby improving symptoms. Acute hemodynamic profiles after SSRI administration in POTS patients have not previously been reported.Methods:Patients with POTS (n=39; F=37, 39 ±9 years) underwent a randomized crossover trial with sertraline 50mg and placebo. Heart rate, systolic, diastolic, and mean blood pressure were measured with the patient seated and standing for 10 min prior to drug or placebo administration, and then hourly for 4 h. The primary endpoint was standing heart rate at 4 h.Results:At 4 h, standing heart rate and systolic blood pressure were not significantly different between sertraline and placebo. Seated systolic (106±12 mmHg vs. 101±8 mmHg; p=0.041), diastolic (72±8 mmHg vs. 69±8 mmHg; p=0.022), and mean blood pressure (86±9 mmHg vs. 81±9 mmHg; p=0.007) were significantly higher after sertraline administration than placebo. At 4 h, symptoms were worse with sertraline than placebo.Conclusions:Sertraline had a modest pressor effect in POTS patients, but this did not translate into a reduced heart rate or improved symptoms.Journal of Psychopharmacology 11/2013; 28(2). DOI:10.1177/0269881113512911 · 2.81 Impact Factor