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Single-dose Study (single-dose + study)
Selected AbstractsSingle-dose study to compare the pharmacokinetics of HFA flunisolide and CFC flunisolideJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2002Arno Nolting Abstract The hydrofluoroalkane (HFA) formulation of the inhaled corticosteroid flunisolide is a modification of the original chlorofluorocarbon (CFC) formulation. HFA flunisolide replaces CFC with an HFA propellant and uses a built-in spacer in its pressurized metered-dose inhaler. The average HFA flunisolide particle size is 1.2 ,m compared with 3.8 ,m for the CFC formulation. The smaller particle size improves lung targeting, allowing a reduction in the HFA flunisolide dose relative to CFC flunisolide while maintaining comparable efficacy. In a study of 12 healthy men, pharmacokinetic parameters were determined after single doses of 1000 ,g CFC flunisolide delivered without a spacer, 340 ,g HFA flunisolide delivered through a spacer, and 516 ,g HFA flunisolide delivered without a spacer. A standard noncompartmental analysis of the concentration data was performed and mean (±,S.D.) pharmacokinetic values were reported. Peak plasma concentrations (observed Cmax) were similar for the three treatments. Area under the curve up to the time corresponding to the last measurable concentration (AUC0,tlast) was similar for the CFC and HFA flunisolide, plus spacer groups (4.4,±,1.6 ng·h/mL and 5.0,±,4.2 ng·h/mL, respectively); however, AUC0,tlast for the HFA flunisolide without spacer group was comparatively lower than for the CFC group (3.5,±,1.6 ng·h/mL). Observed Cmax and AUC0,tlast for 6,-OH flunisolide, the first-pass metabolite of flunisolide and an indicator of oropharyngeal deposition, were significantly higher in the CFC flunisolide group than in either HFA flunisolide group. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:424,432, 2002 [source] Prophylactic use of anti-emetic medications reduced nausea and vomiting associated with exenatide treatment: a retrospective analysis of an open-label, parallel-group, single-dose study in healthy subjectsDIABETIC MEDICINE, Issue 10 2010C. Ellero Diabet. Med. 27, 1168,1173 (2010) Abstract Aims, Transient nausea and, to a lesser extent, vomiting are common adverse effects of exenatide that can be mitigated by dose titration and usually do not result in treatment discontinuation. This retrospective analysis of data from a phase 1, open-label, parallel-group, single-dose study in healthy subjects evaluated the effect of oral anti-emetics on exenatide-associated nausea and vomiting and on the pharmacokinetics of exenatide. Methods, A single subcutaneous dose (10 ,g) of exenatide was administered to 120 healthy subjects (19,65 years, BMI 23,35 kg/m2). Incidences of nausea and vomiting were compared between 60 subjects premedicated with two oral anti-emetics 30 min before the exenatide dose and 60 non-premedicated subjects. Similarly, the area under the concentration-time curve (AUC) and the maximum observed concentration (Cmax) of plasma exenatide concentrations over 8 h post-dose were compared. Results, Among all subjects [61% male, 32 ± 12 years, body mass index (BMI) 29.1 ± 3.4 kg/m2 (mean ± sd)], mild to moderate nausea was the most frequent adverse event after exenatide dosing. Vomiting was also observed. Subjects premedicated with anti-emetics experienced significantly less nausea and vomiting (16.7 and 6.7%, respectively) vs. non-premedicated subjects (61.7 and 38.3%, respectively; P -value < 0.0001 for both nausea and vomiting). The mean area under the concentration-time curve and the maximum observed concentration AUC and Cmax of plasma exenatide concentrations during 8 h post-dose were not significantly different between groups. Conclusion, Administration of oral anti-emetics before a single 10-,g exenatide dose was associated with significant reductions in treatment-emergent nausea and vomiting, with no discernible effect on the pharmacokinetics of exenatide. Use of anti-emetic therapy may provide a short-term strategy to minimize the nausea and vomiting associated with exenatide treatment. [source] H1 -antihistaminic activity of cetirizine and fexofenadine in allergic childrenPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 3 2003F. Estelle R. Simons The clinical pharmacology of H1 -antihistamines has not yet been optimally studied in children and other special groups of patients. Our objective was to determine the onset, extent, and duration of H1 -antihistaminic activity of cetirizine and fexofenadine in the pediatric population. We performed a prospective, randomized, placebo-controlled, double-blind, crossover, single-dose study of these H1 -antihistamines in 15 allergic children, mean±SEM age 8.8±0.5 years. We used suppression of the histamine-induced wheal and flare as the primary outcome. Compared with pre-dose baseline, cetirizine 10 mg suppressed the wheals significantly (p,0.05) from 2 to 24 h and the flares significantly from 1 to 24 h, achieving 77±SEM 10% to 86±9% suppression of the wheal from 2 to 7 h and 85±6% to 88±6% suppression of the flare from 2 to 24 h, inclusive. Compared with baseline, fexofenadine 30 mg did not suppress the wheals or flares significantly at any time, achieving 40±9% to 54±9% wheal suppression from 2 to 7 h and 45±11% to 68±9% flare suppression from 2 to 7 h, inclusive. Compared with placebo, cetirizine suppressed the wheals and flares significantly from 2 to 24 h. Compared with placebo, fexofenadine suppressed the wheals significantly at 4 and 6 h, and the flares from 4 to 7 h. Cetirizine suppressed the wheals and flares significantly more than fexofenadine at 2 h (wheals), and at 3 and 24 h (flares). Placebo did not suppress the wheals and flares significantly at any time. In children age 6,11 years, cetirizine 10 mg has a rapid onset of H1 -antihistaminic activity, a 24-h duration of action, and greater H1 -activity than fexofenadine 30 mg. Higher doses of fexofenadine should be tested in children. [source] Clinical pharmacology of the H1 -receptor antagonists cetirizine and loratadine in childrenPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 2 2000F. Estelle R. Simons H1 -receptor antagonists are widely used in children but are not as well-studied in children as they are in adults. Our objective was to determine the onset and duration of action and the relative potency of the H1 -receptor antagonists cetirizine and loratadine in children. We performed a prospective, randomized, placebo-controlled, double-blind, crossover, single-dose study of cetirizine and loratadine using suppression of the histamine-induced wheal and flare as the primary outcome. In 15 allergic children, mean age 9 years, compared with baseline, cetirizine (10 mg) suppressed the wheals and flares significantly from 0.25 to 24 h, achieving nearly 100% of flare suppression from 2 to 24 h, inclusive, and loratadine (10 mg) suppressed the wheals and flares significantly from 0.75 to 24 h, inclusive. Cetirizine suppressed the wheals and flares significantly more than loratadine from 0.25 to 1 h, inclusive, and at 0.5, 1, 2, 3, 5, 6, 7, and 24 h, respectively. Placebo also suppressed the wheal and flare significantly at some assessment times. Cetirizine and loratadine both have excellent antihistaminic activity in children, with a rapid onset of action and a 24-h duration of action in this population. [source] Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2007Yifan Zhang What is already known about this subject ,,Gliclazide has been considered metabolized by CYP2C9. ,,Its modified release formulation, gliclazide MR, shows low pharmacokinetic variability in Whites but high variability in Chinese. What this study adds ,,The results of this study show that the pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism. ,,CYP2C19 genetic polymorphism might be responsible for the high pharmacokinetic variability of gliclazide MR in Chinese. Aims To investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics of gliclazide modified release (MR) in healthy Chinese subjects. Methods In a single-dose pharmacokinetic study, 24 healthy male subjects with various CYP2C9 and CYP2C19 genotypes received an oral dose of 30 mg gliclazide MR and plasma was sampled for 72 h postdose. In a multiple-dose pharmacokinetic study, 17 other CYP2C9*1 homozygotes with various CYP2C19 genotypes received 30 mg gliclazide MR once daily for 6 days and plasma was sampled after the last dose. The plasma concentrations of gliclazide were measured using a validated LC/MS/MS method. CYP2C9 and CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Results In the single-dose study, no significant difference in any pharmacokinetic parameters was found in CYP2C9*1/*1, *1/*3 and *1/*13 subjects. In contrast, the AUC0,, of gliclazide was significantly increased by 3.4-fold [95% confidence interval (CI) 2.5, 4.7; P < 0.01] in CYP2C19 poor metabolizer (PM) subjects compared with CYP2C19*1 homozygotes. The half-life (t1/2) was prolonged from 15.1 to 44.5 h (P < 0.01). Similar differences were found in the multiple-dose study. The parameters of gliclazide AUCss, AUC0,, and Cmax were 3.4-fold (95% CI 2.9, 4.0), 4.5-fold (95% CI 3.8, 5.4) and 2.9-fold (95% CI 2.4, 3.4) increased (P < 0.01) in CYP2C19 PM subjects, respectively, compared with CYP2C19*1 homozygotes, and t1/2 was increased from 13.5 to 24.6 h (P < 0.01). Conclusions The pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism. [source] Pharmacokinetics and pharmacodynamics of TF-505, a novel nonsteroidal 5,-reductase inhibitor, in normal subjects treated with single or multiple dosesBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2002Tomoe Fujita Aims To assess the tolerability, pharmacokinetics and pharmacodynamics of a novel nonsteroidal,, and,, noncompetitive,, inhibitor,, of,, type,, I,, and,, type,, II,, 5,-reductases, (,)-(S)-4-[1-[4-[1-(4-isobutylphenyl) butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), after single and multiple oral doses in healthy volunteers. Methods In the single-dose study, six young adult males in each dose group received 25 mg or 50 mg of TF-505, and six older males (, 40 years) in each dose group received 75 mg or 100 mg of TF-505. The subjects were given the drug in ascending dose and in the fasting state. Six subjects also received 50 mg of TF-505 after breakfast in a two-period crossover manner. In the multiple-dose study, six older males in each dose group received 12.5 mg or 25 mg TF-505 after breakfast daily for 7 days. Plasma concentrations of TF-505, dihydrotestosterone (DHT) and testosterone were measured. The pharmacokinetics of TF-505 were analysed by a compartment model with first-order absorption, first-order elimination and a lag time. Pharmacokinetic and pharmacodynamic relationships were evaluated by indirect response modelling with inhibition of input. Results Maximum plasma concentration (Cmax) and the area under the concentration,time curve (AUC) increased proportionately after the single dose up to 50 mg and with the multiple doses. Linearity was not detected between 75 and 100 mg of TF-505. Dose dependency was also noted for the effect of TF-505 on DHT concentrations following single doses up to 50 mg and multiple doses. Plasma DHT concentrations decreased maximally to 58.2, 49.5, 54.2 and 49.8% of basal values at 8,12 h after single administration of 25, 50, 75 and 100 mg TF-505, respectively, and to 60.5 and 49.4% at the 7th and 5th dose following multiple doses of 12.5 and 25 mg TF-505, respectively. The predicted effect curves matched the observed data when the indirect response model was applied to the time course of the suppressant effect of TF-505 on plasma DHT concentrations after both the single and multiple studies. Fifty percent inhibitory concentrations (IC50) of 0.82, 1.48, 1.31 and 0.88 µ g ml,1, zero-order rate constants for the onset of plasma DHT concentration changes (kin) of 17.8, 17.4, 17.0 and 10.7% h,1 and first-order rate constants,, for,, increase,, in,, plasma,, DHT,, concentrations,, to,, basal,, values,, (kout),, of,, 0.17,,, 0.16,,, 0.17,, and,, 0.10 h,1,, for,, the,, single,, study,, at,, doses,, of,, 25,,, 50,,, 75,, and 100 mg, respectively, were attained. In the multiple-dose study, IC50s were 1.74 and 1.49 µg ml,1 for the 12.5 and 25 mg doses, respectively. No serious adverse events related to TF-505 were observed. Conclusions TF-505 was well tolerated in healthy male volunteers. Accumulation of TF-505 in plasma was not observed during multiple dosing. The indirect response model described the relationships between pharmacokinetics and pharmacodynamics of TF-505. Such modelling is expected to yield an appropriate dosage regimen in subsequent clinical trials. [source] | ||||||||||