Effect Of Dosing Interval Research Articles

Effect of dosing interval on pharmacokinetics of fentanyl pectin nasal spray from a crossover study.

To evaluate the effects of different dosing intervals on multiple-dose pharmacokinetics, and safety and tolerability of fentanyl pectin nasal spray (FPNS). This was an open-label study in healthy volunteers. Five FPNS treatments (1 × 100 μg; 2 × 100 μg at 4-, 2-, and 1-hour intervals, and 8 × 100 μg consecutively) were administered to the right nostril, with a ≥ 3-day washout period. Blood samples were collected at predose and up to 1,440 minutes postdose. Plasma fentanyl concentrations were determined. Pharmacokinetic parameters-peak concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve (AUC)-were derived using noncompartmental method. For the two-dose regimens, pharmacokinetic parameters were compared between doses using a paired t-test with p < 0.05 as statistically significant. Thirteen subjects were enrolled and 10 completed the study. Median tmax was 10-15 minutes across five regimens. Cmax post the second dose significantly increased for 1-hour (p < 0.0001) and 2-hour (p < 0.001) but not 4-hour intervals (p = 0.462). C(max) and AUC(0-24) following 8 × 100 μg were approximately fivefold of those following 1 × 100 μg. Dizziness (11.9 percent) and somnolence (4.9 percent) were most common adverse events (AEs). 12.9 percent of patients discontinued due to AEs. FPNS exhibited consistently rapid t(max). When intervals between two doses were shorter, the difference in C(max) between the first and second dose was larger. All regimens of FPNS were well tolerated. Exposure reached a plateau after eight consecutive doses, suggesting potential limited absorption through the nasal mucosa.

Effect of dosing interval on pharmacokinetics and safety of fentanyl pectin nasal spray.

148 Background: Fentanyl pectin nasal spray(FPNS) contains fentanyl citrate and is approved for treatment of breakthrough cancer pain. Nasal delivery allows direct nasal epithelium-to-blood absorption of fentanyl, and thus rapid and effective pain relief. This study evaluated the effect of dosing interval on pharmacokinetics (PK) and safety/tolerability of FPNS. Methods: This was an open-label randomized study in healthy volunteers. Five treatments were administered under naltrexone block to the right nostril, with a ≥3-day washout period: 1 x 100 μg (A); 2 x 100 μg, 4-hr (B), 2-hr (C), and 1-hr apart (D); and 8 x 100 μg consecutively (E). Blood samples were collected and analyzed for plasma fentanyl concentrations. PK data were derived using a non-compartmental model method. Results: 13 subjects were enrolled, 10 (77%) completed the study. For the two-dose regimens, Cmax was higher after the second dose than the first; the increase was statistically significant for the 1- and 2-hr intervals, but not the 4-hr. There were no significant differences in AUC among them. Eight consecutive 100-µg doses resulted in an ~5-fold in Cmax and AUC of those of a single 100-µg dose, suggesting a less than dose proportional increase in rate (peak) and extent (AUC). No new adverse events (AEs) were observed. 53% of subjects reported ≥1 AE, with dizziness (11.9%) and somnolence (4.9%) most common. 12.9% of subjects discontinued due to AEs. All AEs rapidly decreased to sustained low levels after 4–5 weeks. Conclusions: FPNS at 100-800 µg was well tolerated. The shorter the dosing interval, the higher the second Cmax. Dosing interval had no effect on AUC. Exposure plateaued after 8 consecutive 100 µg doses to the same nostril, suggesting an additional safety feature of FPNS. [Table: see text]

Effect of dosing interval on the efficacy of topical ophthalmic gatifloxacin against Enterococcus faecalis in an in vitro pharmacokinetic model simulating the local eye compartment

Improved dosing regimens have been proposed for various antimicrobial agents by application of pharmacokinetic/pharmacodynamic (PK/PD) principles. However, for topical ophthalmic use there are several limitations to changing the dosing regimen, such as drug formulation and bioavailability. In this study, we investigated the relationship between dosing interval and antibacterial efficacy in an in vitro PK model mimicking post-operative endophthalmitis. The in vitro PK model simulated the aqueous humour concentration following topical application of 0.3% gatifloxacin ophthalmic solution to rabbit eyes. A clinical isolate of Enterococcus faecalis was exposed to gatifloxacin three times repeatedly at various intervals from 0 h to 8 h. The area between the control growth curve and the bacterial killing and re-growth curve for 24 h (ABBC) was used to evaluate efficacy. The ABBC showed bell-shaped dependence on the dosing interval with a peak at 3 h. Under limited condition of total exposure amount, i.e. area under the concentration–time curve, the antimicrobial efficacy appears to be associated with the cumulative time of a 24-h period such that the concentration exceeds the minimum inhibitory concentration ( T > MIC) rather than the peak concentration:MIC ratio. The length of intermission of T > MIC during repeated dosing appears to be proportional to the decrease in efficacy of gatifloxacin against E. faecalis. A longer dosing interval, as long as T > MIC is continuous, would likely be more efficient at preventing post-operative enterococcal endophthalmitis. However, further investigation is necessary to explore whether this model is applicable to a variety of pathogens and drugs.

Characterization of 1-methyl-4-[4′-amino]phenyl-1,2,3,6-tetrahydropyridine toxicity in the mouse

We examined the effects of pretreatment with clorgyline or deprenyl, selective inhibitors of MAO-A and -B respectively, as well as the selective DA uptake inhibitor GBR 12909, on the toxicity of MPTP analog. In addition, we examined the effects of 4'-amino MPTP 1 month after administration and characterized the anatomical changes induced by this agent. Finally, we evaluated the effect of dosing interval on 4'-amino MPTP toxicity

Effects of dosing intervals on the development of tolerance to high dose transdermal nitroglycerin

To investigate the antiischemic efficacy and development of tolerance to transdermal nitroglycerin, 14 patients with chronic, stable angina pectoris were studied using continuous ambulatory electrocardiographic monitoring. Patients demonstrated initial hemodynamic responsiveness to sublingual nitroglycerin and were titrated to a maximally tolerated dose of 30 to 60 mg/24 hours (52 ± 5 mg). Two crossover phases were used in a randomized, double-blind, placebo-controlled manner: continuous nitroglycerin therapy (patches containing active drug worn for 24 hours) and intermittent nitroglycerin therapy (12-hour active drug followed by a 12-hour nitrate-free period). There were no differences in frequency or duration of ischemic episodes between the placebo days of each phase. A significant effect in frequency of episodes was observed between placebo and treatment days of continuous therapy (p < 0.05). Nonsignificant reductions in frequency and duration of ischemic episodes also occurred during intermittent therapy. The major antiischemic effect of transdermal nitroglycerin therapy occurred during the first day of treatment but was lost by 48 hours. Reductions in frequency and duration of ischemic episodes (p < 0.05) were present on day 1 of continuous therapy but ischemic episodes returned to placebo levels by day 2, suggesting the development of tolerance. Intermittent therapy did not prevent the development of tolerance on day 2 of treatment. The results demonstrate that the use of high doses of transdermal nitroglycerin in patients with chronic, stable coronary artery disease produced a beneficial reduction in the frequency and duration of ischemia. However, the antiischemic benefit was lost between 24 and 48 hours after the onset of continuous and intermittent therapy, presumably due to tolerance. Alternate doses and nitrate-free periods require further study to determine if the beneficial effects on ischemia are sustained.