Zaleplon, pharmacokinetics

Rosen AS, Fournie P, Darwish M, et al. Zaleplon pharmacokinetics and absolute bioavailability. Biopharm Drug Depos 1999 20 171-175. 

Drover DR Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives Zaleplon, zolpidem and zopiclone. Clin Pharmacokinet 2004 43 227. [PMID 15005637]... 

The newer sedative-hypnotics that are not benzodiazepines are rapidly becoming the first-line treatment for insomnia. These agents not only have pharmacodynamic advantages over benzodiazepines in terms of their mechanism of action, but perhaps more importantly, pharmacokinetic advantages as well. Three nonbenzodiazepine sedative-hypnotic agents that are now available are zaleplon (a pyrazolopyrimidine), zopiclone (a cyclopyrrolone not available in the United States), and zolpidem (an imidazopyridine) (Figs. 8—28-8—30 Table 8—4). 

The method was described and validated for intra- and interday variation for the quantitation of zaleplon in plasma and for pharmacokinetic application, using methanol-ammonium acetate buffer (50 50, v/v) as a mobile phase and drotaverine hydrochloride as the IS and a flow rate of 1.4 ml/min with UV detection of the effluent at 232 nm at ambient... 

The pharmacokinetics of zaleplon in elderly subjects is not significantly different from that in young healthy subjects [38]. Nevertheless, Drover [39] contends that this conclusion may indicate a lack of adequate studies in this area. As described earlier, zaleplon is metabolized primarily by the liver and undergoes significant presystemic metabolism. Consequently, the oral clearance of zaleplon is reduced, and the drug effect is prolonged in patients with hepatic impairment [40]. The clearance of zaleplon is not altered in patients with mild to moderate renal insufficiency [40] (Tab. 3). 

Darwish M (1999) The relationship between the pharmacokinetics and pharmacodynamics of zaleplon. Eur Neuropsychopharmacol 5 (Suppl) S361... 

Wickland C, Patat A (1999) The safety and pharmacokinetics of zaleplon in hepatically impaired patients. Sleep Res 2 (Suppl 1) 171... 

The pharmacokinetics and absolute oral systemic availability of zaleplon have been assessed in a partially randomized, single-dose, crossover study in 23 healthy subjects, who received intravenous infusions of zaleplon 1 and 2.5 mg during the first and second periods and were then randomly assigned to receive an oral dose of 5 mg or an intravenous infusion of 5 mg in a crossover design (7). The oral and intravenous doses of zaleplon were well tolerated. Somnolence, abnormal vision, diplopia, and dizziness were the most commonly reported adverse events. 

The pharmacokinetics and pharmacodynamics of zaleplon (10 or 20 mg) and zolpidem (10 or 20 mg) have been investigated in a randomized, double-blind, crossover, placebo-controlled study in 10 healthy volunteers with no history of sleep disorder (15). The half-life of zaleplon was significantly shorter than that of zolpidem. Zaleplon produced less sedation than zolpidem at the two doses studied, and the sedation scores in the zaleplon groups returned to baseline sooner than in the zolpidem groups. Zaleplon had no effect on recent or remote recall, whereas zolpidem had a significant effect on both measures. 

The addition of alcohol to the Z drugs, zaleplon, Zolpidem, and zopiclone, produces additive sedative effects without altering their pharmacokinetics (20). 

The interaction of zaleplon with digoxin has been investigated in 20 subjects (22). There were one or more adverse effects in 18% of those who took digoxin alone and 35% of those who took digoxin plus zaleplon, but these were all mild and resolved quickly. Zaleplon had no significant effects on selected pharmacokinetic and pharmacodynamic properties of digoxin. 

Drover D, Lemmens H, Naidu S, Cevallos W, Darwish M, Stanski D. Pharmacokinetics, pharmacodynamics, and relative pharmacokinetic/pharmacodynamic profiles of zaleplon and zolpidem. Clin Ther 2000 22(12) 1443-61. 

Sanchez Garcia P, Paty I, Leister CA, Guerra P, Frias J, Garcia Perez LE, Darwish M. Effect of zaleplon on digoxin pharmacokinetics and pharmacodynamics. Am J Health Syst Pharm 2000 57(24) 2267-70. 

The effects of zaleplon on the pharmacokinetics and phar-macodjmamics of steady-state digoxin have been studied in 20 healthy men aged 18 5 years (309). There was no interaction. 

The pharmacokinetics and absolute oral systemic availability of zaleplon have been assessed in a partially randomized, single-dose, crossover study in 23 healthy subjects, who received intravenous infusions of zaleplon 1 and 2.5 mg during the first and second periods and were... 

Benzodiazepines impair psiychomotor performance, but neither ebasitine nor mizolastine (both non-sedating antihistamines) further impair this. An enhanced sedative effect would be expected if known sedative antihistamines are given with benzodiazepines. Diphenhydramine did not alter the pharmacokinetics of zaleplon. 

Zaleplon, zolpidem and zopiclone are metabolised by several cytochrome CYP450 isoenzymes and it has been suggested that because of this, other drugs which affect a particular isoenzyme such as CYP3A4, may have less effect on their metabolism. However, their pharmacokinetics are affected by potent inducers such as rifampicin and by inhibitors such as the azole antifungals. Buspirone undergoes CYP3A4-mediated metabolism in the liver. 

Diclofenac reduces the dose of midazolam needed to produce sedation and hypnosis. Diazepam has a small effect on the pharmacokinetics of diclofenac, ibuprofen and naproxen. Diazepam and indometacin appear not to interact adversely, although feelings of dizziness may be increased. Zaleplon and ibuprofen appear not to interact... 

A randomised, single-dose study in 17 healthy subj ects found that ibuprofen 600 mg had no effect on the pharmacokinetics of zaleplon 10 mg. ... 

Digoxin toxicity occurred in two elderly patients and rises in serum digoxin levels have been seen in others when they were given alprazolam. A reduction in the urinary clearance of digoxin has been described during the use of diazepam. No pharmacokinetic interaction seems to occur with digoxin and eszopiclone, zaleplon, or Zolpidem. 

Zaiepion. Zaleplon 10 mg daily given to 20 healthy subjects for 5 days had no significant effects on the steady-state pharmacokinetics of digoxin 375 micrograms daily. There were no significant differences in QTc or PR intervals. ... 

Zaleplon. A single 75-mg dose of imipramine had no efifeet on the pharmacokinetics of zaleplon 20 mg, and psychomotor tests showed only short term additive effects lasting 1 to 2 hours. ... 

---