ime. Multiday administration of ondansetron has been shown to slow colonic transit in normal volunteers. Ondansetron has no effect on plasma prolactin concentrations.
Pharmacokinetics
Absorption
Ondansetron is well absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. After a single dose of Zuplenz (ondansetron) oral soluble film 8 mg under fasting conditions (n=46), the peak plasma concentrations were achieved in 1.3 hours and the mean elimination half-life was 4.6 hours in healthy subjects. The mean (±S.D.) C max and AUC were 37.28 (±14.9) ng/mL and 225 (±88.1) ng•h/mL, respectively. In the same study, mean ondansetron Cmax and AUC following administration of 8 mg Zuplenz oral soluble film were comparable to those after 8 mg ondansetron ODT (orally disintegrating tablet). The systemic exposure after administration of Zuplenz oral soluble film 8 mg with or without water was found to be comparable.
In a study using ondansetron tablets, ondansetron systemic exposure did not increase proportionately to dose. AUC from a 16 mg tablet was 24% greater than predicted from an 8 mg tablet dose. This may reflect some reduction of first-pass metabolism at higher oral doses.
Food Effect
When Zuplenz 8 mg was administered with a high fat meal, the mean time to peak plasma concentration (T max) was delayed by approximately 1 hour while AUC was similar to that under fasting conditions. Under the same fed conditions, both Cmax and AUC were comparable between Zuplenz 8 mg and ondansetron ODT 8 mg.
Distribution
Plasma protein binding of ondansetron as measured in vitro was 70% to 76% over the concentration range of 10 to 500 ng/mL. Circulating drug also distributes into erythrocytes.
Metabolism and Excretion
Ondansetron is extensively metabolized in humans, with approximately 5% of a radiolabeled dose recovered as the parent compound from the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation. Although some nonconjugated metabolites have pharmacologic activity, these are not found in plasma at concentrations likely to significantly contribute to the biological activity of ondansetron. The metabolites are observed in the urine.
In vitro metabolism studies have shown that ondansetron is a substrate for human hepatic cytochrome P-450 enzymes, including CYP1A2, CYP2D6, and CYP3A4. In terms of overall ondansetron turnover, CYP3A4 played the predominant role. Because of the multiplicity of metabolic enzymes capable of metabolizing ondansetron, it is likely that inhibition or loss of one enzyme (e.g., CYP2D6 genetic deficiency) will be compensated by others and may result in little change in overall rates of ondansetron elimination. Ondansetron elimination may be affected by cytochrome P-450 inducers.
Gender Effects
Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of ondansetron's absorption is greater in women than men. It is not known whether these gender-related differences were clinically important.
Table 4: Mean Pharmacokinetic Parameters by Gender in Healthy Volunteers After A Single 8 mg Zuplenz Oral Soluble Film Dose Gender Mean Weight (kg) n Cmax (ng/mL) Tmax (h) T 1/2 (h) AUC (h•ng/mL)
M F 62 56.7 39 7 35.2 49.1 1.67 1.7 4.54 5.39 207 323
Elderly
A reduction in clearance and increase in elimination half-life are seen in patients ov |
