Ondansetron Hydrochloride (Page 5 of 7)

12.3 Pharmacokinetics

Absorption
Ondansetron is absorbed from the gastrointestinal tract and undergoes some first-pass metabolism. Mean bioavailability in healthy subjects, following administration of a single 8 mg tablet, is approximately 56%.
Ondansetron systemic exposure does not increase proportionately to dose. The area under curve (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 Effects: Bioavailability is also slightly enhanced by the presence of food.
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.
Elimination
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 metabolites are observed in the urine. The primary metabolic pathway is hydroxylation on the indole ring followed by subsequent glucuronide or sulfate conjugation.
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.
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.
Specific Populations
Age: Geriatric Population: A reduction in clearance and increase in elimination half-life are seen in patients older than 75 years compared to younger subjects [see Use in Specific Populations (8.5)] . Sex: Gender differences were shown in the disposition of ondansetron given as a single dose. The extent and rate of absorption are greater in women than men. Slower clearance in women, a smaller apparent volume of distribution (adjusted for weight), and higher absolute bioavailability resulted in higher plasma ondansetron concentrations. These higher plasma concentrations may in part be explained by differences in body weight between men and women. It is not known whether these sex-related differences were clinically important. More detailed pharmacokinetic information is contained in Tables 5 and 6.

Table 5: Pharmacokinetics in Male and Female Healthy Subjects after a Single Dose of a Ondansetron 8 mg Tablet

Age-group (years) Sex (M/F)

Mean Weight (kg)

N

Peak Plasma Concentration (ng/mL)

Time of Peak Plasma Concentration (h)

Mean Elimination Half-life (h)

Systemic Plasma Clearance L/h/kg

Absolute Bioavailability

18 to 40 M F

69.0 62.7

6 5

26.2 42.7

2.0 1.7

3.1 3.5

0.403 0.354

0.483 0.663

61 to 74 M F

77.5 60.2

6 6

24.1 52.4

2.1 1.9

4.1 4.9

0.384 0.255

0.585 0.643

≥75 M F

78.0 67.6

5 6

37.0 46.1

2.2 2.1

4.5 6.2

0.277 0.249

0.619 0.747

Table 6: Pharmacokinetics in Male and Female Healthy Subjects after a Single Dose of a Ondansetron 24 mg Tablet

Age-group (years) Sex (M/F)

Mean Weight (kg)

N

Peak Plasma Concentration (ng/mL)

Time of Peak Plasma Concentration (h)

Mean Elimination Half-life (h)

18 to 43 M F

84.1 71.8

8 8

125.8 194.4

1.9 1.6

4.7 5.8

Renal Impairment: Renal impairment is not expected to significantly influence the total clearance of ondansetron as renal clearance represents only 5% of the overall clearance. However, the mean plasma clearance of ondansetron was reduced by about 50% in patients with severe renal impairment (creatinine clearance less than 30 mL/min). The reduction in clearance was variable and not consistent with an increase in half-life [see Use in Specific Populations (8.7)] .
Hepatic Impairment: In patients with mild-to-moderate hepatic impairment, clearance is reduced 2-fold and mean half-life is increased to 11.6 hours compared with 5.7 hours in healthy subjects. In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), clearance is reduced 2-fold to 3-fold and apparent volume of distribution is increased with a resultant increase in half-life to 20 hours [see Dosage and Administration (2.2), Use in Specific Populations (8.6)] .
Drug Interaction Studies
CYP 3A4 Inducers: Ondansetron elimination may be affected by cytochrome P-450 inducers. In a pharmacokinetic trial of 16 epileptic patients maintained chronically on CYP3A4 inducers, carbamazepine, or phenytoin, a reduction in AUC, C max , and t ½ of ondansetron was observed. This resulted in a significant increase in the clearance of ondansetron. However, this increase is not thought to be clinically relevant [see Drug Interactions (7.2)] .
Chemotherapeutic Agents: Carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron [see Drug Interactions (7.4)] .
Antacids: Concomitant administration of antacids does not alter the absorption of ondansetron.

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