OXYCODONE HYDROCHLORIDE (Page 7 of 10)

12.3 Pharmacokinetics

The activity of oxycodone hydrochloride tablets is primarily due to the parent drug oxycodone. Oxycodone hydrochloride tablets are designed to provide immediate release of oxycodone.

Table 2: Pharmacokinetic Parameters (Mean±SD)

Dose\Parameters

AUC

(ngxhr/mL)

C max

(ng/mL)

T max

(hr)

C min

(ng/mL)

C avg

(ng/mL)

Half-Life

(hr)

Single Dose

Pharmacokinetics

Oxycodone Hydrochloride

5 mg tabs x 3

133.2±33

22.3±8.2

1.8±1.8

n/a

n/a

3.73±0.9

Oxycodone Hydrochloride

15 mg tab

128.2±35.1

22.6±7.6

1.4±0.7

n/a

n/a

3.55±1.0

Oxycodone Hydrochloride

Liquid Concentrate

15 mg oral solution

130.6±34.7

21.3±6.1

1.9±1.5

n/a

n/a

3.71±0.8

Oxycodone Hydrochloride

30 mg tab

268.2±60.7

39.3±14.0

2.6±3.0

n/a

n/a

3.85±1.3

Food-Effect,

Single Dose

Oxycodone Hydrochloride

10 mg/10 mL oral

sol’n (fasted)

105±6.2

19.0±3.7

1.25±0.5

n/a

n/a

2.9±0.4

Oxycodone Hydrochloride

10 mg/10 mL oral

sol’n (fed)

133±25.2

17.7±3.0

2.54±1.2

n/a

n/a

3.3±0.5

Multiple-Dose

Studies

AUC

(72-84)

Oxycodone Hydrochloride

5 mg tabs q6h x 14

Doses

113.3±24.0

15.7±3.2

1.3±0.3

7.4±1.8

9.4±2.0

n/a

Oxycodone Hydrochloride

3.33 mg (3.33 mL)

oral sol’n.

q4h x 21 doses

99.0±24.8

12.9±3.1

1.0±0.3

7.2±2.3

9.7±2.6

n/a

Absorption About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lowersystemicc and/or first-pass metabolism of oxycodone. The relative oral bioavailability of oxycodone hydrochloride tablets 15 mg and 30 mg tablets, compared to the 5 mg oxycodone hydrochloride tablets, is 96% and 101% respectively. Oxycodone hydrochloride 15 mg tablets and 30 mg tablets are bioequivalent to the 5 mg oxycodone hydrochloride tablets (see Table 2 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride 5 mg tablets at doses of 5 mg, 15 mg (three 5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride tablets.

Figure1
(click image for full-size original)

Food Effects
A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution (see Table 2). In addition, food caused a delay in T max (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets.

Distribution
Following intravenous administration, the volume of distribution (V ss ) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Special Populations ( 8.2)].

Elimination
Metabolism
A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism, and is catalyzed by CYP3A4. Oxymorphone is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6 [see Drug Interactions ( 7)]. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present.

Excretion
Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone hydrochloride tablets was 3.5 to 4 hours.

Specific Populations
Age: Geriatric Population
Population pharmacokinetic studies conducted with oxycodone hydrochloride tablets, indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.

Hepatic Impairment
In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic impaired patients [see Use in Specific Populations ( 8.6)].

Renal Impairment
This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function [see Use in Specific Populations ( 8.7)].

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