XTAMPZA ER (Page 9 of 11)

12.3 Pharmacokinetics

The activity of XTAMPZA ER is primarily due to the parent drug oxycodone. XTAMPZA ER is designed to provide delivery of oxycodone over 12 hours.

Absorption

XTAMPZA ER is not bioequivalent to oxycodone extended-release tablets. In the fasted state, both peak serum concentration (Cmax ) and extent of absorption (AUC) are lower for XTAMPZA ER, and in the fed state, Cmax is lower, but AUC is similar.

Compared to immediate-release oxycodone solution dosed under fasted conditions the mean Cmax of oxycodone from XTAMPZA ER is lower (73% and 43% lower for fasted and fed administration, respectively) and the median time to peak plasma concentration (Tmax ) is approximately 3 hours longer. The extent of absorption of oxycodone from XTAMPZA ER is less than from immediate-release oxycodone oral solution in the fasted state (relative bioavailability of 75%), but comparable in the fed state (relatively bioavailability of 114%).

The peak plasma concentration of oxycodone from XTAMPZA ER occurs approximately 4.5 hours after fed dose administration. Upon repeated dosing with XTAMPZA ER in healthy subjects in pharmacokinetic studies, steady-state levels were achieved within 24-36 hours. Oxycodone is extensively metabolized and eliminated primarily in the urine as both conjugated and unconjugated metabolites. The apparent elimination half-life (t½ ) of oxycodone following the administration of XTAMPZA ER when dosed in the fed state was 5.6 hours compared to 3.2 hours for immediate-release oxycodone.

Food Effects

The oral bioavailability of oxycodone from XTAMPZA ER is greater when taken with food than when taken in the fasted state. The oral bioavailability is dependent on the food consumed and is greatest following a high-fat and high-calorie meal with an increase in Cmax of 100-150% and AUC of 50-60% compared to the fasted state. Following a medium-fat medium-calorie meal, the Cmax increased by 84% and AUC by 28% compared to the fasted state. Following a low-fat low-calorie meal, Cmax was 19% higher and AUC was comparable, relative to the fasted state.

Pharmacokinetic Profile of XTAMPZA ER Intact and Sprinkled

Plasma concentration over time has been measured following administration of XTAMPZA ER capsule contents intact with food and sprinkled. The pharmacokinetic profile for the capsule contents sprinkled was equivalent to intact capsule administration (Table 7).

Table 7: Oxycodone Pharmacokinetic Parameters, Administration of Capsule Contents and Intact Capsules (36 mg)
Treatment Cmax (ng/mL) Tmax (hr) AUC0-INF (hr∙ng/mL)
Values shown for Cmax and AUC0-INF are mean (standard deviation); values shown for Tmax are median (minimum — maximum).
Intact XTAMPZA ER Capsules (fed) 55.3 (13.6) 4.5 (1.5 – 9.0) 540 (143)
Sprinkled XTAMPZA ER Capsule Contents (fed) 48.1 (12.0) 4.5 (2.5 – 9.0) 528 (130)

Distribution

Following intravenous administration, the steady-state volume of distribution (Vss ) for oxycodone was 2.6 L/kg. Oxycodone binding to plasma protein at 37°C and a pH of 7.4 was about 45%. Once absorbed, oxycodone is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. Oxycodone has been found in breast milk [see Use in Specific Populations (8.2)].

Elimination

In humans, oxycodone is extensively metabolized. Oxycodone and its metabolites are excreted primarily via the kidney.

Metabolism

Oxycodone is extensively metabolized by multiple metabolic pathways to produce noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. Noroxycodone and noroxymorphone are the major circulating metabolites. CYP3A mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a lower contribution from CYP2D6-mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs [see Drug Interactions (7)].

Noroxycodone exhibits very weak anti-nociceptive potency compared to oxycodone; however, it undergoes further oxidation to produce noroxymorphone, which is active at opioid receptors. Although noroxymorphone is an active metabolite and present at relatively high concentrations in circulation, it does not appear to cross the blood-brain barrier to a significant extent. Oxymorphone is present in the plasma only at low concentrations and undergoes further metabolism to form its glucuronide and noroxymorphone. Oxymorphone has been shown to be active and to possess analgesic activity but its contribution to analgesia following oxycodone administration is thought to be clinically insignificant. Other metabolites (α- and ß-oxycodol, noroxycodol, and oxymorphol) may be present at very low concentrations and demonstrate limited penetration into the brain as compared to oxycodone. The enzymes responsible for keto-reduction and glucuronidation pathways in oxycodone metabolism have not been established.

Excretion

Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free and conjugated oxycodone 8.9%, free noroxycodone 23%, free oxymorphone less than 1%, conjugated oxymorphone 10%, free and conjugated noroxymorphone 14%, reduced free and conjugated metabolites up to 18%. The total plasma clearance was approximately 1.4 L/min in adults.

Specific Populations

Age: Geriatric Population

The plasma concentrations of oxycodone are nominally affected by age, being 15% greater in elderly as compared to young subjects (age 21-45).

Sex

Across individual pharmacokinetic studies, oxycodone plasma exposures for female subjects were up to 20% higher than for male subjects, even after considering differences in body weight or BMI. The reason for this difference is unknown [see Use in Specific Populations (8)].

Renal Impairment

Data from a pharmacokinetic study involving 13 patients with mild to severe renal dysfunction (creatinine clearance <60 mL/min) showed peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, and AUC values for oxycodone, noroxycodone, and oxymorphone 60%, 50%, and 40% higher than normal subjects, respectively. This was accompanied by an increase in sedation, but not by differences in respiratory rate, pupillary constriction, or several other measures of drug effect. There was an increase in mean elimination t½ for oxycodone of 1 hour.

Hepatic Impairment

Data from a study involving 24 patients with mild to moderate hepatic dysfunction show peak plasma oxycodone and noroxycodone concentrations 50% and 20% higher, respectively, than healthy subjects. AUC values are 95% and 65% higher, respectively. Oxymorphone peak plasma concentrations and AUC values are lower by 30% and 40%. The mean elimination t½ for oxycodone increased by 2.3 hours.

Drug Interaction Studies

CYP3A4 Inhibitors

CYP3A4 is the major enzyme involved in noroxycodone formation. Co-administration of a 10 mg single dose of oxycodone extended –release tablet and the CYP3A4 inhibitor ketoconazole (200 mg BID) increased oxycodone AUC and Cmax by 170% and 100%, respectively [see Drug Interactions (7)].

CYP3A4 Inducers

A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively [see Drug Interactions (7)].

CYP2D6 Inhibitors

Oxycodone is metabolized in part to oxymorphone via CYP2D6. While this pathway may be blocked by a variety of drugs such as certain cardiovascular drugs (e.g., quinidine) and antidepressants (e.g., fluoxetine), such blockade is not expected to be of clinical significance for XTAMPZA ER [see Drug Interactions (7)].

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