TARGINIQ ER (Page 10 of 11)

12.3 Pharmacokinetics

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

Cutting, breaking, chewing, crushing, or dissolving TARGINIQ ER impairs the extended-release delivery mechanism and results in the rapid release and absorption of a potentially fatal dose of oxycodone.

Absorption

Oxycodone
Oxycodone from TARGINIQ ER tablets was rapidly absorbed with the median Tmax 3 to 4 hours following a single oral administration over a range of doses from 10 mg/5 mg to 80 mg/40 mg. About 60% to 87% of an oral dose of oxycodone reaches the central compartment in comparison to a parenteral dose. This high oral bioavailability is due to low pre-systemic and/or first-pass metabolism. Dose proportionality for oxycodone has been established for the 10 mg/5 mg, 20 mg/10 mg, and 40 mg/20 mg TARGINIQ ER tablet strengths for both peak plasma concentrations (Cmax ) and extent of absorption (AUC) (see Table 8 and Table 9, below) following single or multiple oral dose with q12h administration. Steady-state plasma concentrations are reached in approximately 2 days for oxycodone and naloxone and for their metabolites.

Naloxone Absolute bioavailability of naloxone from TARGINIQ ER tablets was very low (≤ 2%) following oral administration. However in an abuse potential study conducted in nondependent drug users, naloxone bioavailability was much higher (approximately 31%) following intranasal administration of crushed TARGINIQ ER 40 mg/20 mg tablets, due to circumvention of GI and hepatic first-pass naloxone metabolism. Mean AUC and Cmax values of naloxone were 29.9 nghr/mL and 20.2 ng/mL following intranasal administration of crushed TARGINIQ ER 40 mg/20 mg tablets, while mean AUC and Cmax values were 0.833 ng hr/mL and 0.0845 ng/mL under normal use condition [see Drug Abuse and Dependence (9.2)].

Table 9. Pharmacokinetic Parameters for Oxycodone (Mean [SD])
† for single-dose, AUC = AUC0-inf ; for multiple-dose, AUC = AUCtau
†† median (range)
Data obtained from healthy subjects receiving naltrexone.
Regimen TARGINIQ ER Dose (mg/mg) AUC (ng•hr/mL)† Cmax (ng/mL) Tmax (hour) †† Trough Conc. (ng/mL)
Single Dose 10/5 130 [25.6] 12.1 [2.67] 3 [1, 6] NA
20/10 247 [62.7] 22.2 [4.19] 3 [1, 6] NA
40/20 506 [128] 40.9 [9.52] 3.5 [1, 6] NA
Multiple Dose 10/5 q12h 129 [33.4] 15.0 [3.25] 1.75 [1, 5] 5.69 [1.78]
40/20 q12h 507 [100] 57.0 [10.0] 2 [0.5, 5] 24.7 [5.68]
Table 10. Pharmacokinetic Parameters for Naloxone (Mean [SD])
† for single-dose, AUC = AUC0-inf ; for multiple-dose, AUC = AUCtau
†† median (range)
Data obtained from healthy subjects receiving naltrexone.
Regimen TARGINIQ ER Dose (mg/mg) AUC (ng•hr/mL)† Cmax (ng/mL) Tmax (hour) †† Trough Conc. (ng/mL)
Single Dose 10/5 0.136 [0.141] 0.0306 [0.0236] 5 [1, 12] NA
20/10 0.657 [0.585] 0.0839 [0.0812] 1.5 [0.5, 12] NA
40/20 0.833 [0.526] 0.0845 [0.0834] 2 [1, 16] NA
Multiple Dose 10/5 q12h 0.416 [0.367] 0.0725 [0.0885] 3.75 [0.5, 8] 0.0154 [0.00882]
40/20 q12h 1.55 [1.02] 0.217 [0.173] 5 [0.5, 12] 0.0711 [0.0410]

Food Effect:

Administration of TARGINIQ ER with a standardized high-fat meal did not meaningfully affect the extent of absorption of oxycodone, naloxone, or naloxone-3β-glucuronide. In the clinical trial program, TARGINIQ ER was administered to chronic pain patients without regard to meals. Therefore, TARGINIQ ER can be administered with or without food.

Distribution

Oxycodone
Plasma protein binding for oxycodone measured in healthy subjects was <24%. Following IV administration, the mean volume of distribution for oxycodone (0.07 mg/kg) was 245 L. Once absorbed, oxycodone is distributed to skeletal muscle, liver, intestinal tract, lungs, spleen, and brain. Oxycodone is found in breast milk [see Use in Specific Populations (8.3)]. Oxycodone crossed the blood-brain barrier in preclinical species.

Naloxone
Plasma protein binding for naloxone measured in healthy subjects, was <60%. Following IV administration, the mean volume of distribution for naloxone (0.035 mg/kg) was 378 L. It is not known whether naloxone passes into breast milk. Naloxone crossed the blood-brain barrier in preclinical species.

Elimination

Metabolism

Oxycodone:
Oxycodone metabolism is primarily mediated by CYP3A4/5 and CYP2D6. Oxycodone is mainly metabolized to Phase 1 metabolites including noroxycodone, oxymorphone and noroxymorphone. Oxycodone metabolites are present in plasma at lower concentrations than the parent drug. Noroxycodone and noroxymorphone are the major metabolites in the blood circulation. The mean molar ratio of metabolite to parent (oxycodone), as evaluated by AUC across proposed therapeutic doses of TARGINIQ ER, was 0.928 for noroxycodone, 0.379 for noroxymorphone, and 0.0251 for oxymorphone, respectively.

Naloxone:
Naloxone metabolism is primarily mediated by UGT1A8 and UGT2B7. Naloxone is mainly metabolized to 6β-naloxol, naloxone-3β-glucuronide and 6β-naloxol-3β-glucuronide. The mean molar ratio of metabolite to parent (naloxone), as evaluated by AUC across proposed therapeutic doses TARGINIQ ER was 31.5 for 6β-naloxol, 1459 for naloxone-3β-glucuronide, and 1301 for 6β-naloxol-3β-glucuronide, respectively. Naloxone metabolites were present in plasma at higher concentrations than the parent drug, especially for naloxone-3β-glucuronide and 6β-naloxol-3β-glucuronide due to the extremely low plasma naloxone concentrations following oral administration of TARGINIQ ER.

Excretion

Oxycodone:
Oxycodone is rapidly eliminated from the body with a mean t1/2 of approximately 3.9-5.3 hours after a single oral dose administration of TARGINIQ ER in healthy subjects. Oxycodone and its metabolites are excreted in both urine and feces. Following an IV dose (0.07 mg/kg), the mean total plasma clearance was 47.8 L/hour in healthy subjects. Following TARGINIQ ER 10/5 mg administration, the mean renal clearance was approximately 3.66-4.37 L/hour. Following an oral dose of oxycodone immediate-release (15 mg), the mean total urine recovery (48 hour cumulative recovery) of oxycodone and its metabolites from 16 healthy subjects was 72%. These findings suggest that metabolism is the major route of elimination.

Naloxone:
Naloxone is eliminated from the body with mean t1/2 ranging from 4.1 to 17.2 hours after a single oral dose administration of TARGINIQ ER in healthy subjects. The mean total plasma clearance was 217 L/hour following an IV dose (0.035 mg/kg), and the mean renal clearance was 7.85-31.9 L/hour following an oral dose of TARGINIQ ER 10 mg/5 mg. These findings suggest that the metabolism is the major route of elimination.

Special Populations

Age: Geriatric Population

A prospective study conducted in 2 age groups (younger: 19-44 years old vs. elderly: 65-77 years old) to assess age effects on the PK of TARGINIQ ER (10 mg/5 mg) demonstrated slightly higher steady state oxycodone AUC (18% increase), and higher steady state naloxone AUC (82% increase) for elderly subjects compared with younger subjects. [see Use in Specific Populations (8.6)]

Sex

Pharmacokinetic properties of TARGINIQ ER were not affected by sex.

Hepatic Impairment

Oxycodone:
Oxycodone pharmacokinetics from TARGINIQ ER was significantly altered by hepatic impairment, especially in subjects with moderate or severe hepatic impairment as compared with healthy subjects. Mean oxycodone AUC was 99.1, 143, 319 and 314 nghr/mL for healthy subjects, and subjects with mild, moderate, and severe hepatic impairment, respectively. The mean increase in oxycodone AUC was approximately 43%, 219%, and 210% for subjects with mild, moderate, and severe hepatic impairment, respectively, as compared with that for healthy subjects. Mean oxycodone Cmax was 9.00, 10.8, 18.1 and 17.2 ng/mL for healthy subjects, and subjects with mild, moderate, and severe hepatic impairment, respectively. The mean increase in oxycodone Cmax was approximately 20%, 101%, and 91% for subjects with mild, moderate, and severe hepatic impairment, respectively, as compared with that for healthy subjects.

Naloxone:
Following oral TARGINIQ ER administration, mean naloxone AUC0-t was 0.115, 1.02, 0.459 and 1.12 ng•hr/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. Mean naloxone Cmax was 0.0345, 0.0435, 0.0347 and 0.0678 ng/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. The mean increase in naloxone Cmax was approximately 976%, 758%, and 1575% for subjects with mild, moderate, and severe renal impairment, respectively, as compared with that for healthy subjects [see Use in Specific Populations (8.7)].

Renal Impairment

Oxycodone:
Following oral TARGINIQ ER administration, mean oxycodone AUC was 111, 171, 186 and 253 nghr/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. The mean increase in oxycodone AUC was approximately 53%, 66% and 124% for subjects with mild, moderate and severe renal impairment, respectively, as compared with that for healthy subjects. Mean oxycodone Cmax was 10.6, 11.7, 14.4 and 17.8 ng/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. The mean increase in oxycodone Cmax was approximately 10%, 35%, and 67% for subjects with mild, moderate, and severe renal impairment, respectively, as compared with that for healthy subjects. [see Use in Specific Populations (8.8)]

Naloxone:
Following oral TARGINIQ ER administration, mean naloxone AUC0-t was 0.115, 1.02, 0.459 and 1.12 nghr/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. Mean naloxone Cmax was 0.0345, 0.0435, 0.0347 and 0.0678 ng/mL for healthy subjects, and subjects with mild, moderate, and severe renal impairment, respectively. The mean increase in naloxone Cmax was approximately 976%, 758%, and 1575% for subjects with mild, moderate, and severe renal impairment, respectively, as compared with that for healthy subjects [see Use in Specific Populations (8.8)].

Drug Interaction Studies

Oxycodone
At therapeutic concentrations, TARGINIQ ER is not expected to affect concomitantly administered medicines metabolized by CYP1A2, CYP2A6, CYP2C9/19, CYP2D6, CYP2E1 and CYP3A4. There were no pharmacokinetic drug interactions between oxycodone and naloxone.

CYP3A4 Inhibitors:
CYP3A4 is the major enzyme involved in noroxycodone formation. Co-administration of an oxycodone controlled release tablet (10 mg single dose) 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 has not been shown to be of clinical significance with TARGINIQ ER [see Drug Interactions (7)].

Naloxone
UGT1A8 and 2B7 are responsible for the metabolism of naloxone. Metabolic drug interactions with naloxone are unknown.

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