Hysingla ER (Page 10 of 11)

12.3 Pharmacokinetics

AbsorptionHYSINGLA ER is a single-entity extended-release formulation of hydrocodone that yields a gradual increase in plasma hydrocodone concentrations with a median T_max of 14 – 16 hours noted for different dose strengths. Peak plasma levels may occur in the range of 6 -30 hours after single dose HYSINGLA ER administration.

Systemic exposure (AUC and C_max ) increased linearly with doses from 20 to 120 mg. Both C_max and AUC increased slightly more than dose proportionally (Table 6). The mean terminal half-life (t_1/2 ) was similar for all HYSINGLA ER dose strengths ranging from 7 to 9 hours.

Table 6 Mean (SD) Single-Dose Pharmacokinetic Parameters of HYSINGLA ER

* median (minimum, maximum)
Dose Strength (mg)	AUCinf (ng•h/mL)	Cmax (ng/mL)	Tmax * (h)
20	284 (128)	14.6 (5.5)	16 (6, 24)
40	622 (252)	33.9 (11.8)	16 (6, 24)
60	1009 (294)	53.6 (15.4)	14 (10, 30)
80	1304 (375)	69.1 (17.2)	16 (10, 24)
120	1787 (679)	110 (44.1)	14 (6, 30)

As compared to an immediate-release hydrocodone combination product, HYSINGLA ER at the same daily dose results in similar bioavailability but with lower maximum concentrations at steady state (Figure 3).

Figure 3. Mean Steady-State Plasma Hydrocodone Concentration Profile

Steady-state plasma hydrocodone concentrations were confirmed on day 3 of once-daily dosing of HYSINGLA ER. The extent of accumulation of systemic exposure was 1.3 and 1.1 fold with respect to AUC and C_max at steady-state. The mean terminal half-life (t_1/2 ) at steady state was 7 hours. Median T_max values were 14 hours (range: 12 to 24 hours) on both Day 1 and Day 5 following once daily administration of HYSINGLA ER for five days. Daily fluctuation in peak to trough plasma levels of hydrocodone were higher at 80 mg and 120 mg doses of HYSINGLA ER compared to 30 mg dose (Table 7).

Table 7 Mean (SD) Steady-State Hydrocodone Pharmacokinetic Parameters

* Mean (minimum, maximum); Percentage fluctuation in plasma concentration is derived as (Cmax ,ss – Cmin , ss)*100/Cavg,ss.
Regimen	AUC24,ss (ng•h/mL)	Cmax ,ss (ng/mL)	Cmin ,ss (ng/mL)	%Fluctuation*
HYSINGLA ER
30 mg q24h	443 (128)	26.4 (7.4)	16.7 (5.2)	61 (6.4,113)
80 mg q24h	1252 (352)	82.6 (25.7)	28.2 (12)	105 (36,214)
120 mg q24h	1938 (729)	135 (50)	63.6 (29)	97.9 (32, 250)

Food Effects
C_max and AUC of HYSINGLA ER 120 mg tablets were similar under low fat conditions relative to fasting conditions (17% and 9% higher, respectively). C_max was higher (54%) under high fat conditions relative to fasting conditions; however, AUC of HYSINGLA ER 120 mg tablets was only 20% higher when co-administered with a high fat meal. HYSINGLA ER may be administered without regard to meals.

Distribution
Following administration of HYSINGLA ER, the typical (70 kg adult) value of apparent volume of distribution (V/F) is 402 L, suggesting extensive tissue distribution. The extent of in vivo binding of hydrocodone to human plasma proteins was minimal with a mean % bound at 36%.

Elimination
Metabolism
Hydrocodone exhibits a complex pattern of metabolism, including N -demethylation, O -demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites. CYP3A4 mediated N -demethylation to inactive norhydrocodone is the primary metabolic pathway of hydrocodone with a lower contribution from CYP2B6 and CYP2C19. The minor metabolite hydromorphone (<3% of the circulating parent hydrocodone) was mainly formed by CYP2D6 mediated O -demethylation with a smaller contribution by CYP2B6 and CYP2C19. Hydromorphone may contribute to the total analgesic effect of hydrocodone.

Excretion
Hydrocodone and its metabolites are cleared primarily by renal excretion. The percent of administered dose excreted unchanged as hydrocodone in urine was 6.5% in subjects with normal renal function, and 5.0%, 4.8%, and 2.3% in subjects with mild, moderate, and severe renal impairment, respectively. Renal clearance (CLr) of hydrocodone in healthy subjects was small (5.3 L/h) compared to apparent oral clearance (CL/F, 83 L/h); suggesting that non-renal clearance is the main elimination route. Ninety-nine percent of the administered dose is eliminated within 72 hours. The mean terminal half-life (t_1/2 ) was similar for all HYSINGLA ER dose strengths ranging from approximately 7 to 9 hours across the range of doses.

Specific Populations
Age: Geriatric Patients
Following administration of 40 mg HYSINGLA ER, the pharmacokinetics of hydrocodone in healthy elderly subjects (65 to 77 years) are similar to the pharmacokinetics in healthy younger subjects (20 to 45 years). There were no clinically meaningful increase in C_max (16%) and AUC (15%) of hydrocodone in elderly as compared with younger adult subjects [see Use in Specific Populations (8.5)].

Sex
Systemic exposure of hydrocodone (C_max and AUC) was similar between males and females.

Hepatic Impairment
After a single dose of 20 mg HYSINGLA ER in subjects (8 each) with normal hepatic function, mild, moderate or severe hepatic impairment based on Child-Pugh classifications, mean hydrocodone C_max values were 16, 15, 17, and 18 ng/mL, respectively. Mean hydrocodone AUC values were 342, 310, 390, and 415 ng.hr/mL for subjects with normal hepatic function, mild, moderate or severe hepatic impairment, respectively. Geometric mean hydrocodone C_max values were -6%, 5%, and 5% and AUC values were -14%, 13%, and 4% in patients with mild, moderate or severe hepatic impairment, respectively, when compared with subjects with normal hepatic function.

The mean in vivo plasma protein binding of hydrocodone across the groups was similar, ranging from 33% to 37% [see Use in Specific Populations (8.6)].

Renal Impairment
After a single dose of 60 mg HYSINGLA ER in subjects (8 each) with normal renal function, mild, moderate, or severe renal impairment based on Cockcroft-Gault criteria and end stage renal disease (with dialysis) patients, mean hydrocodone C_max values were 40, 50, 51, 46, and 38 ng/mL, respectively. Mean hydrocodone AUC values were 754, 942, 1222, 1220, and 932 ng.hr/mL for subjects with normal renal function, mild, moderate or severe renal impairment and ESRD with dialysis, respectively. Hydrocodone C_max values were 14%, 23%, 11% and -13% and AUC values were 13%, 61%, 57% and 4% higher in patients with mild, moderate or severe renal impairment or end stage renal disease with dialysis, respectively [see Use in Specific Populations (8.7)].

Drug Interaction Studies
CYP3A4
Co-administration of HYSINGLA ER (20 mg single dose) and CYP3A4 inhibitor ketoconazole (200 mg BID for 6 days) increased mean hydrocodone AUC and C_max by 135% and 78%, respectively [see Warnings and Precautions (5.5) and Drug Interactions (7)].

CYP2D6
The 90% confidence interval (CI) of the geometric means for hydrocodone AUC_inf (98 to 115%), AUC_t (98 to 115%), and C_max (93 to 121%) values were within the range of 80 to 125% when a single dose of HYSINGLA ER 20 mg was co-administered with CYP2D6 inhibitor paroxetine (20 mg treatment each morning for 12 days). No differences in systemic exposure of hydrocodone were observed in the presence of paroxetine.