Mycapssa (Page 4 of 6)

12.3 Pharmacokinetics

Absorption

In healthy subjects, similar systemic exposure (AUC) was observed between a single dose oral administration of MYCAPSSA (20 mg octreotide acetate), and a single dose of subcutaneous Sandostatin IR (0.1 mg octreotide acetate). Peak octreotide levels (Cmax ) were 33% lower following oral administration compared to the subcutaneous route. Absorption time was longer following oral administration compared to the subcutaneous route; peak concentrations were reached at a median of 1.67–2.5 hours after 20 mg MYCAPSSA administration compared to 0.5 hours for the subcutaneous administration.

In healthy subjects, after single-dose oral administration of MYCAPSSA, the systemic exposure of octreotide (Cmax , AUC0-24 , and AUC0-inf ) increased dose-proportionally at doses ranging from 3–40 mg.

In patients with acromegaly, there was a dose-related increase in the mean plasma octreotide concentrations after chronic administration of MYCAPSSA 40 mg (20 mg bid), 60 mg (40 mg AM / 20 mg PM), and 80 mg (40 mg AM / 40 mg PM) bid. Mean peak concentrations (Cmax ) following chronic dosing were lower in patients with acromegaly (mean [CV%] = 2.51 ng/mL [80%] and 5.30 ng/mL [76%] at 20 and 40 mg bid, respectively) compared to single-dose peak concentrations observed in healthy subjects at the same dose (mean [CV%] = 3.62 [53%] and 8.21 ng/mL [88%] at 20 and 40 mg, respectively).

Effect of Food on Oral Absorption

In healthy subjects, data from a single-dose, crossover PK study of food effect demonstrated that administration of MYCAPSSA 20 mg capsules with food led to an approximate 90% decrease in the rate (Cmax ) and extent of absorption (AUC0-t ).

Distribution

In healthy volunteers, the distribution half-life (tα½ ) of octreotide acetate from plasma after subcutaneous administration was 0.2 h, the volume of distribution (Vdss) was estimated to be 13.6 L, and the total body clearance ranged from 7–10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin.

In patients with acromegaly, the Vdss following subcutaneous administration was increased compared to healthy volunteers, estimated to be 21.6 L; mean peak concentrations were lower in acromegaly patients compared to healthy volunteers (2.8 ng/mL vs 5.2 ng/mL, respectively after 0.1 ng/mL dose).

Elimination

According to data obtained with the immediate-release octreotide subcutaneous injection, approximately 32% of the dose is excreted unchanged in the urine.

In healthy subjects, there was no effect of route of administration on octreotide elimination, and comparable mean elimination half-lives (t½ ) of 2.3 hours and 2.7 hours were demonstrated between subcutaneous injection and oral octreotide treatments, respectively.

In patients with acromegaly, elimination after chronic dosing was slightly slower than that seen in healthy volunteers, with mean apparent half-life values at steady state ranging from 3.2–4.5 hours across doses (20 mg, 40 mg, 60 mg, and 80 mg). Elimination is complete approximately 48 hours after the last dose in patients who have achieved steady-state plasma levels. Minimal accumulation (approximately 10%) was observed in patients after repeat administration of MYCAPSSA.

Specific Populations

Geriatric Patients

In patients 65 years of age and older, after subcutaneous administration of octreotide acetate, the half-life of octreotide increased significantly (46%) and clearance of octreotide decreased significantly (26%).

Patients with Renal Impairment

Exposure in patients with severe renal impairment was not substantially different from that of the matched controls. Following oral administration of a single dose of 20 mg MYCAPSSA to patients with severe renal impairment (eGFR 15–29 mL/min/1.73m2) and patients with end-stage renal disease (ESRD) requiring dialysis, patients with ESRD on dialysis had a 46% decrease in clearance with a corresponding 87% increase in AUC and 85% increase in t½ compared to matched healthy subjects. ESRD patients had higher mean plasma concentrations than did those with severe renal impairment with higher mean values for Cmax (9.30 ng/mL compared to 6.13 ng/mL in the matched controls), AUC0–t (68.0 h∙ng/mL compared to 32.2 h∙ng/mL in the matched controls), AUCinf (69.5 h∙ng/mL compared to 32.4 h∙ng/mL in the matched controls), and t½ (7.09 hr compared to 3.84 hr in the matched controls), consistent with the known effect of renal impairment on octreotide exposure [see Use in Specific Populations (‎8.6)].

Patients with Hepatic Impairment

In patients with liver cirrhosis, after subcutaneous administration of octreotide acetate, prolonged elimination of drug was observed, with octreotide acetate t½ increasing from 1.9–3.7 hr and total body clearance decreasing from 7–10 L/hr to 5.9 L/hr, whereas patients with fatty liver disease showed t½ increased to 3.4 hr and total body clearance of 8.2 L/hr.

Drug Interactions

Limited published data indicate that somatostatin analogs including MYCAPSSA may decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of GH [see Drug Interactions (‎7.2)].

Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs.

Table 3 Effect of Co-administered Drugs on MYCAPSSA Systemic Exposure
Co-administered drug and dosing regimen MYCAPSSA
Dose (mg) Mean Ratio (ratio with/without co-administered drug) No Effect=1.0
Change in AUC Change in Cmax
*
Clinically significant [see Dosage and Administration (‎2) and Drug Interactions (‎7.1, ‎7.2)]
Mean ratio with 90% CI (with/without co-administered drug, e.g., 1= no change, 0.6 = 40% decrease,1.3=1.3-fold increase in exposure)
Esomeprazole 40 mg QD on days 2-7 20 mg on Day 1 and 20 mg on Day 7 0.59* (0.40 – 0.88) 0.55* (0.40 – 0.75)
Metoclopramide 20 mg 40 mg 0.91 (0.61 – 1.35) 0.95 (0.62 – 1.44)
Loperamide 4 mg 40 mg 0.97 (0.65 – 1.44)3 0.91 (0.59 – 1.39)3
Table 4 Effect of MYCAPSSA on Systemic Exposure of Co-administered Drugs
Co-administered drug and dosing regimen MYCAPSSA
Dose (mg)* Mean Ratio (ratio with/without co-administered drug) No Effect=1.0
Change in AUC Change in Cmax
*
Single dose unless otherwise noted.
Clinically significant [see Dosage and Administration (‎2) and Drug Interactions (‎7.1, ‎7.2)]
Mean ratio with 90% CI (with/without co-administered drug, e.g., 1= no change, 0.6 = 40% decrease, 1.5=1.5-fold increase in exposure)
Cyclosporine 300 mg 20 mg 0.38 (0.31 – 0.46) 0.29 (0.22 – 0.37)
Digoxin 0.5 mg 40 mg 1.0 (0.94 – 1.13) 0.63 (0.55 – 0.72)
Lisinopril 20 mg 40 mg 1.40 (1.21 – 1.61) 1.50 (1.32 – 1.71)
Ethinyl Estradiol 0.06 mg 40 mg 0.94 (0.86 – 1.03) 0.92 (0.83 – 1.01)
Levonorgestrel 0.3 mg 40 mg 0.76 (0.67 – 0.86) 0.62 (0.54 – 0.71)

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