Mechanism Of Action
Octreotide exerts pharmacologic actions similar to the natural hormone somatostatin, but is a more potent inhibitor of GH, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses luteinizing hormone (LH) response to gonadotropin-releasing hormone (GnRH), decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide.
In a single-dose PK study conducted in healthy volunteers, inhibition of GH (as measured by Cavg) was observed in all subjects receiving MYCAPSSA, as compared to their GH levels prior to MYCAPSSA.
In a study designed to assess the duration of MYCAPSSA-induced increased intestinal permeability, an increase in paracellular permeability was observed 2 hours after MYCAPSSA administration and returned to baseline by 5.5 hours after MYCAPSSA administration. MYCAPSSA-induced permeability is completely reversible within this timeframe.
MYCAPSSA maintained GH and IGF-1 levels in patients with acromegaly.
Single doses of octreotide acetate given subcutaneously have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In clinical trials the incidence of gallstone or biliary sludge formation was markedly increased [see WARNINGS AND PRECAUTIONS].
Octreotide acetate may cause clinically significant suppression of TSH [see WARNINGS AND PRECAUTIONS].
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 1.67â€“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 3â€“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).
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 7â€“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).
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 3.2â€“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.
In patients 65 years of age and older, after subcutaneous administration of octreotide acetate, the halflife 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 15â€“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), AUC0â€“t (68.0 hâ€¢ng/mL compared to 32.2 hâ€¢ng/mL in the matched controls), AUCinf (69.5 hâ€¢ng/mL compared to 32.4 hâ€¢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].
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 1.9â€“3.7 hr and total body clearance decreasing from 7â€“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.
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].
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|
|Esomeprazole 40 mg QD on days 2-7||20 mg on Day 1 and 20 mg on Day 7||0.591|
(0.40 - 0.88)2
(0.40 - 0.75)2
|Metoclopramide 20 mg||40 mg||0.91|
(0.61 - 1.35)
(0.62 - 1.44)
|Loperamide 4 mg||40 mg||0.97|
(0.65 - 1.44)3
(0.59 - 1.39)3
|1Clinically significant [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]|
2Mean 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)
Table 4 : Effect of MYCAPSSA on Systemic Exposure of Co-administered Drugs
|Co-administered drug and dosing regimen||MYCAPSSA|
|Dose (mg)1||Mean Ratio (ratio with/without co-administered drug) No Effect=1.0|
|Change in AUC||Change in Cmax|
|Cyclosporine 300 mg||20 mg||0.382|
(0.31 - 0.46)3
(0.22 - 0.37)3
|Digoxin 0.5 mg||40 mg||1.0|
(0.94 - 1.13)3
(0.55 - 0.72)3
|Lisinopril 20 mg||40 mg||1.402|
(1.21 - 1.61)3
(1.32 - 1.71)3
|Ethinyl Estradiol 0.06 mg||40 mg||0.94|
(0.86 - 1.03)3
(0.83 - 1.01)3
|Levonorgestrel 0.3 mg||40 mg||0.762|
(0.67 - 0.86)3
(0.54 - 0.71)3
|1Single dose unless otherwise noted.|
2Clinically significant [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS]
3Mean 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)
The efficacy of MYCAPSSA was established in a 9 month, randomized, double-blind, placebocontrolled study (NCT03252353) that enrolled 56 patients with acromegaly.
In the overall study population, 54% were female and the average age of patients was 55 years. 91% of patients were Caucasian, 5% Asian, 2% Black, and 2% Other. The percentage of patients with previous pituitary surgery was 88%. The baseline IGF-1 levels (the average of 2 assessments measured within 2 weeks of randomization) was 0.80 times ULN (range: 0.5â€“1.1 times ULN) in the patients treated with MYCAPSSA and 0.84 times ULN (range: 0.3â€“1.1 times ULN) in patients treated with the placebo.
In this study, patients initiated MYCAPSSA treatment twice daily 1 month after their last injection of somatostatin analogs. The starting dose was 40 mg (20 mg in the morning and 20 mg in the evening). Dose increase was allowed during dose titration to 60 mg (40 mg in the morning and 20 mg in the evening) and to a maximal dose of 80 mg daily (40 mg in the morning and 40 mg in the evening) until patients were deemed adequately controlled based on biochemical results and/or clinical judgement. Patients then maintained their target dose until end of treatment.
The primary efficacy endpoint was somatostatin dose-adjusted proportion of patients who maintain their biochemical response, defined as an IGF-1 levels less than or equal to the ULN at the end of 9 months of treatment. 58% of patients treated with MYCAPSSA vs. 19% of patients treated with placebo maintained their biochemical response.
25% of patients treated with MYCAPSSA required discontinuation of MYCAPSSA and treatment with other somatostatin analogs at some point during the 9-month study. Criteria for somatostatin analog rescue were IGF-1 levels higher than 1.3 times ULN and exacerbation of acromegaly signs and symptoms on two consecutive assessments while treated for at least 2 weeks with 80 mg/day or other reasons such as adverse reactions or patientâ€™s decision.