Muse (Alprostadil) - Description and Clinical Pharmacology

DESCRIPTION

MUSE^® (alprostadil) is a single-use, medicated transurethral system for the delivery of alprostadil to the male urethra. Alprostadil is suspended in polyethylene glycol 1450 (as excipient) and is formed into a medicated pellet (micro-suppository measuring 1.4 mm in diameter by 3 mm or 6 mm in length) that resides in the tip of a translucent hollow applicator. MUSE is administered by inserting the applicator stem into the urethra after urination. The pellet containing alprostadil is delivered by depressing the applicator button (see Figure 1). The components of the delivery system are constructed of medical grade polypropylene. Each MUSE system is packaged in an individual foil pouch.

Alprostadil is a white to off-white crystalline powder with a melting point between 115° and 116°C. Its solubility at 35°C is 8000 mcg per 100 mL double-distilled water. The inactive ingredient in MUSE is polyethylene glycol 1450, USP. There are no other active agents or excipients in MUSE.

MUSE is available in 4 dosage strengths: 125 mcg, 250 mcg, 500 mcg, and 1000 mcg.

CLINICAL PHARMACOLOGY

Mechanism of Action: Prostaglandin E₁ is a naturally occurring acidic lipid that is synthesized from fatty acid precursors by most mammalian tissues and has a variety of pharmacologic effects. Human seminal fluid is a rich source of prostaglandins, including PGE₁ and PGE₂, and the total concentration of prostaglandins in ejaculate has been estimated to be approximately 100–200 mcg/mL. In vitro, alprostadil (PGE₁) has been shown to cause dose-dependent smooth muscle relaxation in isolated corpus cavernosum and corpus spongiosum preparations. Additionally, vasodilation has been demonstrated in isolated cavernosal artery segments that were pre-contracted with either norepinephrine or prostaglandin F_{2 α}. When alprostadil was injected into the corpus cavernosum of pigtail monkeys in vivo, dose-dependent increases in cavernosal artery blood flow were observed.

In human studies using Doppler duplex ultrasonography, intraurethral administration of 500 mcg of MUSE resulted in an increase in cavernosal artery diameter and a 5- to 10-fold increase in peak systolic flow velocities. These results suggest that intraurethral alprostadil is absorbed from the urethra, transported throughout the erectile bodies by communicating vessels between the corpus spongiosum and corpora cavernosa, and able to induce vasodilation of the targeted vascular beds.

The vasodilatory effects of alprostadil on the cavernosal arteries and the trabecular smooth muscle of the corpora cavernosa result in rapid arterial inflow and expansion of the lacunar spaces within the corpora. As the expanded corporal sinusoids are compressed against the tunica albuginea, venous outflow through subtunical vessels is impeded and penile rigidity develops. This process is referred to as the corporal veno-occlusive mechanism.

The most notable systemic effects of alprostadil are vasodilation, inhibition of platelet aggregation, and stimulation of intestinal and uterine smooth muscle. Intravenous doses of 1 to 10 micrograms per kilogram of body weight lower blood pressure in mammals by decreasing peripheral resistance. Reflex increases in cardiac output and heart rate may accompany these effects.

Pharmacokinetics:

About 80% of alprostadil administered by MUSE is absorbed within 10 minutes and is rapidly cleared from the systemic circulation by the lungs, leaving barely detectable systemic blood levels.

Absorption: MUSE is designed to deliver alprostadil directly to the urethral lining for transfer via the corpus spongiosum to the corpora cavernosa. Intraurethral administration of MUSE is preceded by urination, and the residual urine disperses the medicated pellet, permitting alprostadil to be absorbed by the urethral mucosa. The transurethral absorption of alprostadil after MUSE administration is biphasic. Initial absorption is rapid, with approximately 80% of an administered dose absorbed within 10 minutes. The mean time to the maximum plasma PGE₁ concentration after a 1000 mcg intraurethral dose of MUSE is approximately 16 minutes.

In 10 normal human volunteers, endogenous PGE₁ levels in the ejaculate averaged 31 mcg (range 0–161 mcg). In these same volunteers, an average of 123 mcg of additional PGE₁ (range 30–369 mcg) was present in the ejaculate obtained 10 minutes after the highest dose (1000 mcg) of MUSE. The mean total endogenous PGE content (PGE₁, PGE₂, 19-OH-PGE₁, and 19-OH-PGE₂) of the ejaculate in these subjects was 444 mcg (range 0–1423 mcg).

Distribution: Following MUSE administration, alprostadil is absorbed from the urethral mucosa into the corpus spongiosum. A portion of the administered dose is transported to the corpora cavernosa through collateral vessels, while the remainder passes into the pelvic venous circulation through veins draining the corpus spongiosum. The half-life of alprostadil in humans is short, varying between 30 seconds and 10 minutes, depending on the body compartment in which it is measured and the physiological status of the subject. Nearly all of the alprostadil entering the central venous circulation is removed in a single pass through the lungs; thus peripheral venous plasma levels of PGE₁ are low or undetectable (<2 picograms/mL) after MUSE administration. The mean maximum plasma PGE₁ concentration following intraurethral administration of the highest dose of MUSE (1000 mcg) was barely detectable (11.4 picograms/mL). In a study of 14 subjects, the plasma PGE₁ level was shown to be undetectable within 60 minutes of MUSE administration in most subjects.

Metabolism: Alprostadil is rapidly metabolized locally by enzymatic oxidation of the 15-hydroxyl group to 15-keto-PGE₁. The enzyme catalyzing this process has been isolated from many tissues in the lower genitourinary tract including the urethra, prostate, and corpus cavernosum. 15-keto-PGE₁ retains little (1–2%) of the biological activity of PGE₁. 15-keto-PGE₁ is rapidly reduced at the C₁₃-C₁₄ position to form the most abundant metabolite in plasma, 13,14-dihydro,15-keto PGE₁ (DHK-PGE₁), which is biologically inactive. The majority of DHK-PGE₁ is further metabolized to smaller prostaglandin remnants that are cleared primarily by the kidney and liver. Between 60% and 90% of PGE₁ has been shown to be metabolized after 1 pass through the pulmonary capillary beds.

Excretion: After intravenous administration of tritium-labeled alprostadil in man, labeled drug disappears rapidly from the blood in the first 10 minutes, and by 1 hour radioactivity in the blood reaches a low level. The metabolites of alprostadil are excreted primarily by the kidney, with approximately 90% of an administered intravenous dose excreted in the urine within 24 hours of dosing. The remainder is excreted in the feces. There is no evidence of tissue retention of alprostadil or its metabolites following intravenous administration.

Pharmacokinetics in Special Populations:

Pulmonary Disease: The near-complete pulmonary first-pass metabolism of PGE₁ is the primary factor influencing the systemic pharmacokinetics of MUSE and is a reason that peripheral venous plasma levels of PGE₁ are low or undetectable (<2 picograms/mL) following MUSE administration. Patients with pulmonary disease therefore may have a reduced capacity to clear the drug. In patients with the adult respiratory distress syndrome (ARDS), pulmonary extraction of intravascularly administered alprostadil was reduced by approximately 15% compared to a control group of patients with normal respiratory function (66±3.2% vs. 78±2.4%).

Geriatrics: The effects of age on the pharmacokinetics of alprostadil have not been evaluated.

CLINICAL TRIALS

The MUSE system was evaluated in 7 placebo-controlled trials of various design in over 2500 patients with a history of erectile dysfunction of various etiologies. These trials assessed erectile function in the clinic and sexual intercourse in outpatient settings. In studies of sexual performance, patients were screened in the clinic, generally using doses of 125 mcg to 1000 mcg, for a satisfactory erectile response, then sent home with the selected dose or placebo for evaluation of sexual performance. Not all patients beginning titration had a successful dose and some patients could not tolerate MUSE, principally because of penile pain, so that the success rates in the studies described below must be understood to represent response rates only in patients who were successfully titrated.

In 2 identical multicenter, double-blind, placebo-controlled, parallel-group studies, 1511 monogamous and heterosexual patients with a mean 4-year history of erectile dysfunction and at least a 3-month history of no erections adequate for sexual intercourse without medical assistance, were enrolled and began dose titration in the clinic with doses between 125 mcg and 1000 mcg. 996 patients (66%) completed dose titration, achieved an erection sufficient for intercourse, and were randomized equally to placebo or active treatment and followed during at-home treatment for up to 3 months. 874 patients and partners completed 3 months of follow-up. About 10%, 20%, 30%, and 40% of patients were titrated to 125 mcg, 250 mcg, 500 mcg, and 1000 mcg, respectively. Couples on active therapy were more likely to have at least 1 successful sexual intercourse (65% vs. 19%) than were couples on placebo. Among patients who reported successful intercourse at least once with active treatment, approximately 7 of 10 MUSE systems resulted in successful sexual intercourse. Results were similar in patients with erectile dysfunction stemming from surgery or trauma, diabetes, vascular disease, or other etiologies, and were similar in Caucasians and non-Caucasians. In administrations resulting in sexual intercourse, the duration of erections sufficient for penetration was 6 minutes on placebo and 16 minutes on active drug. Successful therapy with MUSE was associated with improvement in the quality of life measures of “emotional well-being” for patients and “relationship with partner” for both patients and their female partners.