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Rayos

CLINICAL PHARMACOLOGY

Mechanism of Action

Naturally occurring corticosteroids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs, such as prednisone, are primarily used for their potent anti-inflammatory effects in disorders of many organ systems.

Corticosteroids, such as prednisone, cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.

Prednisone is a synthetic adrenocortical steroid drug with predominantly corticosteroid properties. Some of these properties reproduce the physiological actions of endogenous glucocorticosteroids, but others do not necessarily reflect any of the adrenal hormones' normal functions; they are seen only after administration of large therapeutic doses of the drug. The pharmacological effects of prednisone which are due to its corticosteroid properties include: promotion of gluconeogenesis; increased deposition of glycogen in the liver; inhibition of the utilization of glucose; anti-insulin activity; increased catabolism of protein; increased lipolysis; stimulation of fat synthesis and storage; increased glomerular filtration rate and resulting increase in urinary excretion of urate (creatinine excretion remains unchanged); and increased calcium excretion.

Depressed production of eosinophils and lymphocytes occurs, but erythropoiesis and production of polymorphonuclear leukocytes are stimulated. Inflammatory processes (edema, fibrin deposition, capillary dilatation, migration of leukocytes and phagocytosis) and the later stages of wound healing (capillary proliferation, deposition of collagen, cicatrization) are inhibited.

Prednisone can stimulate secretion of various components of gastric juice. Suppression of the production of corticotropin may lead to suppression of endogenous corticosteroids. Prednisone has slight mineralocorticoid activity, whereby entry of sodium into cells and loss of intracellular potassium is stimulated. This is particularly evident in the kidney, where rapid ion exchange leads to sodium retention and hypertension.

Pharmacokinetics

The pharmacokinetic profile of RAYOS has an approximately 4-hour lag time from that of immediate-release prednisone formulations. While the pharmacokinetic profile of RAYOS when given with food differs in terms of lag time from IR prednisone, its absorption, distribution, and elimination processes are comparable.

Absorption

Prednisone is released from RAYOS when taken with food approximately 4 hours after oral ingestion. This causes a delay in the time until peak plasma concentrations (Tmax) are achieved. Median Tmax of RAYOS in 27 healthy male subjects was 6.0 - 6.5 hours compared to 2.0 hours for an immediate-release (IR) formulation. Subsequently, prednisone was absorbed at the same rate as the IR formulation. Peak plasma concentrations (Cmax) and exposure, as indicated by AUC0-last and AUC0-∞, were comparable for both prednisone IR and RAYOS administered 2.5 hours after a light meal or with normal meal (Figure 1).

Figure 1: Mean Plasma Levels of Prednisone After a Single Dose of 5 mg Prednisone Administered as a 5 mg RAYOS Tablet or a 5 mg Immediate-Release (IR) Tablet

Mean Plasma Levels of Prednisone - Illustration

A: 5 mg IR tablet under fasting conditions, administered at 2 am, B: 5 mg RAYOS, administered 2.5 hours after a light evening meal, and C: 5 mg RAYOS administered immediately after dinner

In a study with 24 healthy subjects, oral absorption of prednisone from RAYOS was significantly affected by the intake of food. Under standard fasting conditions, both the maximum plasma concentration (Cmax) and the bioavailability of RAYOS were significantly lower than under fed conditions, shortly after intake of a high fat meal.

RAYOS at dose levels of 1 mg, 2 mg, and 5 mg showed dose-proportionality in terms of peak and systemic exposure (Cmax, AUC0-∞, and AUC0-last) for the parent drug prednisone as well as for the active metabolite prednisolone.

Metabolism

Prednisone is completely converted to the active metabolite prednisolone, which is further metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates. The exposure of prednisolone is 4-6 fold higher than that of prednisone.

Excretion

The terminal half-life of both prednisone and prednisolone from the administration of RAYOS was 2-3 hours, which is comparable to that from the IR formulation.

Special Populations

The effects of gender, age, renal impairment, and hepatic impairment on the pharmacokinetics of prednisone or prednisolone after administration of RAYOS have not been evaluated.

Clinical Studies

The efficacy of RAYOS in the treatment of rheumatoid arthritis was assessed in one multicenter, double-blind, placebo-controlled, randomized, 12-week trial in patients ≥ 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients were enrolled who were not currently treated with corticosteroids but had received non-biologic DMARD therapy for at least 6 months before receipt of study medication, and had an incomplete response to DMARD therapy alone. Patients were randomized in a 2:1 ratio to treatment with RAYOS 5 mg (n=231) or placebo (n=119) administered at 10 pm. A total of 350 patients were enrolled and ranged in age from 27 to 80 years (median age 57 years) with 84% females. Race was distributed as follows: 98% Caucasian, 1% African-American, and < 1% Asian.

The percentage of patients with improvement in rheumatoid arthritis at 12 weeks using ACR response criteria (ACR20) was assessed as the primary endpoint, and ACR20, ACR50 and ACR70 responses for patients treated with RAYOS 5 mg versus placebo are shown in Table 1. The relative efficacy of RAYOS compared to immediate-release prednisone has not been established.

Table 1: ACR Responses (Percentage of Patients)

ACR Response at 12 Weeks RAYOS 5 mg
N=231
Placebo
N=119
RAYOS 5 mg – Placebo (95% CI)
ACR20 47% 29% 17% (7.2, 27.6)
ACR50 22% 10% 12% (4.4, 19.6)
ACR70 7% 3% 4% (0.1, 8.7)

All missing values were imputed as non-responders.

The results of the components of the ACR response criteria are shown in Table 2.

Table 2: Components of ACR Response

Parameter RAYOS 5 mg + DMARD
N=231
Placebo + DMARD
N=119
Baseline Week 12 Baseline Week 12
Tender joint counta 12.6 (6.2) 7.9 (6.8) 12.5 (5.9) 9.8 (6.7)
Swollen joint counta 8.4 (4.4) 4.8 (4.8) 8.6 (4.7) 6.1 (5.4)
Patient assessment of painb 55.3 (21.9) 33.0 (24.5) 50.5 (23.3) 39.6 (24.7)
Patient global assessmentc 57.4 (20.1) 36.2 (24.5) 50.9 (20.9) 43.0 (22.4)
Physician global assessmentc 55.2 (16.1) 31.9 (19.7) 54.1 (17.4) 40.4 (21.8)
Disability index (HAQ-DI)d 1.3 (0.6) 1.1 (0.6) 1.3 (0.6) 1.2 (0.6)
ESR (mm/hr) 33.0 (16.6) 25.2 (16.8) 32.9 (20.0) 26.5 (19.7)
CRP (mg/dL) 9.3 (13.2) 7.5 (10.7) 11.8(18.0) 9.7 (12.1)
Mean (SD) is presented. Baseline values were carried forward for patients with missing data at Week 12.
a28-joint count
bPatient assessment of arthritis pain. Visual analog scale: 0 = no pain, 100 = very intensive pain
cPatient or physician global assessment of disease activity. Visual analog scale: 0 = not active at all, 100 = extremely active
dHealth Assessment Questionnaire Disability Index; 0=best, 3=worst, measures the patient's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity

The percentage of patients achieving ACR20 responses by visit is shown in Figure 2.

Figure 2: ACR20 Response Over 12 Weeksa

ACR20 Response Over 12 Weeks - Illustration

aThe same patients may not have responded at each time point.

The percent change from baseline in the duration of morning stiffness at 12 weeks was assessed as a prespecified secondary endpoint. Patients treated with RAYOS had a median decrease in the duration of morning stiffness of 55% compared to 33% in placebo-treated patients (20% estimated median difference between treatment groups with 95% confidence interval [7, 32]). This corresponds to a median duration of morning stiffness of 46 minutes in the NP01 group and 85 minutes in the placebo group.

Last reviewed on RxList: 7/2/2013
This monograph has been modified to include the generic and brand name in many instances.

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