XURIDEN Oral granules Ref.[10388] Active ingredients: Uridine triacetate

Hereditary orotic aciduria (uridine monophosphate synthase deficiency) is a rare congenital autosomal recessive disorder of pyrimidine metabolism caused by a defect in uridine monophosphate synthase (UMPS). The UMPS gene encodes uridine 5′monophosphate synthase, a bifunctional enzyme that catalyzes the final two steps of the de novo pyrimidine biosynthetic pathway in mammalian cells.

The defect in UMP synthase in hereditary orotic aciduria has two primary biochemical consequences. First, the blockade of de novo UMP synthesis results in a systemic deficiency of pyrimidine nucleotides, accounting for most clinical consequences of the disease. Second, orotic acid from the de novo pyrimidine pathway that cannot be converted to UMP is excreted in the urine, accounting for the common name of the disorder, orotic aciduria. Orotic acid crystals in the urine can cause episodes of obstructive uropathy.

XURIDEN delivers uridine into the circulation, where it can be used by essentially all cells to make uridine nucleotides, compensating for the genetic deficiency in synthesis in patients with hereditary orotic aciduria. When intracellular uridine nucleotides are restored into the normal range, overproduction of orotic acid is reduced by feedback inhibition, so that urinary excretion of orotic acid is also reduced.

Absorption

XURIDEN delivers 4- to 6-fold more uridine into the systemic circulation compared to equimolar doses of uridine itself. Maximum concentrations of uridine in plasma following oral XURIDEN are generally achieved within 2 to 3 hours, and the half-life ranges from approximately 2 to 2.5 hours.

A study in patients with hereditary orotic aciduria included an assessment of plasma uridine pharmacokinetics in 4 patients. Three of the patients were previously treated with oral uridine. On Day 0 (baseline), these three patients received their usual daily dose of oral uridine as a single dose (150 to 200 mg/kg once daily) and on Day 1, initiated oral XURIDEN treatment (60 mg/kg once daily). A fourth patient was enrolled who was naïve to uridine replacement therapy. The dose of XURIDEN was increased on Day 116 to 120 mg/kg once daily in two patients (Patients 3 and 4) and plasma uridine concentrations were assessed on Day 160 (44 days after the dose increase).

Plasma uridine levels in all four patients are depicted in Figure 2. Pharmacokinetic parameters are summarized in Table 3. Mean exposure to plasma uridine as assessed by C_max and AUC was greater after oral XURIDEN than after oral uridine (approximately 4-fold on an equiweight basis, and 6-fold on an equimolar basis), although individual differences in relative bioavailability were noted. Plasma concentrations of the uridine catabolite uracil were generally below the limit of quantitation in all patients.

Table 3. Pharmacokinetic Parameters for Plasma Uridine*:

* Data shown are from patients previously treated with oral uridine
^† The dose of XURIDEN was increased on Day 116 to 120 mg/kg per day. Serial plasma samples were taken on Day 160 (4 4 days after the dose increase) for plasma uridine levels.
^‡ T_max range is expressed as the minimum and maximum values obtained

Figure 2. Plasma Uridine Following Oral Administration of Uridine (Day 0) or XURIDEN (Days 1, 28 and 160) in Patients with Hereditary Orotic Aciduria:

Food Effect on Uridine PK

A study in healthy adult subjects receiving a slightly different formulation of uridine triacetate granules (6 gram dose) under fed and fasted conditions showed no difference in the overall rate and extent of uridine exposure.

Distribution

Circulating uridine is taken up into mammalian cells via specific nucleoside transporters, and also crosses the blood brain barrier.

Excretion

Uridine can be excreted via the kidneys, but is also metabolized by normal pyrimidine catabolic pathways present in most tissues.

Drug Interaction Studies

In vitro enzyme inhibition data did not reveal meaningful inhibitory effects of uridine triacetate or uridine on CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. In vitro enzyme induction data did not reveal an inducing effect of uridine triacetate or uridine on CYP1A2, CYP2B6, or CYP3A4.

In vitro data showed that uridine triacetate was a weak substrate for P-glycoprotein. Uridine triacetate inhibited the transport of a known P-glycoprotein substrate, digoxin, with an IC50 of 344 µM. Due to the potential for high local (gut) concentrations of the drug after dosing, the interaction of XURIDEN with orally administered P-gp substrate drugs cannot be ruled out.

In vivo data in humans are not available.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of uridine triacetate.

Uridine triacetate was not genotoxic in the Ames test, the mouse lymphoma assay and the mouse micronucleus test.

Orally administered uridine triacetate did not affect fertility or general reproductive performance in male and female rats at doses up to 2000 mg/kg per day (about 2.7 times the maximum recommended human dose (MRHD) of 120 mg/kg per day on a body surface area basis).

The efficacy of XURIDEN was evaluated in a 6-week open-label study in 4 patients with hereditary orotic aciduria (3 male, 1 female; age range from 3 to 19 years). Three patients were previously treated with uridine and were switched at study entry to XURIDEN. All patients were administered XURIDEN orally at a daily dosage of 60 mg/kg once daily. Following the initial 6-weeks, all 4 patients continued to receive XURIDEN daily in the extension phase of the study at dosages of 60 to 120 mg/kg for a total duration of 24 months.

The study assessed changes in the patients' pre-specified hematologic parameters during the initial 6-week period and the extension phase. The pre-specified hematologic parameters were: neutrophil count and percent neutrophils (Patient 1), white blood cell count (Patient 2), and mean corpuscular volume (Patients 3 and 4). For patients switched from oral uridine to oral XURIDEN (Patients 1, 2, and 3), the primary endpoint was stability of the hematologic parameter; for the treatment-naïve patient (Patient 4), the primary endpoint was improvement of the hematologic parameter.

Secondary endpoints were urine orotic acid and orotidine levels, and growth (height and weight) for all patients.

Table 4 summarizes the changes in the patients' pre-specified hematologic parameters at Week 6 and 24 Months compared to baseline. After 6 weeks of treatment, Patients 1 and 3 met the pre-specified criteria for stability of the hematologic parameter. When Patient 2 was switched from uridine to XURIDEN treatment, the pre-specified parameter of white blood cell count remained stable; however, documentation of a low white blood cell count prior to uridine initiation was not available. Patient 4 did not meet the pre-specified endpoint of improvement of the hematologic parameter.

By 24 months of treatment with XURIDEN, the pre-specified hematologic parameter for Patient 1 worsened, but the assessment was confounded by Cohen syndrome with associated neutropenia, which was diagnosed after the patient completed the study. The pre-specified hematologic parameters for Patients 2, 3, and 4 remained essentially unchanged.

Table 4. Pre-Specified Hematologic Parameters at Baseline, 6 Weeks and 24 Months in XURIDEN-Treated Patients with Hereditary Orotic Aciduria:

At baseline, Patients 1, 2, and 3, previously treated with uridine, had normal urine orotic acid levels, and those remained stable after 6 weeks of treatment with XURIDEN. All four patients had normal urine orotidine levels at baseline which remained stable after 6 weeks of treatment with XURIDEN. After 24 months of treatment, urine orotic acid and orotidine levels remained stable in all four patients.

The treatment effect of XURIDEN on growth was assessed in the three pediatric patients (Patients 1, 3, and 4). At baseline, weight and height were at or below the lower limit of normal for age for all three patients. After 24 months of treatment, each patient’s growth parameters remained essentially unchanged.

Case reports

Nineteen (19) case reports of patients with hereditary orotic aciduria have been documented in published literature. Eighteen (18) patients were diagnosed as infants or children between the ages of 2 months and 12 years and were treated with exogenous sources of uridine. One patient, diagnosed at age 28, was not treated with exogenous uridine.

All 19 patients presented with significantly elevated levels of urinary orotic acid. Fifteen of 19 had abnormal hematologic parameters at presentation, including 15 with megaloblastic anemia, 8 with leukopenia and at least 2 with neutropenia. Oral administration of exogenous sources of uridine was reported to significantly improve hematologic abnormalities (megaloblastic anemia, leukopenia and neutropenia) within 2 to 3 weeks in almost all documented cases when administered in sufficient amounts. Concentrations of urinary orotic acid were significantly reduced within 1 to 2 weeks of initiating uridine replacement therapy. Some fluctuation in levels of urinary orotic acid were observed, but always at much lower levels than those reported prior to treatment. Improvements in body weight were also documented over time with continued uridine replacement therapy.

The effects of exogenous uridine were maintained over months and years, as long as treatment continued at sufficient doses (with appropriate dose increases based on body weight increases). Most hematologic abnormalities and orotic aciduria reappeared within days up to 2 or 3 weeks when administration of uridine was stopped or the dose was reduced. If treatment was interrupted for longer periods, body weight growth receded. If absolute dosages were not adjusted adequately to compensate for body weight gains, signs and symptoms of hereditary orotic aciduria recurred.