CLINICAL PHARMACOLOGY
Mechanism of Action
Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis induced by ifosfamide.
Analogous to the physiological cysteine-cystine system, mesna is rapidly oxidized to its major metabolite, mesna disulfide (dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly eliminated by the kidneys.
In the kidney, the mesna disulfide is reduced to the free thiol compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites (acrolein and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step in the detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein and to other urotoxic metabolites.
In multiple human xenograft or rodent tumor model studies of limited scope, using IV or IP routes of administration, mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or multiple courses) failed to demonstrate interference with antitumor efficacy.
Pharmacokinetics
At doses of 2-4 g/m2, the terminal elimination half-life of ifosfamide is about 4-8 hours. As a result, in order to maintain adequate levels of mesna in the urinary bladder during the course of elimination of the urotoxic ifosfamide metabolites, repeated doses of Mesna are required.
IV-IV-IV Regimen
After intravenous administration of an 800-mg dose, the half-lives of mesna and dimesna in the blood are 0.36 hours and 1.17 hours, respectively. Approximately 32% and 33% of the administered dose was eliminated in the urine in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered was eliminated within 4 hours. Mesna has a plasma clearance of 1.23 L/h/kg.
IV-Oral-Oral Regimen
The half-life of mesna ranged from 1.2-8.3 hours after administration of intravenous plus oral doses of Mesna, as recommended in the DOSAGE AND ADMINISTRATION section. The urinary bioavailability of oral mesna ranged from 45-79% of intravenously administered mesna. Food does not affect the urinary availability of orally administered mesna. Approximately 18-26% of the combined intravenous and oral mesna dose appears as free mesna in the urine. When compared to intravenously administered mesna, the intravenous plus oral dosing regimen increases systemic exposures (150%) and provides more sustained excretion of mesna in the urine over a 24-hour period. Approximately 5% of the mesna dose is excreted during the 12-24 hour interval, as compared to negligible amounts in patients given the IV regimen. The fraction of the administered dose of mesna excreted in the urine is independent of dose. Protein binding of mesna is in a moderate range (69-75%).
Special Populations
Gender Effect
An analysis was conducted in four male and four female volunteers; no differences in plasma pharmacokinetics were detected.
Pediatrics and Geriatrics
Pharmacokinetic data of mesna in pediatric and geriatric patients are not available.
Hepatic and Renal Insufficiency
No clinical studies were conducted to evaluate the effect of hepatic impairment or renal impairment on the pharmacokinetics of Mesna.
Drug-Drug Interaction
No clinical drug interaction studies have been conducted with Mesna.
Clinical Studies
IV Mesna
Hemorrhagic cystitis produced by ifosfamide is dose dependent (Table 1). At a dose of 1.2 g/m2 ifosfamide administered daily for 5 days, 16-26% of the patients who received conventional uroprophylaxis (high fluid intake, alkalinization of the urine, and the administration of diuretics) developed hematuria (>50 RBC/hpf or macrohematuria) (Morgan, Einhorna, Costanzi). In contrast, none of the patients who received Mesna Injection together with this dose of ifosfamide developed hematuria (Einhorna,b). In two randomized studies, (Fukuoka, Scheef), higher doses of ifosfamide, from 2 to 4 g/m2 administered for 3-5 days, produced hematuria in 31-100% of the patients. When mesna was administered together with these doses of ifosfamide, the incidence of hematuria was less than 7%.
| Table 1 |
| Percent of Mesna Patients Developing Hematuria (≥50 RBC/hpf or macrohematuria) |
| Study | Conventional Uroprophylaxis (number of patients) | Standard Mesna IV Regimen (number of patients) |
| Uncontrolled Studies | | |
| MORGAN* | 16% (7/44) | - |
| COSTANZI* | 26% (11/43) | - |
| EINHORNa* | 18% (7/38) | 0% (0/21) |
| EINHORNb* | - | 0% (0/32) |
| Controlled Studies | | |
| FUKUOKA** | 31% (14/46) | 6% (3/46) |
| SCHEEF** | 100% (7/7) | 0% (0/8) |
| *Ifosfamide dose 1.2 g/m2 d x 5 |
| **Ifosfamide dose 2 to 4 g/m2 d x 3-5 |
Oral Mesna
Clinical studies comparing recommended intravenous and oral mesna dosing regimens demonstrated incidences of grade 3-4 hematuria of <5%. Study D07093-0018 was an open label, randomized, two-way crossover study comparing three IV doses with an initial IV dose followed by two oral doses of mesna in patients with cancer treated with ifosfamide at a dose of 1.2-2.0 g/m2 for 3-5 days. Study MED504 was a randomized, multicenter study in cancer patients receiving ifosfamide at 2.0 g/m2 for 5 days. In both studies, development of grade 3 or 4 hematuria was the primary efficacy endpoint. The percent of patients developing hematuria in each of these studies is presented in Table 2.
| Table 2 |
| Percent of Mesna Patients Developing Grade 3 or 4 Hematuria |
| | Mesna Dosing Regimen |
| Study | Standard IV Regimen (number of patients) | IV + Oral Regimen (number of patients) |
| D07093-0018 | 0% (0/30) | 3.6% (1/28) |
| MED504 | 3.7% (1/27) | 4.3% (1/23) |
A crossover pharmacokinetic study supports the low incidence of grade 3 or 4 hematuria with the recommended intravenous and oral mesna dosing regimens used in the two controlled studies.
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