Sodium 3-mercaptopropanesulphonate

Endpoint summary

Description of key information

Mesna is practically nontoxic up to 41 g/m² (corresponds to 1.07 g/kg bw) in patients. Mesna is oxidized to dimesna in plasma. Mesna and dimesna do not enter most of cells, except kidney cells. It is rapidly eliminated in the urine (during the first 4 hours). Dimesna undergo reduction to mesna in kidney. Half-life of mesna in plasma is 22 min (if administered i.v. as mesna) and 2.7 hours (if administered i.v. as dimesna). The maximum plasma concentration of mesna was reached approximately 1.7 hours after the start of dimesna infusion. Dimesna does not interfere with the pharmacokinetic profiles of mesna and cisplatin/cisplatin metabolites. 

Additional information

Pharmacokinetics of mesna

The pharmacokinetics of mesna (sodium 2-mercaptoethane sulphonate) and its inactive disulphide, dimesna, were investigated using high performance liquid chromatography in six normal subjects following intravenous and oral administration of 800 mg mesna (James et al., 1987). Six healthy caucasian subjects (three male, three female; ages 26-54 years; body weights 44-72) took part in the study. Treatments were randomized at each dosing period so that three subjects were randomly assigned to receive an intravenous dose of mesna of 800 mg and three to receive the same solution containing 800 mg mesna orally, diluted in approximately 200 ml orange drink immediately before ingestion. After an interval of 7 days the subjects received the alternate form of medication. Blood samples (3 mL) were collected at the following times: 0 (baseline), 5, 10, 15, 20, 30, 45 min, and 1, 2, 3 and 4 h after intravenous dosing and at 0, 15, 20, 30, 45 min, and 1, 1.25, 1.5, 2, 2.5, 3 and 4 h after oral dosing. Urine was collected during the following periods: 0 (baseline), 0-4 and 4-8 h. Mesna and dimesna were measured in specimens; elimination rate constants (k), half-life, and total body clearance were determined.

Mesna underwent rapid oxidation to dimesna in plasma. After i.v. administration, the mean half-life of mesna is 22 min and that of dimesna is 1.17 hours. Following oral administration, the maximum peak concentration of mesna in plasma occurred late in the sampling period (at 1, 2.5, 3 and 4 hours) and for dimesna (at 2, 2.5 and 3 hours). Compared with i.v. administration, the onset of significant plasma levels of mesna/dimesna following oral administration is delayed approximately 1 h. Following intravenous administration of mesna, maximum concentrations occurred in the 0-4 h urine collection, while the maximum mesna concentration occurred in either the 0-4 h or 4-8 h urine sample after oral mesna. Compared with i.v. administration of mesna, overall availability of mesna in urine after oral administration is approximately 50%. The onset of urinary excretion of mesna after oral administration is delayed and more prolonged, perhaps due to sustained absorption from the gastrointestinal tract. After both i.v. and oral mesna the urinary excretion of mesna is predominantly during the first 4 hours.

Pharmacokinetics of BNP7787 (dimesna) and mesna

Pharmacokinetics of dimesna was studied in 25 patients who received cisplatin treatments to determine its chemoprotective action against cisplatin-induced side effects (Verschraagen et al., 2003). In the kidneys, intestine, and liver, BNP7787 is believed to undergo intracellular conversion into 2-mercaptoethane sulfonate (mesna), which can locally inactivate toxic platinum species.

25 patients with solid tumours received an intravenous (i.v.) infusion of 75 mg/m² cisplatin alone over a 1-hour period. Three weeks later, they received cisplatin immediately preceded by a 15-minute i.v. infusion of BNP7787 (dimesna) at dose levels of 4.1 -41.0 g/m². BNP7787 was also given alone 1 week before the course with cisplatin. These results are relevant for the evaluation of the toxicity of dimesna and its toxicokinetic behaviour in humans. All patients who entered the phase I trial received the combination of cisplatin and BNP7787 every 3 weeks. The BNP7787 dose was escalated according to the protocol in which 3 patients were treated at each dose level (4.1, 8.2, 12.3, 18.4, and 27.6 g/m²) and 6 patients were treated at the highest dose level (41 g/m²). As an additional safety precaution, it was decided to include 2 intermediate dose levels of BNP7787 (23.0 g/m² in 3 patients and 34.5 g/m² in 1 patient). There was no intra-patient dose escalation. At each dose level, 1 patient provided blood samples for the pharmacokinetics (PK) study, whereas at the highest dose level of 41 g/m² BNP7787, 6 patients underwent PK (pharmacokinetics) sampling. 14 patients, 6 men and 8 women, aged 37 to 65 years, were entered in the PK component of the study. Not all patients underwent sampling during all 3 treatments; 12 of 14 patients underwent sampling when receiving BNP7787 alone and in combination with cisplatin. For the HPLC analysis of BNP7787 and its metabolite mesna, 3-mL blood samples were collected at the following time points: just before treatment and at 8, 15, 25, 35, and 45 minutes and 1, 1.25, 1.75, 2.25, 4.25, and 6.25 hours after the BNP7787 infusion was started. PK parameters, consisting of final half-life (t1/2), AUC(0-t), area under the curve to infinity AUC(0-infinity), mean residence time (MRT), total body clearance (CL), and steady-state volume of distribution (Vss), Cmax, and tmax were determined.

At the highest BNP7787 dose (41 g/m²), a mean Cmax of BNP7787 of 14.1 mmol/L was reached at the end of the 15-minute infusion, whereas a mean peak value for mesna of 323 µmol/L was reached at approximately 1.7 hours after the BNP7787 infusion was started. The BNP7787 and mesna curves after the BNP7787 administration were similar to the curves obtained after BNP7787 followed by cisplatin. Linear pharmacokinetics were observed for the AUC(0-infinity) and Cmax of BNP7787 and mesna, respectively. The mean normalised Cmax values of BNP7787 for all patients with and without cisplatin were 123.4 and 136.1 x 10E-3 x m²/L, respectively, which were at least 38-fold higher than the mean normalised Cmax values of mesna (3.2 and 3.3 x 10E-3 x m²/L, respectively). The mean normalized AUC(0 -infinity) of mesna was approximately 8% of the normalized AUC(0 -infinity) of BNP7787. The lower mesna concentration is probably because mesna is more reactive with (hydrated) cisplatin than its disulfide BNP7787. This substantial difference in the mesna plasma concentration explains in part why the administration of BNP7787 does not inactivate cisplatin and, therefore, does not interfere with the antitumor activity of cisplatin in animal studies (please refer to references cited in the article). In contrast, interference with cisplatin antitumor activity has been observed after mesna administration in animal tumour models. The mean t1/2 of BNP7787 in plasma was 1.4 hours, whereas mesna was excreted more slowly (i.e., mean t1/2 of 2.7 hours). This was also reflected by the mean residence time (MRT) of mesna, which was approximately 2 times longer than that of BNP7787 (i.e., 4.5 and 1.9 hours, respectively). The slow formation of mesna after BNP7787 administration is in contrast to the rapid formation of mesna disulfides in the circulation after mesna administration. This is most likely because of a difference in mechanism (i.e., nonenzymatic oxidation of mesna to mesna disulfides in the circulation versus enzymatic reduction of BNP7787 to mesna locally in renal, intestinal, and liver cells). The Vss and CL of BNP7787 were approximately 0.26 L/kg and 9.2 L /h x 1.73 m², respectively, which suggests that BNP7787 was principally present in plasma and the interstitial fluid space compartments. This observation supports the hypothesis that BNP7787 is not taken up in most cells, except for renal, intestinal, and liver cells. In these cells BNP7787 is believed to be enzymatically reduced into mesna.

The effects of cisplatin on the patients’ PK parameters of BNP7787 were estimated by the ratio of the geometric means in the absence or presence of cisplatin treatment. No significant differences were detected between the calculated PK values of mesna in the presence or absence of cisplatin (unadjusted and adjusted P values .05) when all patients at each BNP7787 dose level were included. This was also the case for the values of the PK parameters of BNP7787 at all dose levels (unadjusted and adjusted P values 0.05).

Conclusion

Dimesna was relatively nontoxic at doses up to 41 g/m² (corresponds to 1.07 g/kg bw; based on the body weight of 70 kg (relevant for workers) and body height of 173 cm, resulting in body surface area of 1.83 m²). The frequently reported events related to BNP7787 included flushing or a warm feeling, nausea, and vomiting. The symptoms disappeared promptly after the end of the infusion. Dimesna is reduced in kidney to mesna and the the maximum plasma concentration of mesna was reached approximately 1.7 hours after the start of the BNP7787 infusion. The combination of BNP7787 with cisplatin did not alter the pharmacokinetic profiles of mesna or the cisplatin metabolites. At the higher dose levels of BNP7787 (18.4 to 41 g/m2), there appeared to be no mutual interaction between BNP7787 and intact cisplatin, which needs to be confirmed in a larger number of patients. The absence of a mutual interaction between BNP7787 and intact cisplatin is consistent with the observation that several patients had objective tumour responses with BNP7787 and cisplatin administration.

The calculation of body surface area is performed according to the formula given on: http://flexikon.doccheck.com/de/Dubois-Formel (2013 -01 -23)

Co-administration of mesna with anticancer drugs during pregnancy

Doxorubicin and ifosfamide are highly active drugs for the treatment of high-grade sarcomas, but little is known on the optimal management of young patients who develop such malignancies during pregnancy (Mir et al., 2012). Mesna was a part of chemotherapy regimen which was co-administered with doxorubicin and ifosfamide to patients with high-grade sarcoma diagnosed during the third trimester of pregnancy. Mesna served to lessen anticancer drugs toxicity. Mesna was administered continuously via i.v. infusion, 100% of ifosfamide dose (total dose: 5 g/m²/cycle) 15 min before starting ifosfamide and 100% of ifosfamide dose for the 8 hours following the end of ifosfamide infusion. A favourable outcome for both the mother and the offspring was in all cases. Maternal and neonatal pharmacokinetic data for ifosfamide were obtained from one patient and did not evidence a transplacental transfer of this drug. The newborn children had further normal development.

Mesna was used during course of anticancer therapy in a woman, who had Ewing's sarcoma of the pelvic bones (Merimsky et al., 1999). Three courses of three-weekly doxorubicin (50 mg/m²) plus ifosfamide and mesna (each 5 g/m²) (ADR-IFX) were given in the 27th, 30th, and 33rd week of gestation. Nausea and vomiting were controlled by i.v. granisetron 3 mg/day. No prophylactic bone marrow support was planned. Complete pain relief was achieved following the second course of ADR-IFX. Only one episode of grade 3 myelotoxicity, i.e., neutropenia without fever, was observed following the third course on a routine blood count, requiring no antibiotic treatment, nor hospitalization. Fetal monitoring and repeated ultrasonographic evaluations showed mild intrauterine growth retardation without fetal stress. MRI evaluation performed after the three cycles of chemotherapy revealed partial regression of the tumour. A Caesarean section was planned and performed at the beginning of the 36th gestation week. The newborn was a 42 cm length and 1300 g weight female. A fourth course of ADR-IFX was administered two weeks later, followed by definitive surgery, consisting of a large resection of the iliac bone and hemisacrectomy sacrificing the SI, S2 and S3 roots. Pathologic evaluation of the surgical specimen documented complete resection and 80% necrosis of the tumour. Planned adjuvant chemotherapy consisted of ifosfamide (12 g/m² given by continuous infusion over three days) plus etoposide (100 mg/m²/day i.v. for three days) according to our adult Ewing's sarcoma protocol was started. Etoposide was rapidly aborted due to severe allergic reaction to the drug observed within the first minutes of infusion. Despite prophylactic administration of granulocyte colony stimulating factor (GCSF) the patient experienced neutropenic fever after each of the two ifosfamide courses. The chemotherapy was discontinued. A dose of 46 Gy (four MV photons, 2 Gy x5/week, isocentric AP-PA fields) was subsequently delivered to the tumour bed and the right hemipelvis after ovarian transpositioning. 24- months later, the patient was disease-free and her daughter showed no chemotherapy- related late effects.

A case of both successful maternal treatment outcome and normal fetal outcome in a patient who was diagnosed with Burkitt’s lymphoma (BL) and aggressively treated with 6 different chemotherapy agents during the second and third trimesters of pregnancy was reported (Lam, 2006). Mesna was included in the CODOX-M/IVAC Regimen for Treatment of Burkitt’s Lymphoma. The treatment of the pregnant woman with 2 cycles of systemic intensive polychemotherapy including cyclophosphamide, vincristine, doxorubicin, cytarabine, etoposide, ifosfamide, mesna, and intrathecal cytarabine with growth factor did not result in any congenital malformations or acute adverse effects in the fetus. Long-term follow-up of the child remains necessary to evaluate possible long-term complications.

Conclusion: Chemotherapy consisting of doxorubicin (50 mg/m2), ifosfamide (5 g/m2), and mesna, supported by intravenous granisetron (3 mg/day), was safely administered during the third trimester.The data point to the relative feasibility and efficacy of this combination of adriamycin and ifosfamide during pregnancy. The neo-adjuvant treatment yielded a 80% necrosis, while the baby remained normal, although small in size and weight. The long-term effects on mental and physical development of the baby, together with the possible risk of future malignancy need to be monitored.