Influence of Mesna on the Pharmacokinetics of Cisplatin and Carboplatin in Pediatric Cancer Patients

Abstract

Mesna, a reactive thiol, often encounters cisplatin and carboplatin in combination protocols involving oxazaphosphorines and platinum drugs. This co-administration might be unfavorable based on the inactivation of platinum drugs by thiol groups in vitro. We investigated whether mesna influences the pharmacokinetics of platinum drugs when co-administered with cisplatin or carboplatin. The pharmacokinetics of platinum drugs were investigated in 18 pediatric patients receiving either cisplatin or carboplatin in a combination with or without mesna. In cisplatin patients, a decrease in the distribution clearance of total platinum was observed when mesna was co-administered (CLd, 2.2 +/- 0.1 mL/min.kg; n = 3), compared to cisplatin without mesna (CLd, 4.8 +/- 1.5 mL/min.kg; n = 5) (p = 0.029, t-test). This might have been caused by an influence of mesna in slowing down the protein binding of cisplatin since a trend (p = 0.057) in prolonged distribution half-life of total platinum was also observed when mesna was present (t(1/2a) 65 +/- 21 min; n = 3) compared to cisplatin without mesna (t(1/2a), 32 +/- 18 min; n = 5). However, the impact of these changes on the area under the concentration time curve (AUC), total clearance (CLt), and volume of distribution (V) for total platinum and ultrafilterable platinum species was hardly noticeable. In carboplatin patients, when mesna was co-administered: AUC (2.5 +/- 0.4 mg.min/mL.400 mg/m2; n = 5) CLt, (6.8 +/- 5.1 mL/min.kg; n = 6), and V (0.7 +/- 0.4 L/kg; n = 6) for ultrafilterable platinum species were not significantly different from when carboplatin were administered without mesna: AUC (2.3 +/- 1.3 mg.min/mL.400 mg/m2; n = 4), CLt (5.8 +/- 4.6 mL/min.kg; n = 5), and V (1.1 +/- 1.1 L/kg; n = 5). Hence, mesna does not significantly influence the pharmacokinetics of cisplatin and carboplatin in pediatric cancer patients.

The mechanism of mesna in protection from cisplatin-induced ovarian damage in female rats

“…Though the protection of mesna was achieved without attenuating the efficacy of co-administered anti-cancer agents such as ifosfamide and cyclophosphamide [20], there was inconsistence in the effect on platinum chemotherapeutic agents. It was reported that the active thiol monomer of mesna could bind to platinum drugs and reduce their efficacy by a direct reaction with platinum molecule [37,38] while Kangarloo et al [39] ruled out the influence of mesna on the pharmacokinetics of cisplatin and carboplatin. In the present study, we measured the influence of cisplatin and mesna on the cisplatin sensitive HepG2 cell line either with single administration or co-administration.…”

Intensive chemotherapy improves survival in pediatric high‐grade glioma after gross total resection: results of the HIT‐GBM‐C protocol

“…The cycle was placed at the end of the radiation treatment because it was expected to cause bone marrow suppression; this would have cause a risk for interruption of radiation if the cycle was given earlier 22. The infusion times of ifosfamide and cisplatin were separated by positioning the etoposide infusion in between, so that mesna was not infused during cisplatin infusion or at times of peak plasma levels 26, 27. After radiation therapy, the chemotherapy continued with further cycles of PEI in Weeks 10, 14, 18, 22, 26, and 30, as well as vincristine in Weeks 13, 17, 21, 25, and 29.…”

Reproductive Toxic Effects of Cisplatin and Its Modulation by the Antioxidant Sodium 2-Mercaptoethanesulfonate (Mesna) in Female Rats

“…Importantly, mesna does not interfere with the pharmacokinetics of cisplatin. 19,24,25 We sought to address the effects of multiple exposures to cisplatin on the future reproductive capabilities by studying adverse effects of prior injections of cisplatin on the reproductive function of female rats. In addition, we sought to determine the degree of protection against the adverse reproductive effects of cisplatin by using mesna.…”