Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Fennec Pharmaceuticals (EU) Limited, Block A, 5th Floor, The Atrium, Blackthorn Road, Sandyford, Dublin 18, Ireland
Pharmacotherapeutic group: not yet assigned
ATC code: not yet assigned
The mechanism of sodium thiosulfate protection against ototoxicity is not fully understood, but may include increasing levels of endogenous antioxidants, inhibition of intracellular oxidative stress, and direct interaction between cisplatin and the thiol group in sodium thiosulfate to produce inactive platinum species.
Concurrent incubation of sodium thiosulfate with cisplatin decreased the in vitro cytotoxicity of cisplatin to tumour cells; delaying the addition of sodium thiosulfate to these cultures prevented the protective effect.
The is no clinical pharmacodynamic information available beyond that given within the mechanism of action section.
The efficacy of sodium thiosulfate (STS) in preventing cisplatin (CIS)-induced ototoxicity was studied in two multicentre studies in which 112 paediatric patients with various solid tumour types were treated with STS following each administration of CIS. Safety has been established using 1 to 5 doses of sodium thiosulfate per chemotherapy cycle, with regimens varying from 1 dose of CIS+STS per cycle to 5 doses of CIS+STS per cycle.
Study 1 was a multicentre, randomised, controlled, open-label study to assess the efficacy and safety of STS in reducing ototoxicity in children receiving CIS chemotherapy for standard risk hepatoblastoma (SR-HB). Children between 1 month and 18 years of age with histologically confirmed newly diagnosed HB were eligible. Children were randomised 1:1 to receive STS after each CIS dose (CIS+STS arm) or to receive CIS alone.
CIS was administered as a 6-hour intravenous infusion. Four courses of CIS were given pre-surgery and 2 additional courses were given post-surgery.
In the CIS+STS arm, the STS intravenous infusion was administered over 15 minutes, beginning 6 hours after completion of each CIS infusion. Doses of STS were dependent on the child’s weight as follows: children >10 kg received an equivalent of 12.8 g/m² STS, children ≥5 to ≤10 kg received an equivalent of 9.6 g/m² STS, and children <5 kg received an equivalent of 6.4 g/m² STS.
A total of 129 children were registered and 114 children were randomised in the study (61 patients in the CIS+STS arm and 53 patients in the CIS Alone arm). Of the 114 patients randomised, 5 patients withdrew prior to treatment: 2 patients due to withdrawal of parental consent, 2 patients due to reclassification as high risk HB, and 1 due to ineligibility.
Hearing loss was defined as a Brock Grade ≥ 1 measured using audiologic evaluations after the end of study treatment or at an age of at least 3.5 years when a reliable result could be obtained, whichever was later. The proportion of children in the CIS+STS arm with hearing loss at age ≥ 3.5 years (20 children [35.1%]) was approximately one-half compared with the CIS Alone arm (35 children [67.3%] (Table 2). Event free survival and OS were also evaluated.
Table 2. Summary of patient population and hearing loss in study 1:
| CIS alone | CIS + STS | |
|---|---|---|
| Patient population | ||
| N (intent to treat population) | 52 | 57 |
| Age (years), median (min, max) | 1.1 (0.3, 5.9) | 1.1 (0.1, 8.2) |
| Weight (kg) (mean, SD) | 10.25 (3.26) | 10.23 (3.76) |
| N (treated population) | 56 | 53 |
| Number of CIS cycles (mean, SD) | 5.8 (1.0) | 5.9 (0.6) |
| Cumulative CIS dose (mg/m²) (mean, SD) | 362.851 (98.871) | 363.860 (96.607) |
| Cumulative STS dose (g/m²) (mean, SD) | -- | 85.149 (24.390) |
| Patients who experienced hearing loss | ||
| N (intent to treat population) | 52 | 57 |
| Yes, n (%) | 35 (67.3) | 20 (35.1) |
| No, n (%) | 17 (32.7) | 37 (64.9) |
| Relative Risk (95% CI) | 0.521 (0.349, 0.778) | |
| p-value | <0.001 | |
The risk of having hearing loss was statistically significantly lower in the CIS+STS arm compared with the CIS Alone arm, corresponding to a clinically meaningful 48% lower risk after STS treatment.
At a median of 4.27 years of follow up, the hazard ratio between the treatment arms in Event-free survival (EFS) was ([CIS+STS vs CIS Alone]: 0.96; 95% CI: 0.42, 2.23) and in overall survival (OS) (hazard ratio: 0.48; 95% CI: 0.09, 2.61).
Study 2 was a multicentre, randomised, controlled, open-label study to assess the efficacy and safety of STS in preventing hearing loss in children receiving CIS chemotherapy for the treatment of newly diagnosed germ cell tumour (25.6%), hepatoblastoma (5.6%), medulloblastoma (20.8%), neuroblastoma (20.8%), osteosarcoma (23.2%), atypical teratoid/rhabdoid tumour (1.6%), choroid plexus carcinoma (0.8%), and anaplastic astrocytoma (0.8%); or any other malignancy treated with CIS; 7.5% had prior cranial radiation. Children between 1 year and 18 years of age and scheduled to receive a chemotherapy regimen that included a cumulative CIS dose of ≥200 mg/m², with individual CIS doses to be infused over ≤ 6 hours, were eligible. Children were randomised 1:1 to receive either STS 6 hours after each CIS dose (CIS+STS) or chemotherapy that included CIS, without subsequent STS (CIS Alone).
CIS was administered according to the sites' disease-specific cancer treatment protocols in use at the time. When multiple daily doses of CIS were scheduled, the protocol stipulated at least a 10-hour delay between any STS infusion and the beginning of the next day’s CIS infusion.
In the CIS+STS arm, 10.2 g/m² STS was administered by intravenous infusion over 15 minutes, beginning 6 hours after the completion of each CIS infusion. A dose reduction was included for children whose therapeutic protocol administered CIS on a per kg basis due to young age or low body weight, which was 341 mg/kg STS.
The primary endpoint was the proportional incidence of hearing loss between the CIS+STS arm and the CIS alone arm, as defined by comparison of American Speech-language-Hearing Association (ASHA) criteria assessed at baseline and 4-weeks after the final course of cisplatin. EFS, i.e. presence or absence of tumour progression or recurrence or development of subsequent malignant neoplasm, and OS were also evaluated.
A total of 131 children were registered and 125 children were randomised in the study (61 patients in the CIS+STS arm and 64 patients in the CIS Alone arm). Of the 125 patients randomised, 2 patients withdrew prior to treatment: 1 patient due to withdrawal of parental consent, and 1 due to investigator decision.
In the 104 patients who had both baseline and 4-week follow-up hearing assessments, the proportion of children in the CIS+STS arm with hearing loss (14 patients [28.6%]) was approximately one-half of the proportion in the CIS Alone arm (31 patients [56.4%]) (Table 3).
Table 3. Summary of patient population and hearing loss in study 2:
| CIS alone | CIS + STS | |
|---|---|---|
| Patient population | ||
| N (intent to treat population) | 64 | 61 |
| Age (years), median (min, max) | 8.3 (1, 18) | 10.7 (1, 18) |
| N (intent to treat population) | 64 | 59 |
| Weight (kg) (mean, SD) | 37.3 (24.9) | 39.1 (28.3) |
| N (safety population) | 64 | 59 |
| Number of CIS cycles (mean, SD) | 3.8 (1.5) | 3.1 (1.4) |
| Cumulative CIS dose (mg/m²) (mean, SD) | 391.47 (98.40) | 337.57 (118.33) |
| Cumulative STS dose (g/m²) (mean, SD) | -- | 108.23 (80.24) |
| Patients who experienced hearing loss | ||
| N (efficacy population) | 55 | 49 |
| Yes, n (%) | 31 (56.4) | 14 (28.6) |
| No, n (%) | 24 (43.6) | 35 (71.4) |
| Relative Risk (95% CI) | 0.516 (0.318, 0.839) | |
| p-value | 0.0040 | |
The risk of having hearing loss was statistically significantly lower in the CIS+STS arm compared with the CIS Alone arm, corresponding to a clinically meaningful 48% lower risk after STS treatment.
At a median of 5.33 years of follow up, the hazard ratio in EFS between arms was ([CIS+STS vs CIS Alone]: 1.27; 95% CI: 0.73, 2.18). A disparity in OS was observed (hazard ratio: 1.79; 95% CI: 0.86, 3.72). In patients categorised post-hoc with localised disease, the hazard ratio between arms in EFS was (hazard ratio: 1.02; 95% CI: 0.49, 2.15) and in OS (hazard ratio: 1.23; 95% CI: 0.41, 3.66).
Sodium thiosulfate is poorly absorbed after oral administration and has to be administered intravenously. At the end of a sodium thiosulfate intravenous infusion, plasma levels of sodium thiosulfate are maximal and decline rapidly thereafter with a terminal elimination half-life of approximately 50 minutes. A return to pre-dose levels occurs within 3 to 6 hours after infusion. More than 95% of sodium thiosulfate excretion in urine occurs within the first 4 hours after administration.
Hence, there is no plasma accumulation when sodium thiosulfate is administered on 2 consecutive days.
In children and adults, the maximum sodium thiosulfate plasma levels after a 15-minute infusion of a dose equivalent to 12.8 g/m² was approximately 13 mM. Thiosulfate plasma levels change in a dose proportional manner. Age did not appear to influence the maximum plasma levels of sodium thiosulfate or the decline afterwards. A population PK model incorporating growth and maturation variables for the paediatric population showed that the predicted sodium thiosulfate plasma levels at the end of infusion were consistent across the recommended dose levels for the indicated age and body weight ranges.
Sodium thiosulfate does not bind to human plasma proteins. Sodium thiosulfate is an inorganic salt and thiosulfate anions do not readily cross membranes. Hence, the volume of distribution appears largely confined to extracellular spaces and estimated at 0.23 L/kg in adults. In animals, sodium thiosulfate has been found to distribute to the cochlea. Distribution across the blood brain barrier or placenta appears absent or limited. Thiosulfate is an endogenous compound ubiquitously present in all cells and organs. Endogenous serum thiosulfate levels were 5.5 ± 1.8 µM in adult volunteers.
Metabolites of sodium thiosulfate have not been determined as part of clinical studies. Thiosulfate is an endogenous intermediate product of sulfur-containing amino acid metabolism. Thiosulfate metabolism does not involve CYP enzymes; it is metabolised through thiosulfate sulfur transferase and thiosulfate reductase activity to sulfite, which is rapidly oxidised to sulfate.
Sodium thiosulfate (thiosulfate) is excreted through glomerular filtration. After administration, thiosulfate levels in urine are high, and approximately half of the sodium thiosulfate dose is retrieved unchanged in urine, nearly all excreted within the first 4 hours after administration. Thiosulfate renal clearance compared well with inulin clearance as a measure for the GFR.
Excretion of endogenously produced thiosulfate in bile was very low and did not increase after sodium thiosulfate administration. No mass balance studies have been performed, but it is expected that non-renal clearance will mainly result in renal excretion of sulfates. A small part of the sulfane sulfur of sodium thiosulfate may become part of endogenous cellular sulfur metabolism.
In haemodialysis patients, total clearance of sodium thiosulfate was 2.04 ± 0.72 mL/min/kg (off dialysis) compared to 4.11 ± 0.77 mL/min/kg in healthy volunteers. This clearance was essentially similar to the non-renal clearance observed in the healthy volunteers (1.86 ± 0.45 mL/min/kg). In the absence of any glomerular filtration in haemodialysis patients, this only resulted in approximately a 25% increase in the maximum thiosulfate plasma levels and nearly a 2-fold increase in total exposure. The plasma concentration of thiosulfate is deemed to be the most important parameter associated with the efficacy of the product. Moreover, the most frequent adverse reactions are considered to be related to the sodium load with sodium thiosulfate administration and concurrent electrolyte imbalances (see section 4.4). Non-clinical studies indicated that dose limiting acute effects were related to the sodium intake. Sodium thiosulfate is only intended to be administered in conjunction with cisplatin chemotherapy. Cisplatin is contraindicated in patients with pre-existing renal impairment and, therefore, in the absence of cisplatin administration sodium thiosulfate would not be administered.
No information is available for use of sodium thiosulfate in patients with hepatic impairment. However, thiosulfate sulfur transferase/reductase activity is ubiquitous, including tissue like red blood cells, liver, kidney, intestine, muscle and brain. Therefore, the changes in thiosulfate pharmacokinetics in hepatically impaired patients are likely limited and without clinical significance.
Sodium thiosulfate does not bind to human plasma proteins. The chemical properties of sodium thiosulfate, along with the observations that sodium thiosulfate does not distribute readily across membrane barriers and is excreted through glomerular filtration, make an interaction with membrane drug transporters unlikely.
Cytochrome P450 enzymes: Sodium thiosulfate is an inducer of CYP2B6 but not of CYP1A2 or CYP3A4. Sodium thiosulfate is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 at clinically relevant concentrations.
Sodium thiosulfate was not genotoxic in an in vitro bacterial reverse mutation assay (Ames test) with or without metabolic activation and was not clastogenic in an in vitro mammalian cell assay (sister chromatid exchange) using human peripheral lymphocytes.
Long-term studies in animals have not been performed to evaluate the potential carcinogenicity of sodium thiosulfate.
There is insufficient information from animal studies to assess the effects of intravenous infusion of sodium thiosulfate on fertility.
There is insufficient information from animal studies to assess developmental risks with intravenous infusion of sodium thiosulfate.
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