Molecular mass: 500.283 g/mol PubChem compound: 123974
Satraplatin is a cytotoxic agent. The primary cytotoxic mechanism of satraplatin is similar to that of other platinum compounds including cisplatin, carboplatin and oxaliplatin, and is based on the formation of DNA adducts. Platinum-DNA adducts, which are formed following uptake of the drug into the nucleus of the cell, activate several cellular processes that mediate the cytotoxicity of these drugs. These processes include the signalling of DNA damage, cell cycle checkpoints and arrest, DNA repair and cell death. Platinum compounds as such are not cell-cycle specific, though cells appear to be maximally sensitive to cisplatin in G1, just prior to the onset of DNA synthesis, and minimally sensitive in peak DNA synthesis, with entry into S-phase resulting in a two-fold decrease in sensitivity.
Although satraplatin-derived platinum is known to bind to DNA, actual platinum-DNA adducts nor metabolites that function as precursors for such adducts have not been characterised for satraplatin.
Satraplatin treatment results in platinum DNA-adduct forming, slowing down of the S phase, resulting in G2 block and subsequent cell death. In addition satraplatin and its metabolite JM-118 were potent irreversible inhibitors of purified and intracellular Trx reductase (TrxR), thus sensitizing the cell for DNA damage. Inhibition of TrxR and angiogenesis represent novel aspects of the mechanisms of action of satraplatin and JM-118. However, a specific anti-angiogenic effect was not proven, and data on TxR are not available for other platinum-based drugs.
The cytotoxic activity of satraplatin has been shown in vitro against various tumour cell lines, including three prostate carcinoma cell lines. The observed cytotoxicity was comparable with other platinum analogues. In addition also some cisplatin resistant tumour cell lines were sensitive to satraplatin treatment in vitro. This may be due to an altered mechanism of cellular uptake (satraplatin by passive diffusion instead of active transport for e.g. cisplatin).
Due to the cytotoxic nature of satraplatin, all pharmacokinetic data were obtained from patient studies. Since irreversibly bound drug is not available to distribute to the site(s) of action, efficacy and safety of satraplatin is expected to be related to the concentration of free platinum (i.e., platinum in PUF), as is the case for e.g. cisplatin and carboplatin.
After oral administration of a single 80 mg/m² dose of satraplatin to patients with refractory nonhematologic cancers, maximum plasma platinum levels of 225 ± 50 ng/ml were reached after 3.5 hours, and maximum PUF platinum levels of 56.9 ± 19.2 ng/ml after 2.5 hours.
Absolute bioavailability of satraplatin has not been determined in humans, but may well be low, in line with the low absolute bioavailability of satraplatin in mice and dogs (see preclinical assessment). Based on renal excretion data, it is concluded that absorption is at least 5%, and probably not much higher.
A food effect was observed; Cmax was reduced by approximately 26% upon satraplatin dosing under high fat fed conditions. AUC0-24h was not reduced to a statistically significant extent. Because of these findings, it is proposed by the applicant that satraplatin be administered either 1 hour before or 2 hours after a meal. However, the pharmacokinetic reason to administer satraplatin under fasting conditions is not completely understood. Although peak exposure to unbound platinum is higher when administered under fasting conditions, variability under fasted and fed conditions appear comparable and total exposure is not significantly different. Furthermore, dose reduction from 120 to finally 80 mg/m² due to AE was an issue in the clinical development program. Still, administration of satraplatin under fed conditions or irrespective of food is not sufficiently investigated in the pivotal clinical studies, and to expect further studies into this matter at this stage is considered unrealistic. Therefore, although the prerequisite for fasting conditions may complicate the use of satraplatin in clinical practice, the proposed administration without food is accepted.
Binding of satraplatin and JM-118 in vitro to plasma proteins was found to be irreversible and increased with time; no reversible protein binding was detected. Binding occurred more rapidly with JM-118 than satraplatin.
Satraplatin binds to plasma proteins. At 0.5 and 8 hours post-dosing, 51% and 89% of platinum was bound to protein. In plasma samples collected 10 hours or later post-dose, approximately 90-94% of platinum was bound to protein. Protein binding of satraplatin was irreversible, similar to that of other platinum drugs, i.e., cisplatin, carboplatin, and oxaliplatin. Since irreversibly bound drug is not available to distribute to the site(s) of action, efficacy and safety is expected to be related to the concentration of free platinum (i.e., platinum in PUF).
The metabolic profile of satraplatin has not been fully elucidated. The only identified platinum (II) metabolite JM-118 accounts for 20-30% of the platinum content in PUF. The formation of JM-118 appears mediated by multiple CYP450s or other NADPH-dependent enzymes. JM-118 was not further metabolized by human CYP450 oxidoreductase. The applicant has not been able to complete the characterisation of the metabolites formed, due to analytical difficulties. Due to this lack of data on the metabolism pathway of satraplatin, the possible importance of certain genetic polymorphisms in the metabolism of satraplatin is unknown.
After absorption, satraplatin appears mainly metabolically cleared, with a terminal half-life of platinum in plasma and PUF being approximately 230 hours. At least part of the formed metabolites are excreted renally. However, it is not possible to make a quantitative prediction of the relative amount of the absorbed dose in humans that is excreted renally, since no mass balance study has been conducted. Based on preclinical data in mice, rats and dogs, it appears that following iv administration, the majority of the dose is excreted via the urine, and only a small amount, approximately 5% via the faeces (see preclinical assessment). These combined data suggest that renal excretion is important for excretion of satraplatin metabolites from the plasma.
Platinum exposure appears to increase roughly linear up to a dose of approximately 100 mg/m². At higher doses, non-linear pharmacokinetics is observed, most probably due to limited solubility of satraplatin. No solubility problems are expected for the proposed 80 mg/m² dose. No unexpected accumulation of plasma and PUF platinum occurs upon multiple once-daily dosing of satraplatin, with an accumulation ratio for plasma platinum and PUF platinum from day 1 to day 5 being 3.0 (95% CI: 2.6-3.5) and 1.5 (95% CI 1.4- 1.7), respectively.
Interpatient variability at a dose of 80 mg/m², the dose utilized in the pivotal SPARC Phase 3 trial, was moderate, with CV values for platinum exposure in PUF of approximately 30% after single and multiple daily dosing. Administration of satraplatin with food did not increase interpatient variability; CV values were comparable whether satraplatin was administered with food or in the fasting state.
The clearance of platinum after satraplatin administration appears to be highly dependent on renal function. Patients with mild renal impairment showed comparable exposure and concentrations for both plasma platinum and PUF platinum on day 1 and day 5 of treatment compared with patients with normal renal function. In severe renally impaired patients, plasma and PUF platinum exposure was increased. At day 1 the PUF platinum exposure was approximately 2.5 times higher at day 1, and 3.6-fold increased at day 5. In moderately renally impaired patients, at day 1 the PUF platinum exposure was approximately 1.5 times higher at day 1, and 1.6-fold higher at day 5. The applicant is requested to provide a dose reduction for moderate and severe renally impaired patients. This proposal should be based on the continuous relationship between creatinine clearance and exposure.
A trend toward decreased platinum levels in plasma and PUF was observed as hepatic function decreased, particularly in patients with Child-Pugh Class B and C impairment. No dose adjustment is considered necessary due to apparent pharmacokinetics-related safety concerns. Based on safety arguments, the applicant proposes a dose reduction in severe hepatically impaired patients, i.e., to start with a dose of 60 mg/m² instead of 80 mg/m².
A gender effect is not relevant for the current indication of satraplatin, However, when future indications would result in female being treated with satraplatin, this should then be further investigated by the applicant.
Satraplatin exposure was reasonably comparable in Japanese and non-Japanese patients. No dose adjustment appears necessary at increased weight. However, the lack of a significant effect of weight or body surface on satraplatin pharmacokinetics argues against the use of a BSA-based dose regimen. The applicant should explain the reason for choosing satraplatin dosing per m². In clinical practise, BSA-based oral dosing will be impractical.
No dose adjustment is considered necessary based on pharmacokinetics in elderly. Patients up to an age of 87 were included in the study program, and a relatively large number of elderly patients were included in the pharmacokinetic studies. Satraplatin is not expected to be used in children for the current application, and therefore the lack of pharmacokinetic data in children is acceptable.
Satraplatin is a non-specific inhibitor of multiple CYP450s (i.e., 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) in vitro. However, IC50 levels are much higher than levels observed in PUF in vivo after administration of oral satraplatin 80 mg/m². Metabolite JM-118 was shown in vitro not to be an inhibitor of CYP450 isoenzymes. In vitro, satraplatin does not induce CYP450 1A2, 3A4, 2B6 and 2C19 nor does it inhibit P-gp. Therefore, based on the results obtained from in vitro experiments, no in vivo interaction studies for satraplatin and JM-118 are required. However, other metabolites have not been characterized, nor tested for enzyme inhibiting or inducing properties. When new metabolites have been characterised, the possibility for drug-drug interaction should be considered for these metabolites. Until this is the case, the lack of data should be indicated in the SPC section 4.5.
Very high local exposures, possibly exceeding the µM range IC50 for CYP3A4 inhibition, may be possible in the gut. Therefore, the applicant should indicate if CYP3A4 is inhibited by satraplatin, and if orally administered satraplatin will or will not affect bioavailability of other CYP3A4 substrates administered simultaneously by the peroral route. A clinical interaction study with oral midazolam should be conducted in order to investigate this possibility.
For the current application, satraplatin is to be combined with prednisone and prednisolone. In the clinical SPARC study, although not formally investigated, no signs of an interaction are apparent.
A couple of issues are considered unresolved, i.e., with respect to the possible inhibition of CYP3A4 by satraplatin in the gut and the dose advice for renally impaired patients.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
