The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates

Marcus, Leigh; Murphy, Robert F.; Fox, Elizabeth; McCully, Cynthia; Cruz, Raphael; Warren, Katherine E.; Meyer, Thorsten; McNiff, Edward F.; Balis, Frank M.; Widemann, Brigitte C.

doi:10.1007/s00280-011-1659-z

Cited by 3 publications

(4 citation statements)

References 32 publications

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“…The toxicity profile in our pediatric population was similar to that in adults, and myelosuppression was the DLT. Myelosuppression was delayed with a median neutrophil nadir in cycle 1 occurring on day 27 (range 5-42,) and platelet count nadir on day 27 (range [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. This was similar to adults where median neutrophil nadir occurred on day 21 (range 2-63) and median platelet count nadir occurred on day 21 (range 2-64).…”

Section: Discussionmentioning

confidence: 75%

“…Platinum concentration in plasma UF was used to calculate satraplatin exposure as it is a measure of the non‐protein‐bound free platinum concentration and has been used as a measure of satraplatin exposure in pre‐clinical studies and adult clinical trials . For an oral drug, satraplatin pharmacokinetics showed relatively limited variability (coefficient of variation 0.37 and 0.39 for C max and AUC 0–24 respectively).…”

Section: Discussionmentioning

confidence: 99%

“…Plasma was separated by centrifugation, and plasma ultrafiltrate (UF) was prepared using Microcon YM‐10 filters. Plasma UF platinum was measured using a validated atomic absorption spectroscopy assay . The lower limit of quantitation was 0.03 mcM (0.015 mcg/ml), and linear range 0.03–2.5 mcM (0.015–1.251 mcg/ml).…”

Section: Methodsmentioning

confidence: 99%

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Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors

Akshintala

Marcus

Warren

et al. 2015

Pediatr Blood Cancer

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Background Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. Procedure Satraplatin was administered orally once daily on days 1–5 of a 28-day cycle at dose level (DL) 1 (60 mg/m2/dose), and DL2 (80 mg/m2/dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. Results Nine patients received 1–15 cycles (median=2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (6–15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. Conclusions The MTD of oral satraplatin in children with solid tumors was 60 mg/m2/dose daily × 5 days every 28 days, which is lower than the adult recommended dose of 80–120 mg/m2/dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicity was observed.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors

Akshintala

Marcus

Warren

et al. 2015

Pediatr Blood Cancer

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“…In view of the data presented herein, satraplatin should be particularly useful in the treatment of DLBCL with primary extranodal lymphoma presentation, for example with lymphoma of the central nervous system, vitreo-retina, testis, or breast. The lipophilic characteristics of satraplatin enables the drug to access the cerebrospinal fluid at sufficient dose levels (24). In addition, its oral availability, with a favorable side-effect profile such as lack of neuro-and ototoxicity, provide the rationale for further investigation of satraplatin in extranodal lymphomas with a special focus on PCNSL as outlined.…”

Section: Cytotoxic Activity Of Satraplatin Against Tumor Cell Lines O...mentioning

confidence: 99%

Satraplatin Demonstrates High Cytotoxic Activity Against Genetically Defined Lymphoid Malignancies

ZANDER¹,

Xue

MARKSON³

et al. 2022

Anticancer Res

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Background/Aim: Satraplatin is an oral platinum analog with proven clinical efficacy and a more favorable toxicity profile, although with increased hematotoxicity, when compared to cisplatin. Hence, we carried out a systematic biomarker analysis to identify hematological malignancies with high susceptibility to satraplatin. Materials and Methods: Halfmaximal inhibitory concentrations (IC 50 ) for satraplatin and cisplatin were determined for 66 different cancer cell lines by CTG Luminescent Cell Viability Assay. In a second step, whole transcriptome RNA sequencing and whole-exome DNA sequencing technology followed by unbiased analysis of gene expression, gene mutation and copy number levels were performed and correlated with drug efficacy. Results: Satraplatin was significantly more active against hematological malignancies compared to solid organ cancer. In addition, satraplatin showed a significantly more potent antiproliferative activity compared to cisplatin in most lymphoma cell lines achieving sub micromolar IC 50 values. Single BCL2 apoptosis regulator (BCL2) gene mutation and 9p21 copy-number deletions including S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency were identified as key characteristics for high sensitivity to satraplatin. Conclusion: Satraplatin demonstrated a high cytotoxic activity in genetically welldefined hematological malignancies which is distinct from that of cisplatin. MTAP deficiency was identified as biomarker of enhanced satraplatin efficacy in hematological cancer-derived cell lines. These data in combination with the lipophilicity of satraplatin provide the rationale for targeting specific lymphatic entities such as primary central nervous system lymphoma and cutaneous T-cell lymphoma to improve clinical outcome.Cisplatin, carboplatin and oxaliplatin are platinum-based drugs that are used throughout the world for cancer treatment (1). All three are intravenously administered and primarily hydrophilic, with similar or even overlapping side-effects including nephrotoxicity, ototoxicity, neurotoxicity, cardiotoxicity, hematological toxicity, hepatotoxicity, and gastrointestinal toxicity. Platinum toxicity is usually the main reason for dose adaptations or even treatment suspension. This is particularly true for cisplatin, with the two most common nephrotoxic sideeffects being acute kidney injury and hypomagnesemia, which is reported to affect up to 90% of cisplatin-treated patients (2). Neurotoxicity and ototoxicity (60-90% of all patients) are the second and third most common platinum toxicities experienced with oxaliplatin, primarily causing neurotoxicity, and cisplatin causing ototoxicity.In order to develop better tolerated platinum compounds with less toxicity, platinum(IV) complexes featuring an octahedral geometry with two additional ligand sites were developed. They follow a classical prodrug concept since it is essential for their anticancer activity that they are reduced to the corresponding platinum(II) analogs in the tumor cell, leading to apoptosis (3). Satrap...

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Modulation of Signaling Enhances the Efficacy of the Combination of Satraplatin and Erlotinib

Avan¹,

Adema²,

Hoebe³

et al. 2014

CDT

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The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates

Abstract: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress.

Cited by 3 publications

References 32 publications

Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors

Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors

Satraplatin Demonstrates High Cytotoxic Activity Against Genetically Defined Lymphoid Malignancies

Modulation of Signaling Enhances the Efficacy of the Combination of Satraplatin and Erlotinib

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