Satraplatin, an Oral Platinum, Administered on a Five-day Every-Five-Week Schedule: a Pharmacokinetic and Food Effect Study

Abstract

Purpose: The study aimed to assess the pharmacokinetic behavior of satraplatin under fasted and fed conditions, and its safety and preliminary antitumor activity in adults with advanced solid tumors. Experimental Design: Satraplatin was administered orally at 80 mg/m 2 once daily with prophylactic antiemetics for 5 consecutive days every 5 weeks. Patients were randomized to receive day 1 and day 5 doses of satraplatin in either the fed or fasted state, the order being reversed for cycle 2. Pharmacokinetic sampling was done during the first two cycles. For all subsequent cycles, patients received satraplatin in the fasted state. Results: Seventeen patients were treated with 60 total cycles of satraplatin. There was no dose-limiting toxicity during cycle 1. Severe hematologic toxicity was rare and the hematologic nadir occurred during week 4. Nausea, vomiting, and diarrhea were grade 1/2. No significant cardiac, renal, hepatic, or neurologic toxicity was observed. The hypothesis that food decreased ultrafiltrate platinum bioavailability could not be rejected, as the lower limit of the 90% confidence intervals for peak plasma concentration and area under the concentration-time curve from time 0 to 24 hours were 56.14% and 73.53%, respectively, both below the 80% bioequivalence acceptance criterion. One partial response (hormone refractory prostate cancer) and four durable stable diseases (breast, ovarian, parotid, and hormone refractory prostate cancer) were confirmed. Conclusions: There is an effect of food on the pharmacokinetics of satraplatin, the clinical significance of which is unclear. It is recommended that satraplatin be administered in the fasting state. This 5-week interval schedule of satraplatin was well tolerated in heavily pretreated patients.Platinum analogs form the mainstay of treatment for a number of cancers, including bladder, head and neck, lung, ovarian, and testicular cancer, and a usual first option against colorectal and esophagogastric cancer. All approved platinum anticancer drugs are administered i.v., with aggressive hydration to avoid acute nephrotoxicity in the case of cisplatin (1, 2). In addition, their efficacy is often limited by cumulative toxicity, particularly neurotoxicity and ototoxicity (1,3,4). Satraplatin [bisacetatoammine-dichloro-cyclohexylamine-platinum(IV)] is a novel, orally bioavailable, platinum agent (5). It was selected from a series of oral platinum compounds because of promising preclinical features including in vitro antitumor activity, in vivo antitumor activity at least comparable with cisplatin and carboplatin in a diversity of murine and human tumor models, and finally its ability to partially circumvent intrinsic and acquired resistance to cisplatin (5-12).When satraplatin was administered every three to four weeks, nonlinear pharmacokinetics, probably due to saturable absorption, were observed (13,14). Subsequently, a daily schedule for five consecutive days was developed, with the dose utilized for phase II and III studies varying between 100 ...

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

“…Pharmacokinetic analyses using atomic absorption spectroscopy performed in two adult phase I trials showed mean plasma UF AUC was 0.28 ± 0.1 and 0.249 ± 0.044 mcg/ml*h and mean C max was 0.047 ± 0.005 and 0.052 ± 0.016 mcg/ml at doses of 60–80 mg/m 2 /dose once daily for 5 days . Similar results were also observed in adult studies that used inductively coupled plasma mass spectrometry to measure ultrafilterable platinum (AUC 0–24 0.419–0.466 mcg/ml*h and C max 0.054–0.057 mcg/ml) . Although two of the adult studies used a similar assay for measuring plasma UF platinum, the adult and pediatric pharmacokinetic evaluations were not performed in the same laboratory, and the possibility that the observed differences in pharmacokinetic parameters were due to differences in the analytical assay cannot be completely excluded.…”

“…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).…”

Organic Anion Transporting Polypeptide 5A1 (OATP5A1) in Small Cell Lung Cancer (SCLC) Cells: Possible Involvement in Chemoresistance to Satraplatin

“…This ultimately results in formation of the highly cytotoxic metabolite JM118 being not a substrate of OATP5A1 (data not shown). However, the narrow dose window of 1.25–5 μM satraplatin for the action of OATP5A1 matches closely the peak plasma concentrations of this drug, and relatively small changes in cellular resistance in this range may result in profound clinical effects 27. This mechanism of chemoresistance in highly refractory SCLC cell lines may be induced by the potential OATP substrate etoposide that is commonly used in conjunction with cisplatin for standard chemotherapy 2.…”

Novel oral anticancer drugs: a review of adverse drug reactions, interactions and patient adherence

“…Sokat ezek közül már klinikai vizsgálatokban tesztelnek. A célzott terápiás szerek egyre bővülő palettája mellett citosztatikumok (például satraplatin) is szerepelnek a vizsgált gyógyszerek között [65]. A második generációs (irreverzíbilis) tirozinkináz-inhibitorok köre még jelentősen bővül, de más hatásmechanizmusú gyógyszerek (például hisztondeacetilázok) tumorellenes hatékonysá-gát is vizsgálják [66,67,68].…”