Serum and intraperitoneal pharmacokinetics of cisplatin within intraoperative intraperitoneal chemotherapy: influence of protein binding

Abstract

Intraperitoneal (i.p.) chemotherapy is a promising therapeutic method to improve the effectiveness of cisplatin in patients with ovarian cancer and peritoneum involvement. Intraperitoneal treatment can be intraoperatively performed just after a complete surgical resection of peritoneal tumor nodules. However, little is known regarding the pharmacokinetics of platinum during intraoperative i.p. chemotherapy (IIC). Serum and i.p. measurements of total and ultrafilterable platinum were performed to determined pharmacokinetic parameters in 11 consecutive patients who received a 2-h IIC with 50 mg/m cisplatin. Protein concentrations were determined in serum and peritoneal liquid at the same times. The cisplatin concentration required to kill OVCAR-3 human ovarian cancer cells and evaluation of cisplatin binding to proteins were determined in vitro. Platinum i.p. concentration decreased rapidly and quickly came under the cytotoxicity threshold (10 mg for 2 h). About 85% of i.p. and serum cisplatin was ultrafilterable during IIC. Platinum concentrations were closely related to protein concentrations. Due to the very low level of serum protein (almost 25 g/l), serum cisplatin binding during chemotherapy was very low (almost 25%), but increased with protein concentration recovery. These pharmacokinetic data show that a sufficient concentration to kill human ovarian cancer is not reached with a single i.p. bath containing 50 mg/m cisplatin for 2 h. A new protocol with a renewed bath and a higher cisplatin concentration is under investigation.

Sustained, low-dose intraperitoneal cisplatin improves treatment outcome in ovarian cancer mouse models

“…2) demonstrate that these cell lines are sensitive to an overall AUC range of 500 ng-day/mL to 2500 ng-day/mL. This is consistent with what is reported in the literature [20]. Figure 3A shows that the microdevice is able to release cisplatin at 37°C in vitro in a linear and reproducible fashion, without an initial burst (r 2 = 0.996, n = 3).…”

HIPEC ROC I: A phase i study of cisplatin administered as hyperthermic intraoperative intraperitoneal chemoperfusion followed by postoperative intravenous platinum‐based chemotherapy in patients with platinum‐sensitive recurrent epithelial ovarian cancer

“…These dose levels were chosen based on pilot and retrospective studies using cisplatin as HIPEC in patients with ovarian carcinoma. 19,20,27 Cisplatin at a dose of 100 mg=m 2 was pre-defined as the highest dose level based on phase III studies demonstrating efficacy with acceptable toxicity at this dose level as normothermic postoperative IP treatment. 5 Dose escalation proceeded according to a standard 313 dose-escalation design.…”

“…16 Robust dose-finding and pharmacokinetic data are scant. [17][18][19][20] Therefore, surgical cytoreduction and HIPEC is a rational but still experimental approach in the management of EOC.…”

The correlation of serum protein association and cellular uptake with lipophilicity and polarity of the backbone substituents of the technetium‐99m‐amine‐oxime chelates

“…It has been well known that lipophilicity is an key parameter that plays significant role in extracellular protein binding and in cellular uptake of a drug. [16][17][18][19][20] However, according to our observation in the experiment, 22 polarity of a substituent on the backbone of a molecule may also play a significant role as does the lipophilicity in protein and cellular binding. In order to investigate the roles of these two structural parameters, this work uses two series of amine-oxime chelates, which at one end of the backbone has an attachment of alkyl chains with different lengths and at the other end either a 2-NI or an aniline group ( Figure 1).…”

“…However, the tumor hypoxia selectivity and pharmacologic effectiveness of a radiotracer in many cases can be diminished by its nonspecific binding to proteins and normal organs in vivo, 14,15 while the level of those non-specific bindings is often determined by the same structural characters of the radiotracer as well. One of the important parameters is lipophilicity that in many circumstances influences the levels of a molecule binding to extracellular serum proteins, 16,17 the rates of penetrating through cellular membranes, 18,19 the affinity of associating to intracellular molecules such as enzymes and DNAs, 20 and the toxicity to cancer cells. 21 It needs to point out that in addition to lipophilicity the role of other parameters such as configuration, charge, and polarity of subsistent on the backbone of a radiotracer playing in cellular binding has not been well documented, while all of those structural characters and parameters can be related to the nature of the backbone substitutions of the radiotracer.…”