Pharmacokinetics Of Cisplatin Research Articles

Preliminary Open-Labeled Study to Examine the Effect of Cilastatin on the Pharmacokinetics of Cisplatin in Patients with Lung Cancer Undergoing Cisplatin-Based Chemotherapy

Preliminary Open-Labeled Study to Examine the Effect of Cilastatin on the Pharmacokinetics of Cisplatin in Patients with Lung Cancer Undergoing Cisplatin-Based Chemotherapy

Pharmacokinetics and Anti-Tumor Efficacy of PEGylated Liposomes Co-Loaded with Cisplatin and Mifepristone.

Although cisplatin is an effective chemotherapy drug used against many types of cancer, it has poor bioavailability, produces severe adverse effects, and frequently leads to tumor resistance. Consequently, more effective formulations are needed. The co-administration of cisplatin with mifepristone, which counters an efflux pump drug-resistance mechanism in tumor cells, has shown important synergism, but without resolving the problem of poor bioavailability. Specificity to tumor tissue and bioavailability have been improved by co-encapsulating cisplatin and mifepristone in a liposomal formulation (L-Cis/MF), which needs further research to complete pre-clinical requirements. The aim of this current contribution was to conduct a pharmacokinetic study of cisplatin and mifepristone in male Wistar rats after administration of L-Cis/MF and the conventional (unencapsulated) formulation. Additionally, the capacity of L-Cis/MF to reduce tumor growth in male nude mice was evaluated following the implantation of xenografts of non-small-cell lung cancer. The better pharmacokinetics (higher plasma concentration) of cisplatin and mifepristone when injected in the liposomal versus the conventional formulation correlated with greater efficacy in controlling tumor growth. Future research on L-Cis/MF will characterize its molecular mechanisms and apply it to other types of cancer affected by the synergism of cisplatin and mifepristone.

Theranostic Hyaluronan Coated EDTA Modified Magnetic Mesoporous Silica Nanoparticles for Targeted Delivery of Cisplatin

One of the eminent capabilities of nanoparticles in drug delivery is active targeting. Mesoporous silica nanoparticles (MSNs) are among the well-known nanocarriers, which have been utilized for gene and drug deliveries due to their particular physical and chemical properties. The present study aimed to introduce an engineered type of EDTA-modified Magnetic Mesoporous Silica Nanoparticles (MMSNs) with hyaluronan coating as a theranostic agent for delivery of an anti-cancer drug (cisplatin). EDTA was first applied as a ligand for platinum-based drug loading. The nanoparticles were synthesized in several steps. The properties of each step were characterized by various techniques such as Fourier transform infrared (FT-IR), X-Ray diffraction (XRD), vibrating sample magnetometer (VSM), and N2 adsorption/desorption. Morphology was also checked by field emission scanning electron microscopy (FE-SEM) and Transmission electron microscopy (TEM). In addition, loading capacity (LC) and loading efficiency, and in vivo release of cisplatin were analyzed through ICP-OES. Eventually, the plasma concentration profile and cisplatin pharmacokinetics parameters after intravenous administration of EDTA-MMSN @ HA were evaluated. The average particle diameters of prepared structure were approximate range of 70–100 nm. The profile release of cisplatin in acidic medium was faster in 72 h, which confirmed the pH-responsive behavior of the nanoparticles. As the results of cytotoxicity showed, coating with HA can improve the internalization of nanoparticles in cancer cells compared to normal cells. Finally, EDTA-MMSN @ HA can be introduced as a new favor biocompatible and biodegradable nanoplatform for targeted drug delivery which can improve pharmacokinetic parameters. Overall, this study successfully synthesized a novel multifunctional pH-responsive MSN for efficient drug delivery and magnetic resonance imaging.

Population pharmacokinetics of cisplatin in small cell lung cancer patients guided with informative priors

Cisplatin-etoposide treatment is recommended as a first line in small cell lung cancer patients (SCLC). However, the prognosis is poor and the dosing is not tailored beyond the body surface area, which is related with indeterminate cisplatin exposure-response relationship. We aimed to evaluate cisplatin pharmacokinetics (PK) and the exposure to unbound cisplatin in SCLC patients using the informative priors, and assess the relationship between the cisplatin exposure and probability of neutropenia. Observational clinical study was performed including 17 cisplatin-treated SCLC patients. External population cisplatin PK models were identified and NONMEM® software and $PRIOR subroutine were used for the model evaluation. The bias and precision of the model-predicted cisplatin concentrations were evaluated. The best models were combined in a final model including several sets of informative priors, which was used to estimate individual cisplatin exposure, analyze the relationship between the exposure and neutropenia and simulate several cisplatin dosing regimens in a virtual patient cohort. The models by Urien with the informative priors best fitted the data. The individual cisplatin exposure ranged between 2430 and 4560μg*h/L. There was a trend of increasing probability of neutropenia and febrile neutropenia with increasing cisplatin exposure. Approximately 50%, 75% and 90% of patients receiving 60mg/m2, 70mg/m2 and 80mg/m2, respectively, achieved the previously identified exposure threshold of 2860μg*h/L. We developed a tool to individualize cisplatin dosing based on the estimated probability of neutropenia. The benefit of more intense dosing regimens in SCLC patients should be further assessed.

The association of cisplatin pharmacokinetics and skeletal muscle mass in patients with head and neck cancer: The prospective PLATISMA study

BackgroundLocally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and increased toxicity has been described. This increased toxicity may be related to altered cisplatin distribution and binding in the fat-free body mass of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in patients with HNSCC. MethodsWe performed a prospective observational study in patients with HNSCC treated with CRT. Patients received standard-of-care chemotherapy with three cycles of cisplatin at a dose of 100 mg/m2 per cycle. Quantitative data on SMM, measured on computed tomography scans and cisplatin pharmacokinetics (total and ultrafilterable plasma concentrations) were collected, as well as data on toxicity. ResultsA total of 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose-limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and SMM, weight, fat-free mass and body surface area (p < 0.005). In a simulation, patients with a low SMM (<25.8 kg) were predicted to reach higher-bound cisplatin concentrations. ConclusionWe found an association between cisplatin pharmacokinetics and SMM; however, this relationship was also seen between cisplatin pharmacokinetics and other body composition descriptors.

Wedelolactone protects against cisplatin-induced nephrotoxicity in mice via inhibition of organic cation transporter 2.

The balance of cisplatin uptake and efflux, mediated mainly by organic cation transporter 2 (OCT2) and multidrug and toxin extrusion 1 (MATE1), respectively, determines the renal accumulation and nephrotoxicity of cisplatin. Using transporter-mediated cellular uptake assay, we identified wedelolactone (WEL), a medicinal plant-derived natural compound, is a competitive inhibitor of OCT2 and a noncompetitive inhibitor of MATE1. Wedelolactone showed a selectivity to inhibit OCT2 rather than MATE1. Cytotoxicity studies revealed that wedelolactone alleviated cisplatin-induced cytotoxicity in OCT2-overexpressing HEK293 cells, whereas it did not alter the cytotoxicity of cisplatin in various cancer cell lines. Additionally, wedelolactone altered cisplatin pharmacokinetics, reduced kidney accumulation of cisplatin, and ameliorated cisplatin-induced acute kidney injury in the Institute of Cancer Research mice. In conclusion, these findings suggest a translational potential of WEL as a natural therapy for preventing cisplatin-induced nephrotoxicity and highlight the need for drug-drug interaction investigations of WEL with other treatments which are substrates of OCT2 and/or MATE1.

Ultra-performance liquid chromatography-tandem mass spectrometry for simultaneous determination of 12 anti-tumor drugs in human plasma and its application in therapeutic drug monitoring

The effectiveness and safety of anti-tumor drugs are clinically important issues, and their therapeutic drug monitoring (TDM) is recommended. This study aimed to develop an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous TDM and exploration of clinical pharmacokinetics of anti-tumor drugs, including cyclophosphamide, ifosfamide, cisplatin, methotrexate, pemetrexed disodium, capecitabine, 5-fluorouracil, gemcitabine, doxorubicin, fulvestrant, tamoxifen, and irinotecan. After magnetic solid-phase extraction of plasma samples, the isotope internal standards and 12 anti-tumor drugs were separated using a ZORBAX Eclipse Plus C18 column (50.0 × 2.1 mm, 1.7 µm) with water containing 0.1% formic acid and acetonitrile as the mobile phase in a total run time of 5.0 min. The developed UPLC-MS/MS method was validated based on the Chinese Pharmacopoeia and the US Food and Drug Administration guidelines for bioanalytical method validation, including assessment of specificity, calibration curves, carryover, accuracy, crosstalk, precision, stability, recovery, dilution integrity, incurred sample reanalysis, and matrix effect. The results showed that a simple, fast, reliable, and specific UPLC-MS/MS method was developed and validated, and all the performance characteristics of the method met the requirements. The response function was established for concentration range of 0.10–25.00 μg/mL for gemcitabine, cyclophosphamide, ifosfamide, methotrexate, pemetrexed disodium, capecitabine, 5-fluorouracil, and cisplatin, and 0.05–12.50 μg/mL for doxorubicin, fulvestrant, tamoxifen, and irinotecan, with a coefficient of correlation of>0.9984 for all the compounds. The precision and accuracy of all the analytes were<6.5% and 5.9%, respectively. Hence, it could be used for TDM and exploration of pharmacokinetics of the aforementioned 12 anti-tumor drugs.

Altered cisplatin pharmacokinetics during nonalcoholic steatohepatitis contributes to reduced nephrotoxicity

Disease-mediated alterations to drug disposition constitute a significant source of adverse drug reactions. Cisplatin (CDDP) elicits nephrotoxicity due to exposure in proximal tubule cells during renal secretion. Alterations to renal drug transporter expression have been discovered during nonalcoholic steatohepatitis (NASH), however, associated changes to substrate toxicity is unknown. To test this, a methionine- and choline-deficient diet-induced rat model was used to evaluate NASH-associated changes to CDDP pharmacokinetics, transporter expression, and toxicity. NASH rats administered CDDP (6 mg/kg, i.p.) displayed 20% less nephrotoxicity than healthy rats. Likewise, CDDP renal clearance decreased in NASH rats from 7.39 to 3.83 mL/min, renal secretion decreased from 6.23 to 2.80 mL/min, and renal CDDP accumulation decreased by 15%, relative to healthy rats. Renal copper transporter-1 expression decreased, and organic cation transporter-2 and ATPase copper transporting protein-7b increased slightly, reducing CDDP secretion. Hepatic CDDP accumulation increased 250% in NASH rats relative to healthy rats. Hepatic organic cation transporter-1 induction and multidrug and toxin extrusion protein-1 and multidrug resistance-associated protein-4 reduction may contribute to hepatic CDDP sequestration in NASH rats, although no drug-related toxicity was observed. These data provide a link between NASH-induced hepatic and renal transporter expression changes and CDDP renal clearance, which may alter nephrotoxicity.

The association of skeletal muscle mass and cisplatin pharmacokinetics in head and neck cancer patients: The prospective PLATISMA study.

6021 Background: Locally advanced head and neck squamous cell carcinoma (HNSCC) is commonly treated with cisplatin-based chemoradiotherapy (CRT). Cisplatin is associated with severe toxicity, which negatively affects survival. In recent years, a relationship between low skeletal muscle mass (SMM) and toxicity has been described. This increased toxicity may be related to an altered cisplatin distribution and binding in the fat-free body mass, of which SMM is the largest contributor. This study aims to investigate the association between cisplatin pharmacokinetics and SMM in HNSCC patients. Methods: We performed a prospective observational study in HNSCC patients treated with CRT with cisplatin. Patients received standard-of-care chemotherapy with three cycles of cisplatin, at a dose level of 100 mg/m2 per cycle. Quantitative data on body size descriptors including SMM, measured on computed tomography scans, and cisplatin pharmacokinetics (total and ultrafilterable plasma concentration) were collected, as well as data on toxicity. Results: 45 evaluable patients were included in the study. A large proportion of the study population had a low SMM (46.7%). The majority of patients (57.8%) experienced cisplatin dose limiting toxicities. Pharmacokinetic analysis showed a significant relationship between cisplatin pharmacokinetics and the body size descriptors SMM, weight, fat-free mass, and body surface area ( p&lt; 0.005). In a simulation, patients with a low SMM were predicted to reach higher bound cisplatin concentrations. The higher concentration of bound cisplatin could be seen as a reflection of the smaller volume of distribution, and could thereby explain the increased toxicity in patients with a low SMM. Conclusions: We found an association between cisplatin pharmacokinetics and SMM. Patients with a low SMM were predicted to reach higher bound cisplatin concentrations, which could be an explanation for the increased toxicity in this patient group. Clinical trial information: Trial NL7469 (NTR7711).

Orphan Designation and Cisplatin/Hyaluronan Complex in an Intracavitary Film for Malignant Mesothelioma.

Pleural mesothelioma is a lung diffuse tumor, whose complete resection is unlikely. Consequently, metastases reappear where the primary tumor was removed. This paper illustrates the orphan medicine designation procedure of an intracavitary cisplatin film and related pharmaceutical development aspects requested by the European Medicines Agency (EMA) in its Scientific Advice. Since cisplatin pharmacokinetics from the implanted film in sheep resulted substantially modified compared to intravenous administration, the formation of a cisplatin/hyaluronan complex had been hypothesized. Here, the interaction between sodium hyaluronate (NaHA) and cisplatin (CisPt) was demonstrated. Size exclusion chromatography qualitatively evidenced the complex in the film-forming mixture, only showing the NaHA peak. Atomic absorption spectroscopy of the corresponding fraction revealed platinum, confirming the interaction. Reverse phase HPLC quantified about 5% free cisplatin in the film-forming mixture, indirectly meaning that 95% was complexed. Finally, a study of CisPt release from the film assessed how CisPt/NaHA complex affected drug availability. In water, a medium without chloride ions, there was no release and the film remained intact for 48 h and longer, whereas the placebo film dissolved in 15 min. In 0.9% NaCl medium, the film became more soluble, dissolving within 3–4 h. However, cisplatin release was still controlled by the existing complex in solution until chloride ions displaced it. While the film modified its dissolution with aging, CisPt release remained unaffected (90% released in 48 h).

Debulking and HIPEC for ovarian cancer: effects of perfusion temperature on morbidity and cisplatin pharmacokinetics

Background: In patients with stage III epithelial ovarian cancer (EOC), the addition of hyperthermic intraperitoneal chemoperfusion (HIPEC) to interval debulking was recently shown to improve survival compared to surgery alone. However, the added benefit of hyperthermia remains unknown. Here, we report secondary outcomes of the OvIP study (NCT02567253), a multicenter randomized trial investigating tumor tissue platinum penetration after normothermic (37°C) versus hyperthermic (41°C) chemoperfusion with cisplatin at 75 or 120 mg/m2.

Population pharmacokinetics and renal toxicity of cisplatin in cancer patients with renal dysfunction.

The pharmacokinetics (PKs) of cisplatin have not been investigated in patients with renal dysfunction, characterized by creatinine clearance (Ccr) < 60mL/min. In this study, we performed a population pharmacokinetic (PPK) analysis of unchanged cisplatin in patients with renal dysfunction. We investigated the effects of renal dysfunction on the PKs and nephrotoxicity of unchanged cisplatin. We enrolled 23 patients with moderate renal dysfunction (Ccr calculated to be 30-60mL/min using the Cockcroft-Gault formula) treated with cisplatin. PPK analysis was performed by nonlinear mixed effect modeling using NONMEM (Version 7.2). We evaluated gender, age, body surface area (BSA), weight, baseline Ccr, baseline serum creatinine (Scr), and baseline urea nitrogen as potential covariates. The final model was evaluated using bootstrap analysis. Renal toxicity was evaluated using Common Terminology Criteria for Adverse Events ver. 4.0. The frequency of severe renal dysfunction (Grade 3/4 Scr elevation) was measured in the population. A one-compartment model adequately described the unchanged cisplatin data. The population mean values for clearance (CLtot) and volume of distribution (Vd) were 19.1L/h [coefficient of variation (CV) 19.4%] and 13.8 L (CV 41.0%), respectively. The final model identified BSA as a significant covariate for CLtot. There were no significant covariates for Vd. No patients suffered from severe nephrotoxicity to the point that hemodialysis was required. Moderate renal dysfunction does not affect the PKs of unchanged cisplatin. The increased serum concentration of cisplatin may not lead to increased toxicity in patients with renal dysfunction. UMIN000007091 (January 17, 2012).

Concomitant lansoprazole ameliorates cisplatin-induced nephrotoxicity by inhibiting renal organic cation transporter 2 in rats.

Cisplatin is used widely for the treatment of multiple solid tumors. Cisplatin-induced nephrotoxicity is caused by renal accumulation of cisplatin via human organic cation transporter 2 (hOCT2). As lansoprazole, a proton pump inhibitor, is known to inhibit hOCT2 activity, lansoprazole might ameliorate cisplatin-induced nephrotoxicity. A previous study showed that concomitant lansoprazole administration ameliorated nephrotoxicity in patients receiving cisplatin. However, the detailed mechanism remains to be clarified. In the present study, the drug-drug interaction between lansoprazole and cisplatin was examined using hOCT2-expressing cultured cells and rat renal slices. Moreover, the effect of lansoprazole on cisplatin-induced nephrotoxicity and the pharmacokinetics of cisplatin in rats was investigated. In the uptake study, lansoprazole potently inhibited the uptake of cisplatin in hOCT2-expressing cultured cells and rat renal slices. The in vivo rat study showed that concomitant lansoprazole significantly ameliorated cisplatin-induced nephrotoxicity and reduced the renal accumulation of platinum up to approximately 60% of cisplatin alone at 72 h after cisplatin intraperitoneal administration. Furthermore, the renal uptake of platinum at 3 min after intravenous cisplatin administration in rats with cisplatin and lansoprazole decreased to 78% of rats with cisplatin alone. In addition, there was no significant difference in the plasma platinum concentration between rats treated with and without lansoprazole at 3 min after cisplatin intravenous administration. These findings suggested that concomitant lansoprazole ameliorated cisplatin-induced nephrotoxicity by inhibiting rOCT2-mediated cisplatin uptake in rats, thus decreasing cisplatin accumulation in the kidney. The present findings provided important information for the establishment of novel protective approaches to minimize cisplatin-induced nephrotoxicity.

Altered Cisplatin Pharmacokinetics during Nonalcoholic Steatohepatitis Contributes to Reduced Nephrotoxicity

Cisplatin is an alkylating antineoplastic agent that is indicated for the treatment of solid malignancies. Cisplatin is preferentially eliminated from systemic circulation via tubular secretion, whereby it exhibits dose‐limiting nephrotoxicity. Interindividual variability in xenobiotic transporter expression is a known contributor to differential cisplatin toxicity and efficacy, and may be the result of genetic, environmental, and pathological contributions. In this study, we aimed to determine if nonalcoholic steatohepatitis (NASH) alters cisplatin pharmacokinetics and if this change elicits differential nephrotoxicity. Sprague Dawley rats fed a control or methionine and choline deficient (MCD) diet to model NASH were given a single bolus dose of cisplatin and sacrificed after 72 h. The MCD diet resulted in a NASH hepatic phenotype that remained unchanged following cisplatin exposure. Drug‐naïve NASH rats also displayed no evidence of differential renal pathology relative to control rats. However, renal necrosis and inflammation were reduced in NASH by 40 and 63% following cisplatin treatment, respectively, relative to healthy controls. Furthermore, kidney weights of cisplatin‐treated control rats were increased by 31%, compared to an 18% increase in NASH. Plasma cisplatin clearance was reduced from 6.78 (control) to 4.04 mL/min in NASH, and cisplatin plasma AUC was significantly increased by 44% in NASH, relative to control. Cumulative urinary elimination of cisplatin was decreased from 73 to 34% of total dose and renal clearance was reduced from 4.64 to 1.49 mL/min in NASH, compared to control. Subsequently, renal intracellular accumulation of cisplatin after 6 h was reduced by 34% in NASH, relative to control. Supporting these findings, expression of proximal tubule cisplatin uptake transporters, Ctr1 and Ctr2, were reduced by 24 and 64%, respectively compared to healthy control rats, whereas expression of Oct1, Oct2, and Oct3 were unchanged. Interestingly, expression of cisplatin efflux transporters Mate1 and Atp7a were reduced by 52 and 31%, respectively, in NASH compared to control. Taken together, these data suggest that NASH alters renal uptake and efflux transporter expression, thereby attenuating cisplatin uptake and clearance in the kidney with a corresponding reduction in renal cell exposure and nephrotoxicity during NASH. As such, this study demonstrates that NASH can influence pharmacokinetics of drugs cleared by renal elimination, which may contribute to adverse drug reactions.Support or Funding InformationThis work is supported by a NIH grant [R01 ES028668] and the Southwest Environmental Health Sciences Center [P30 ES006694]. JLJ is supported by an institutional training grant [T32 ES007091].

Pharmacokinetics of cisplatin during open and minimally-invasive secondary cytoreductive surgery plus HIPEC in women with platinum-sensitive recurrent ovarian cancer: a prospective study.

ObjectiveEvidences from animal models seem to suggest that minimally invasive surgery may enhance cisplatin diffusion when the drug is administered in the context of post-operative hyperthermic intraperitoneal chemotherapy (HIPEC). The present study evaluates the cisplatin pharmacokinetic profile in a prospective series of women with platinum sensitive recurrent epithelial ovarian cancer treated with open secondary cytoreductive surgery (O-SCS) or minimally-invasive secondary cytoreductive surgery (MI-SCS).MethodsCisplatin levels were assessed at 0, 20, 40, 60, and 120 minutes in: 1) blood samples, 2) peritoneal perfusate, and 3) peritoneal biopsies at the end of HIPEC. Median Cmax has been used to identify women with high and low drug levels. Progression-free survival (PFS) was calculated as the time elapsed between SCS+HIPEC and secondary recurrence or last follow-up visit.ResultsNine (45.0%) women received MI-SCS, and 11 (55.0%) O-SCS. At 60 minutes, median cisplatin Cmax in peritoneal tissue was higher in patients treated with MI-SCS compared to O-SCS (Cmax=8.262 µg/mL vs. Cmax=4.057 µg/mL). Furthermore, median cisplatin plasma Cmax was higher in patients treated with MI-SCS compared to O-SCS (Cmax=0.511 vs. Cmax=0.254 µg/mL; p-value=0.012) at 120 minutes. With a median follow-up time of 24 months, women with higher cisplatin peritoneal Cmax showed a longer PFS compared to women with low cisplatin peritoneal levels (2-years PFS=70% vs. 35%; p-value=0.054).ConclusionsWe demonstrate for the first time that minimally invasive route enhances cisplatin peritoneal tissue uptake during HIPEC, further evaluations are needed to confirm the correlation between peritoneal cisplatin levels after HIPEC and survival.Trial RegistrationClinicalTrials.gov Identifier: NCT01539785

Pharmacokinetics of Cisplatin and its Metabolites Following Intravenous Administration in Cancer Patients of Bangladesh

Background: To determine the mean bioavailability of cisplatin at different time interval after intravenous administration of cisplatin of 18-60 years old 50 male Bangladeshi cancer patients.Materials &amp; Methods: Pharmacokinetic and demographic data were collected from 50 various types of male cancer patients received injection cisplatin 50 mg/m2 infusion for over 3 hours every alternate week for 3 weeks and mean population bioavailability were determined.Results: Statistical analysis from data of HPLC reported that the highest mean plasma concentration of cisplatin was found 428.32 μg/dl (±6.092) after 3 hours and highest mean urinary concentration of cisplatin was found 996.56μg/dl (±1.97) after 12 hours (P&lt;0.05). Highest and lowest concentration of four suspected metabolites (CM2, CM3, CM4 and CM5) were identified in blood and corresponding urine with their specific RT (retention time) and Area (P&lt;0.01) which suggestive of previous work.Conclusion: Following I/V administration plasma concentration of cisplatin at different time interval determined the proper dosing dosing interval of the drug and reduce toxicity.KYAMC Journal Vol. 9, No.-3, October 2018, Page 110-114

Phase II randomized study on tissue distribution of cisplatin according to different levels of intra abdominal pressure during HIPEC: Preliminary results. NCT02949791

Endpoints: To evaluate the effects of high intra-abdominal pressure (IAP) during HIPEC on 1) penetration of cisplatin into the residual neoplastic and normal tissues; 2) cisplatin pharmacokinetics; and 3) short-term surgical outcomes.

BIOPHISICAL MODEL OF ISOLATED LUNG CHEMOPERFUSION AND PHARMACOKINETICS OF CISPLATIN

The individualization of cytostatic agent dose is an actual problem in isolated lung chemoperfusion (ILP). Hitherto it has been carried out according to anthropometric data, in particular, the surface area of the body. A biophysical model of ILP based on diffusion cisplatin transfer in the lung is proposed. The model indicates to get the individual drug dose according to physical lung volume, which can be measured by CT-volumetry. Cisplatin pharmacokinetics and model compliance with actual data are considered on the material of 28 ILP. Estimates of lung interstitial and vascular space volumes and diffusion characteristic of capillary membrane are obtained.

Long After Chemotherapy, Cisplatin and Hearing Loss Remain

It is an unfortunate reality that cancer survivors face a lifetime of health consequences related to their cancer treatment. As the population of cancer survivors continues to grow, so does the importance of addressing their medical needs. For patients treated with the chemotherapeutic drug cisplatin, one common consequence of treatment is permanent hearing loss. Reported rates of cisplatin ototoxicity vary widely, though it is believed that at least half of all patients treated with cisplatin will suffer hearing loss. As cisplatin is widely used, this rate of ototoxicity translates to hundreds of thousands of patients affected each year in the United States alone.chemo, cancer, hearing lossAs was detailed in a recent article in this journal, efforts to prevent ototoxicity during cisplatin chemotherapy are ongoing (Hearing Journal. 2018;71(1):26). The success of these efforts likely hinges upon understanding why the cochlea is particularly susceptible to damage by cisplatin. Our recent study, reported in the journal Nature Communications, illustrates the importance of cisplatin pharmacokinetics—the movement of the drug within the body—in understanding ototoxicity (Nat Commun. 2017 Nov 21;8(1):1654). CISPLATIN OTOTOXICITY To effectively study cisplatin ototoxicity in the laboratory, we needed to be able to generate cisplatin-induced hearing loss in mice. Just as a patient receives multiple cycles of cisplatin, each separated by several days of recovery, so did the mice in our study. Auditory brainstem response and distortion product otoacoustic emission testing was performed on the mice, and it showed that cisplatin caused progressive hearing loss that worsened with each successive cycle of administration. Notably, hearing loss also continued to progress weeks after cisplatin administration was ceased, as has been reported for some human patients (J Pediatr Hematol Oncol. 2010 Mar;32(2):119; J Pediatr Hematol Oncol. 2004 Oct;26(10):649; Int J Pediatr Otorhinolaryngol. 2010 Aug;74(8):913). At the core of the cisplatin drug is the metal platinum. In fact, the name cisplatin (“cis-platinum”) is derived from the platinum that gives the drug its cancer-killing properties. This core platinum allowed us to measure tissue concentrations of cisplatin using a highly sensitive technique for detecting metals known as inductively coupled plasma mass spectrometry (ICP-MS). As the mice received successive cycles of cisplatin, drug concentrations across different organs were measured by ICP-MS. Most organs (like the liver, heart, kidney, etc.) effectively eliminated cisplatin in the days and weeks after the drug was given. However, cisplatin remained in the cochlea for much longer, showing no significant decrease in concentration even two months later. We went on to analyze postmortem inner ear tissue from human patients who had received cisplatin, and we found that the drug was retained in their cochleae even 18 months after treatment. In both the laboratory mice and these deceased patients, concentrations of retained cisplatin were highest in the stria vascularis region of the cochlea. This region is responsible for providing blood supply to the cochlea and for maintaining the composition of cochlear fluid. PREVENTIVE OPTIONS Our results demonstrated that over time the cochlea has a higher cumulative exposure to cisplatin than other organs and that, unlike other tissues, the cochlea has very little capacity for removing cisplatin. This may explain why the cochlea is particularly susceptible to cisplatin toxicity. For researchers working to develop a method of preventing cisplatin ototoxicity, our results suggest that the best method of preventing cisplatin ototoxicity may be via prevention of cisplatin uptake into the cochlea in the first place. Once inside the cochlea, cisplatin seems to be there to stay. Identification of drugs that block the uptake of cisplatin through the stria vascularis or directly bind and/or inactivate cisplatin as it enters the cochlea may be a viable path toward prevention of cisplatin ototoxicity. For audiologists, the results of our study underscore the importance of long-term hearing monitoring in patients who have received cisplatin therapy. Late-onset hearing loss is known to occur long after cessation of cisplatin treatment, and these study results suggest that this delayed hearing loss may be related to long-retained cisplatin in the cochlea. Until researchers make significant progress in preventing cisplatin ototoxicity in cancer therapy, it is crucial to continue identifying and treating cancer survivors with cisplatin-induced hearing loss.Andrew M. Breglio, DPhilLisa L. Cunningham, PhD

Resveratrol influences platinum pharmacokinetics: A novel mechanism in protection against cisplatin-induced nephrotoxicity

Cisplatin (CP) is a widely used drug in treatment of solid tumors. However, the use of CP was hampered by its serious side effects especially nephrotoxicity. This study aims to investigate the effect of resveratrol (RES) on CP-induced nephrotoxicity, particularly, the effect of RES on CP pharmacokinetics (PKs). Male white albino rats were divided to four group’s six rats each. The first group received (1%) tween 80 in normal saline and served as control. The second group received RES (30 mg kg−1) per day for 14 consecutive day’s i.p. The third and fourth groups were given a single i.p. injection of CP (6 mg kg−1) with or without pre-treatment of RES (30 mg kg−1per day for 14 consecutive days), respectively. Following administration of CP, plasma, urine and kidney platinum concentration were monitored to study PKs of CP. Five days after the CP injection, rats were killed; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CP treatment significantly deteriorated kidney functions with subsequent alteration in redox balance of the kidney. On the other hand, RES successfully ameliorated CP-induced kidney injury and recovered normal kidney tissue redox status. Importantly, while RES pre-treatment did not significantly alter the plasma CP level, it dramatically decreased the urine concentration of CP and lowered its accumulation into the kidneys. Moreover, it increased CP plasma half-life (t1/2) with subsequent decrease in its elimination rate constant, indicating an important role of PKs modulation in RES protection against CP-induced renal damage. Taken together, RES may protect the kidney tissue from the deleterious effects of CP through constringe of CP renal accumulation and enhancement of CP-induced oxidative stress.