A pilot study of chemotherapy combinations in rats: Focus on mammary cancer treatment in female dogs.

The use of combined chemotherapy is an essential alternative in treating breast cancer. However, knowledge of the pharmacokinetics of drugs is necessary to obtain maximum efficiency of the protocol and reduce adverse reactions. This study suggests for the first time the effect of the association of carboplatin with ivermectin and carboplatin with cyclophosphamide. This investigation was performed with 36 healthy Wistar rats, divided into four groups: group control, carboplatin (C), carboplatin preceded by ivermectin (C + IV), and carboplatin associated with cyclophosphamide (C + CI). Plasma concentrations quantification was performed using the High-Performance Liquid Chromatographic (HPLC) equipment with an Ultraviolet (UV) detector at eight different time points. Then, the animal was euthanized and necropsied. The bioanalytical method was validated for the two matrices (dogs and rats' plasma), with full validation in female dogs and partial validation in rats, as recommended by the EMA. In both matrices, the method was linear and reproducible. Here, we show the results in female rats' plasma. When comparing the experimental rats' groups (C; C + IV, and C + CI), there is a tendency to increase the bioavailability of carboplatin when used in association, a slight increase for C + IV and more evident to the C + CI group with an AUC rise higher than 2-fold (AUC0-∞ = 2983.61 for C; 4459.06 for C + CI; 7064.68 for C + CI min·mg·mL-1). The blood count, biochemistry profile, and histopathology of the organs revealed only alterations inherent to the metabolic effects of the drugs used. The carboplatin association with ivermectin appeared safe for this pilot group. We believe the carboplatin dose can be maintained without risk to the patient. However, in the carboplatin association with cyclophosphamide, a slight reduction in carboplatin's amount is suggested, seeking to avoid increased effects due to cyclophosphamide. Thus, studies with a more significant number per group must confirm the relevance of this pilot study.

Phase I study of weekly nab-paclitaxel plus carboplatin and concurrent thoracic radiotherapy in elderly patients with unresectable locally advanced non-small cell lung cancer.

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥ 75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m2). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m2 because two patients experienced dose-limiting toxicity at 40 mg/m2. The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8-100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2-21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077).

Carboplatin- and Etoposide-Loaded Lactoferrin Protein Nanoparticles for Targeting Cancer Stem Cells in Retinoblastoma In Vitro.

Purpose: Cancer stem cells (CSCs) are known to contribute to tumor relapses by virtue of their chemoresistance. With the knowledge that nanoformulations can overcome drug resistance, we evaluated the efficacy and cytotoxicity of clinical-grade carboplatin (CPT)- and etoposide (ETP)-loaded lactoferrin nanoparticles (Lf-Nps) on total, CD133-enriched (non-CSC), and CD133-depleted (CSC) populations of retinoblastoma (Rb) Y79 cells. Methods: Physicochemical properties of drug-loaded Lf-Nps were measured with transmission electron microscopy and attenuated total reflectance-Fourier transform infrared. The encapsulation efficiency, uptake, and release of drug-loaded Lf-Nps were measured using high-performance liquid chromatography and a UV-visible spectrophotometer. Cytotoxicity of the standard and drug-loaded Lf-Nps was evaluated by the MTT assay. Results: The mean (SD) size and encapsulation efficiency of Lf-CPT and Lf-ETP were 61.2 (3.94) nm, 60% and 45.15 (5.85) nm, 38%, respectively, and the drug release efficiency was highest at pH 6. The increased drug uptake and lower release of drug-loaded Lf-Nps were observed in CSC and non-CSC populations compared to their standard forms. The relative increase of drug uptake and sustained intracellular retention of the drug-loaded Lf-Nps compared to standard drugs showed an enhanced cytotoxicity up to 50%, especially in Rb Y79 CSCs (IC50: CPT, 230.3; Lf-CPT, 118.2; ETP, 198.1; and Lf-ETP, 129) compared to non-CSCs. Conclusions: Our study documents an increase in drug uptake, retention, and cytotoxicity of Lf-CPT and Lf-ETP on Y79 CSCs and non-CSCs as compared to their standard drugs in vitro. The reversal of chemoresistance in the CSC population by nanoformulation appears promising with the potential to pave the way for improved targeted therapy and better clinical outcomes.

Prodrug-based nano-delivery strategy to improve the antitumor ability of carboplatin in vivo and in vitro.

Chemotherapy plays a major role in the treatment of cancer, but it still has great limitations in anti-tumor effect. Carboplatin (CAR) is the first-line drug in the treatment of non-small cell lung cancer, but the therapeutic effect is demonstrated weak. Therefore, we modified CAR with hexadecyl chain and polyethylene glycol, so as to realize its liposolubility and PEGylation. The synthesized amphiphilic CAR prodrugs could self-assemble into polymer micelles in water with an average particle size about 11.8 nm and low critical micelles concentration (0.0538 mg·mL-1). In vivo pharmacodynamics and cytotoxicity experiment evidenced that the polymer micelles were equipped with preferable anti-tumor effect, finally attained the aim of elevating anti-tumor effect and prolonging retention time in vivo. The self-assembled micelles skillfully solve the shortcomings of weak efficacy of CAR, which provides a powerful platform for the application of chemical drug in oncology.

A prospective audit on the use of prophylactic antiemetics and rates of CINV in patients receiving carboplatin AUC≥4 or combination anthracycline-cyclophosphamide.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are two of the most frequently experienced and distressing side effects of cancer treatment. Recent updates by ESMO/MASCC and ASCO on guidelines for prevention of CINV have recommended the addition of a neurokinin-1 receptor antagonist to antiemetic regimens for patients receiving carboplatin-based chemotherapy area under the curve (AUC) ≥4 mg/mL per minute, and an addition of olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy. AIMS: To assess current use of prophylactic antiemetics and rates of CINV in patients under the care of MidCentral Regional Cancer Treatment Service (MRCTS) receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide. METHODS: Data was prospectively collected on patients under the care of MRCTS receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide chemotherapy, including breast cancer patients receiving 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Questionnaires were given to eligible patients to be completed daily from day two to day six of first cycle of chemotherapy only. Data on each patient's gender, age, types of chemotherapies, types of malignancies, presence of nausea or vomiting, number of dry retching or vomiting episodes and anti-emetics were recorded. RESULTS: From 15 September 2018 to 10 August 2019, a total of 44 patients receiving carboplatin-based chemotherapy AUC≥4 and 30 patients receiving combination anthracycline/cyclophosphamide were included. Twenty-two patients (50%) had either emesis or significant nausea in the overall and delayed phase when treated with carboplatin AUC≥4, and only three (7%) in the acute phase. Fourteen patients (56%) had either emesis or significant nausea in the overall phase when treated with FEC chemotherapy, mostly in the acute phase (13 patients) rather than in the delayed phase (9 patients). CONCLUSION: The rates of CINV are high with the existing antiemetic regimens used at MidCentral Regional Cancer Treatment Service. Therefore, in accordance with international guidelines, we will add a neurokinin-1 antagonist to the antiemetic regimens for patients receiving carboplatin-based chemotherapy AUC≥4, and olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy, in an attempt to improve the rates of CINV in these groups. Repeating this audit post-implementation of above recommendations will be important to assess for any improvement.

A phase I pharmacokinetic and safety study of Paclitaxel Injection Concentrate for Nano-dispersion (PICN) alone and in combination with carboplatin in patients with advanced solid malignancies and biliary tract cancers.

PURPOSE: Paclitaxel injection concentrate for nano-dispersion (PICN) is a Cremophor-free, nanotechnology-driven paclitaxel formulation. This phase I study examined the safety, tolerability, pharmacokinetics and maximum tolerated dose (MTD) of PICN alone and in combination with carboplatin. Its early efficacy in unresectable biliary tract cancers (BTCs) was also evaluated. METHODS: This multi-center study comprised two parts. Part A contained a dose-escalation cohort following "3 + 3" design using PICN monotherapy in advanced solid tumors (Part A1); Part A2 dose-expansion cohort was then conducted in advanced BTCs due to observed efficacy in Part A1. Part B1 and B2 evaluated escalating dose of PICN with carboplatin in advanced solid tumors. PICN was administered as a 30 min-infusion every 3 weeks without pre-medications for hypersensitivity reactions. RESULTS: Thirty-six patients received PICN monotherapy in Part A and 21 received PICN plus carboplatin in Part B. The MTD of PICN was determined to be 295 mg/m2 both as a monotherapy and in combination with carboplatin at AUC 5. Dose-proportional exposure in paclitaxel Cmax and AUC was observed overdose range from 175 to 325 mg/m2 for PICN monotherapy and its combination with carboplatin. Carboplatin did not alter PICN exposure. Clinically significant toxicities mainly include neutropenia and peripheral neuropathy. PICN monotherapy yielded a response rate of 20% in unresectable BTCs. CONCLUSION: This study demonstrated the safety and stable pharmacokinetics of PICN as a monotherapy and in combination with carboplatin. Single-agent PICN showed promising antitumor activity in advanced BTCs, warranting further studies to investigate its role in gastrointestinal cancers.

Two cycles of adjuvant carboplatin for clinical stage 1 testicular seminoma in New Zealand centres: A retrospective analysis of efficacy and long-term events.

BACKGROUND: Adjuvant carboplatin reduces relapse risk in clinical stage 1 (CS1) seminoma, though there is a paucity of long-term safety data. AIM: Our objective was to report long-term outcomes of two cycles of adjuvant carboplatin dosed at area under the time-concentration curve (AUC) of 7. METHODS AND RESULTS: We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at our centres in the Midland Region, New Zealand. Of 159 patients, median age 39 years, 153 received two cycles of carboplatin: 147 dosed at AUC7 and 6 at AUC6. Six patients had one cycle of carboplatin AUC7. One patient relapsed at 22 months and died of bleomycin pneumonitis 2 months after achieving a complete response with BEP chemotherapy. Neither RTI (present in 21.3%) nor tumor size >4 cm (in 43.3%) was predictive of relapse. Median follow-up was 106 months. At 15 years, outcomes were: relapse-free survival 99.4%, overall survival 91.4%, disease-specific survival 100%, subsequent malignant neoplasm rate 7.6%, and second testicular germ cell tumor rate 3.85%. One patient had persistent grade 1 thrombocytopenia at 46 months. CONCLUSIONS: These data add to the body of evidence that two cycles of carboplatin AUC7 is safe and effective adjuvant treatment for CS1 seminoma.

GSTP1 and ABCB1 Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel-Based Chemotherapy in Ovarian Cancer.

Variation in drug disposition genes might contribute to susceptibility to toxicities and interindividual differences in clinical management on chemotherapy for epithelial ovarian cancer (EOC). This study was designed to explore the association of GST and ABCB1 genetic variation with hematologic and neurologic toxicity, changes in chemotherapy, and disease prognosis in Brazilian women with EOC. A total of 112 women with a confirmed histological diagnosis of EOC treated with carboplatin/paclitaxel were enrolled (2014-2019). The samples were analyzed by multiplex polymerase chain reaction (PCR) for the deletion of GSTM1 and GSTT1 genes. GSTP1 (c.313A>G/rs1695) and ABCB1 (c.1236C>T/rs1128503; c.3435C>T/rs1045642; c.2677G>T>A/rs2032582) single nucleotide polymorphisms (SNPs) were detected by real-time PCR. Subjects with the GSTP1 c.313A>G had reduced risk of anemia (odds ratio (OR): 0.17, 95% confidence interval (CI): 0.04-0.69, P = 0.01, dominant model) and for thrombocytopenia (OR: 0.27, 95% CI: 0.12-0.64, P < 0.01; OR 0.18, 95% CI 0.03-0.85, P = 0.03, either dominant or recessive model), respectively. The GSTP1 c.313A>G AG genotype was associated with a lower risk of dose delay (OR: 0.35, 95% CI: 0.13-0.90, P = 0.03). The ABCB1 c.1236C>T was associated with increased risk of thrombocytopenia (OR: 0.15, 95% CI: 0.03-0.82, P = 0.03), whereas ABCB1 c.3435C>T had increased risk of grade 2 and 3 neurotoxicity (OR: 3.61, 95% CI: 1.08-121.01, P = 0.03) in recessive model (CC + CT vs. TT). This study suggests that GSTP1 c.313A>G, ABCB1 c.1236C>T, and c.3435C>T SNP detection is a potential predictor of hematological toxicity and neurotoxicity and could help predict the clinical management of women with EOC.

Predicting Chemotherapy-Induced Neutropenia and Granulocyte Colony-Stimulating Factor Response Using Model-Based In Vitro to Clinical Translation.

The ability to predict the incidence of chemotherapy-induced neutropenia in early drug development can inform risk monitoring and mitigation strategies, as well as decisions on advancing compounds to clinical trials. In this report, a physiological model of granulopoiesis that incorporates the drug's mechanism of action on cell cycle proliferation of bone marrow progenitor cells was extended to include the action of the cytotoxic agents paclitaxel, carboplatin, doxorubicin, and gemcitabine. In vitro bone marrow studies were conducted with each compound, and results were used to determine the model's drug effect parameters. Population simulations were performed to predict the absolute neutrophil count (ANC) and incidence of neutropenia for each compound, which were compared to results reported in the literature. In addition, using the single agent in vitro study results, the model was able to predict ANC time course in response to paclitaxel plus carboplatin in combination, which compared favorably to the results reported in a phase 1 clinical trial of 46 patients (r2 = 0.70). Model simulations were used to compare the relative risk (RR) of neutropenia in patients with high baseline ANCs for five chemotherapeutic regimens: doxorubicin (RR = 0.59), paclitaxel plus carboplatin combination (RR = 0.079), carboplatin (RR = 0.047), paclitaxel (RR = 0.031), and gemcitabine (RR = 0.013). Finally, the model was applied to quantify the reduced incidence of neutropenia with coadministration of pegfilgrastim or filgrastim, for both paclitaxel and the combination of paclitaxel plus carboplatin. The model provides a framework for predicting clinical neutropenia using in vitro bone marrow studies of anticancer agents that may guide drug development decisions.

Diversity of dose-individualization and therapeutic drug monitoring practices of platinum compounds: a review.

Introduction: Platinum-derived drugs are commonly used for the treatment of solid tumors. The differences in chemical structures of these molecules lead to different pharmacological properties, in terms of indication, efficacy, and toxicity. Their pharmacokinetics (PK) differ according to their respective renal elimination and have led to many studies investigating their dose optimization. Area covered: This review attempts to summarize and compare PK and pharmacodynamics of cisplatin, carboplatin, and oxaliplatin, with an emphasis on differences of dose calculations and opportunities for therapeutic drug monitoring (TDM) in various patient populations. Expert opinion: Although cisplatin and carboplatin can be considered as analogs since they share the same DNA interacting properties, the slower hydrolysis of the latter results in a better safety profile. Carboplatin is the only drug in oncology to be administrated according to a target area under the curve of concentration versus time, considering that its PK variability is almost fully explained by renal function, not by body size. This enables individual dosing based on predicted carboplatin clearance (along with patients renal characteristics) or on actual clearance with TDM, especially in a high-dose protocol.

Comparative Study of the Mode of Action of Clinically Approved Platinum-Based Chemotherapeutics.

Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cisplatin and oxaliplatin compared to carboplatin, with induction of apoptosis as the preferred mode of cell death. Gene expression profiling displayed modulation of genes related to DNA damage response/repair, cell cycle regulation and apoptosis which was more pronounced upon oxaliplatin treatment. Furthermore, repression of specific DNA repair genes was restricted to oxaliplatin. Transcriptional level observations were further analyzed on the functional level. Uptake studies revealed low intracellular platinum accumulation and DNA platination upon carboplatin treatment. Removal of overall DNA platination was comparable for the three drugs. However, no processing of oxaliplatin-induced interstrand crosslinks was observed. Cisplatin and carboplatin influenced cell cycle distribution comparably, while oxaliplatin had no effect. Altogether, we found a similar mode of action for cisplatin and carboplatin, while the activity of oxaliplatin appeared to differ. This might be clinically relevant as due to the difference in mode of action oxaliplatin could be active in tumors which show resistance towards cisplatin and carboplatin.

Evaluation of the pharmacokinetic drug-drug interaction potential of iohexol, a renal filtration marker.

PURPOSE: Carboplatin dose is calculated based on kidney function, commonly estimated with imperfect creatinine-based formulae. Iohexol is used to measure glomerular filtration rate (GFR) and allows calculation of a more appropriate carboplatin dose. To address potential concerns that iohexol administered during a course of chemotherapy impacts that therapy, we performed in vitro and in vivo pharmacokinetic drug-drug interaction evaluations of iohexol. METHODS: Carboplatin was administered IV to female mice at 60 mg/kg with or without iohexol at 300 mg/kg. Plasma ultrafiltrate, kidney and bone marrow platinum was quantitated by atomic absorption spectrophotometry. Paclitaxel microsomal and gemcitabine cytosolic metabolism as well as metabolism of CYP and UGT probes was assessed with and without iohexol at 300 µg/mL by LC-MS/MS. RESULTS: In vivo carboplatin exposure was not significantly affected by iohexol co-administration (platinum AUC combination vs alone: plasma ultrafiltrate 1,791 vs 1920 µg/mL min; kidney 8367 vs 9757 µg/g min; bone marrow 12.7 vs 12.7 µg/mg-protein min). Paclitaxel microsomal metabolism was not impacted (combination vs alone: 6-α-OH-paclitaxel 38.3 versus 39.4 ng/mL/60 min; 3-p-OH-paclitaxel 26.2 versus 27.7 ng/mL/60 min). Gemcitabine human cytosolic elimination was not impacted (AUC combination vs gemcitabine alone: dFdU 24.1 versus 23.7 µg/mL/30 min). Iohexol displayed no relevant inhibition of the CYP and UGT enzymes in human liver microsomes. CONCLUSIONS: Iohexol is unlikely to affect the clinical pharmacokinetics of carboplatin, paclitaxel, gemcitabine, or other agents used in combination with carboplatin treatment. Measuring GFR with iohexol to better dose carboplatin is unlikely to alter the safety or efficacy of chemotherapy through pharmacokinetic drug-drug interactions.

Pharmacogenomics for the efficacy of platinum-based chemotherapy: Old drugs, new integrated perspective.

Platinum-based chemotherapy remains the cornerstone of treatment for many malignancies. However, although therapeutic efficiency varies greatly among individuals, there is a lack of pharmacogenomic biomarkers that can be used in clinical settings to identify chemosensitive patients and allow stratification. With the development of high-throughput screening techniques and systems biology approaches, a growing body of evidence has shown that platinum resistance is a multifactorial, multi-dimensional, dynamic process incorporating genetic background, tumor evolution and gut microbes. This review critically summarizes potential pharmacogenomic biomarkers for predicting the efficacy of platinum drugs and provides a comprehensive, time-varying perspective that integrates multiple markers.

Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer.

Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.

Inability of Current Dosing to Achieve Carboplatin Therapeutic Targets in People with Advanced Non-Small Cell Lung Cancer: Impact of Systemic Inflammation on Carboplatin Exposure and Clinical Outcomes.

BACKGROUND: The presence of elevated systemic inflammation in people with advanced non-small cell lung cancer (NSCLC) is associated with significantly shorter survival following carboplatin-based chemotherapy. OBJECTIVE: This study investigated whether novel factors, such as systemic inflammation [platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR)], impact carboplatin pharmacokinetics and drug utilisation. The study also examined the ability of current and alternate dosing regimens to meet therapeutic targets. METHODS: Seventy-two people with advanced NSCLC treated with carboplatin-based (460-1050 mg) doublet chemotherapy were recruited and pharmacokinetic data (n = 61) were analysed using non-linear mixed modelling. Covariate analysis was performed to investigate the impact of standard and novel patient characteristics of carboplatin pharmacokinetics. A Monte Carlo simulation of 100,000 representative NSCLC patients evaluated the ability of the Calvert formula and novel dosing strategies to achieve the targeted therapeutic range. The associations between systemic inflammation and chemotherapy drug utilisation (cycles received, relative dose intensity (RDI) and second-line uptake) and clinical endpoints were also investigated in the pharmacokinetic cohort, and two independent cohorts of people with advanced NSCLC from the Chemotherapy Dosing in Cancer-Related Inflammation (CDCRI) database that were administered carboplatin-paclitaxel (n = 37) or carboplatin-gemcitabine (n = 358). RESULTS: In all cohorts, 25-53% of people had elevated systemic inflammation (NLR > 5 or PLR > 300). In the pharmacokinetic cohort, no patients achieved the desired therapeutic target of carboplatin. Carboplatin exposure was related to renal function, as estimated using the Cockcroft-Gault formula, albumin and inflammation (NLR). In the pharmacokinetic cohort, increasing carboplatin area under the curve (AUC) correlated with greater reductions in red blood cells and haemoglobin. In this cohort, the average measured AUC of partial responders was 2.4 mg·min/mL. Also in the pharmacokinetic cohort, only 12% of people with an NLR > 5 received four or more cycles of chemotherapy, compared with 62% of patients with an NLR ≤ 5 (p < 0.001). For people in the CDCRI cohort receiving carboplatin-gemcitabine, those with an NLR > 5 also received less cycles (four or more cycles, 41% vs. 60%; p < 0.01) as well as less second-line chemotherapy (46% vs. 60%; p = 0.02) compared with patients without inflammation. People in the pharmacokinetic cohort with an NLR > 5 had 12 months less median survival compared with people with an NLR ≤ 5 (6.5 vs. 18 months; p = 0.08). Similarly, overall survival was significantly shortened in people in the CDCRI cohort receiving carboplatin-gemcitabine with an NLR > 5 compared with those with an NLR ≤ 5 (7 vs. 12 months; p < 0.001), and Cox regression analysis showed a 1.5-fold (1.3-2.1; p < 0.001) increased hazard of death associated with the increased systemic inflammation. Simulations of the newly developed model-based and Calvert dosing assessed the ability to reach this study's proposed actual target AUC of 2.2-2.6 mg·min/mL. These showed current Calvert dosing was predicted to result in substantial overexposure in patients with high systemic inflammation. The newly developed model showed equivalent levels of carboplatin therapeutic target achievement across the spectrum of inflammation observed in the lung cancer population. CONCLUSION: An alternate model-based dosing strategy for carboplatin was developed and is predicted to result in consistent drug exposure across the population and improve attainment of therapeutic targets. Further studies of this new model are warranted in people with advanced NSCLC.

Investigating current practices in renal function measurement and carboplatin dosing in children with cancer - a UK perspective.

Renal function-based carboplatin dosing is a well-accepted practice in pediatric oncology. However, the accuracy of this approach is only as precise as the method of kidney function measurement, most commonly involving determination of glomerular filtration rate (GFR). Recent work by the Children's Oncology Group has raised concerns over nuclear medicine-based methodologies used to calculate GFR across US clinical centers. Current practices of GFR measurement, methods used to calculate carboplatin dosage and the utility of therapeutic drug monitoring were investigated in 21 UK primary pediatric oncology treatment centers through a questionnaire-based study. Information obtained was compared to results previously published in 2008 following a similar survey. In relation to GFR measurement, the main changes observed were a shift toward a greater number of samples being taken following tracer administration and an increase in number of centers using the Brochner-Mortensen correction factor. In relation to the use of renal function assessment data to inform dosing, EDTA elimination half-life in conjunction with body weight was used to calculate carboplatin dose in 18/21 (86%) centers, with uncorrected GFR and body weight utilized in 9/21 (43%) centers. A total of 14/21 (67%) centers utilize therapeutic drug monitoring approaches to carboplatin treatment in defined patient groups including neonates and infants. Results suggest that while GFR measurement across UK centers is relatively consistent, some uncertainties remain. In addition, for patient sub-populations where there are concerns over the potential for marked inter-patient variability in carboplatin exposures, adaptive dosing approaches are now well established.

Delivery and Effectiveness of Carboplatin via Targeted Delivery Compared to Passive Accumulation of Intravenously Injected Particles Releasing Carboplatin upon Irradiation.

In this study, nanoparticles that release anticancer drugs upon irradiation were developed. Here, MM46 and MM48 tumors in C3He/N mice were irradiated. Furthermore, the intravenously (i.v.) injected nanoparticles were tested for their ability to deliver the anticancer drug, increase the antitumor effect via a synergistic effect of combining targeted anticancer drugs with radiation and decrease adverse effects by localizing the anticancer drug. The nanoparticles were prepared by spraying a mixture of hyaluronic acid and alginate, supplemented with carboplatin, into a solution of CaCl2 and FeCl2 through a 0.8-lm-pore stainless mesh filter. Nanoparticles (1 × 1010) were i.v. injected and irradiated (100-KeV soft X rays, 10-40 Gy) when the accumulation of particles peaked. The nanoparticles were 547 ± 43 nm in diameter. The i.v.-injected nanoparticles accumulated around tumors. Maximum accumulations were observed 9 h post-injection. Subsequently, 10-40 Gy of radiation was administered. The accumulated nanoparticles released the carboplatin and gelatinized their outer shells, which prolonged the intra-tumor concentration of carboplatin and increased the radiation-induced synergistic antitumor effect. The localization of carboplatin by nanoparticles significantly reduced the adverse effects of the anticancer drug.

Evaluation of pharmacokinetics and safety of cetuximab with cisplatin/carboplatin in patients with advanced solid tumor: Result from phase II studies.

The pharmacokinetics and potential drug-drug interactions between cetuximab and cisplatin or carboplatin from two studies (JXBA and JXBB) were evaluated. These studies were multicenter, open-label phase II trials designed to evaluate the drug-drug interactions between cetuximab (400 mg m-2 initial dose) and cisplatin (JXBA; 100 mg m-2) or carboplatin (JXBB; area under the curve [AUC] = 5 mg × min mL-1) with or without 5-fluorouracil (5FU) in patients with advanced solid tumors. Concentrations of cetuximab, cisplatin and carboplatin were determined using analytical methods. The safety and tolerability of cetuximab in combination with cisplatin or carboplatin was also determined in all treated patients. The JXBA study showed that cetuximab serum concentrations were similar when cetuximab was administered alone or in combination with cisplatin. The Cmax, tmax and overall AUC for the cetuximab group (194 µg mL-1, 2.0 hour, 14 900 µg × h mL-1) and the cetuximab and cisplatin combination group (192 µg mL-1, 1.99 hour, 16 300 µg × h mL-1) were similar. The JXBB study showed that mean cetuximab serum concentrations were similar when cetuximab was administered alone or in combination with carboplatin. The Cmax, tmax and overall AUC for the cetuximab group (199 µg mL-1, 1.15 hour, 17 200 µg × h mL-1) and the cetuximab and carboplatin combination group (199 µg mL-1, 3.17 h, 16 800 µg × h mL-1) were similar. Both studies showed that the safety profile was consistent with known side effects of cetuximab, platinum-based therapies and 5-FU. There was no clinically relevant change in cetuximab pharmacokinetics when it was administered in combination with cisplatin or carboplatin.

Investigations of the Kinetics and Mechanism of Reduction of a Carboplatin Pt(IV) Prodrug by the Major Small-Molecule Reductants in Human Plasma.

The development of Pt(IV) anticancer prodrugs to overcome the detrimental side effects of Pt(II)-based anticancer drugs is of current interest. The kinetics and reaction mechanisms of the reductive activation of the carboplatin Pt(IV) prodrug cis,trans-[Pt(cbdca)(NH3)2Cl2] (cbdca = cyclobutane-1,1-dicarboxylate) by the major small-molecule reductants in human plasma were analyzed in this work. The reductants included ascorbate (Asc), the thiol-containing molecules L-cysteine (Cys), DL-homocysteine (Hcy), and glutathione (GSH), and the dipeptide Cys-Gly. Overall second-order kinetics were established in all cases. At the physiological pH of 7.4, the observed second-order rate constants k' followed the order Asc << Cys-Gly ~ Hcy < GSH < Cys. This reactivity order together with the abundances of the reductants in human plasma indicated Cys as the major small-molecule reductant in vivo, followed by GSH and ascorbate, whereas Hcy is much less important. In the cases of Cys and GSH, detailed reaction mechanisms and the reactivity of the various protolytic species at physiological pH were derived. The rate constants of the rate-determining steps were evaluated, allowing the construction of reactivity-versus-pH distribution diagrams for Cys and GSH. The diagrams unraveled that species III of Cys (-SCH2CH(NH3+)COO-) and species IV of GSH (-OOCCH(NH3+)CH2CH2CONHCH(CH2S-)- CONHCH2COO-) were exclusively dominant in the reduction process. These two species are anticipated to be of pivotal importance in the reduction of other types of Pt(IV) prodrugs as well.

Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model.

The blood-brain barrier (BBB) restricts delivery of most chemotherapy agents to brain tumors. Here, we investigated a clinical focused ultrasound (FUS) device to disrupt the BBB in rats and enhance carboplatin delivery to the brain using the F98 glioma model. Methods: In each rat, 2-3 volumetric sonications (5 ms bursts at 1.1 Hz for 75s) targeted 18-27 locations in one hemisphere. Sonication was combined with Definity microbubbles (10 µl/kg) and followed by intravenous carboplatin (50 mg/kg). Closed-loop feedback control was performed based on acoustic emissions analysis. Results: Safety and reliability were established in healthy rats after three sessions with carboplatin; BBB disruption was induced in every target without significant damage evident in MRI or histology. In tumor-bearing rats, concentrations of MRI contrast agent (Gadavist) were 1.7 and 3.3 times higher in the tumor center and margin, respectively, than non-sonicated tumors (P<0.001). Tissue-to-plasma ratios of intact carboplatin concentrations were increased by 7.3 and 2.9 times in brain and tumor respectively, at one hour after FUS and 4.2 and 2.4 times at four hours. Tumor volume doubling time in rats receiving FUS and carboplatin increased by 96% and 126% compared to rats that received carboplatin alone and non-sonicated controls, respectively (P<0.05); corresponding increases in median survival were 48% and 66% (P<0.01). Conclusion: Overall, this work demonstrates that actively-controlled BBB disruption with a clinical device can enhance carboplatin delivery without neurotoxicity at level that reduces tumor growth and improves survival in an aggressive and infiltrative rat glioma model.