Carboplatin Infusion Research Articles

口腔, 中咽頭癌のターゲット動注カルボプラチン化学放射線照射とテガフール/ウラシル療法

The aim of this study was to evaluate the usefulness of targeted intra-arterial carboplatin chemoradiotherapy in allowing less invasive surgery for patients with oral and oropharyngeal squamous cell carcinoma. Twenty patients with previously untreated squamous cell carcinoma of the oral cavity and oropharynx (T4; 8, T2; 12 patients) were treated with targeted transfemoral intra-arterial carboplatin infusion with concurrent hyperfractionated radiotherapy and the administration of tegafur/uracil (UFT). Of 20 patients, 15 underwent surgery after completion of one course of targeted chemoradiotherapy, and five were given another course or radiotherapy only. Eighteen (90%) of 20 patients had a clinically complete response at the primary site and two (10%) had a partial response. Of the 15 patients who underwent tumor resection, 11 (73%) showed histopathological disappearance of cancer cells at the primary site. Sixteen (80 %) of 20 tumors were controlled at the primary site within a mean follow-up of 30 months. Adverse effects were relatively mild. Targeted intra-arterial chemoradiotherapy caused a down-staging of tumors and facilitated the use of less invasive surgery in patients with squamous cell carcinoma of the oral cavity and oropharynx as a result of its favorable anti-tumor effect.

744 POSTER Hepatic arterial infusion of carboplatin mixed with degradable starch microspheres by using implanted reservoir in patients with advanced hepatocellular carcinoma

744 POSTER Hepatic arterial infusion of carboplatin mixed with degradable starch microspheres by using implanted reservoir in patients with advanced hepatocellular carcinoma

A Phase I study of concurrent RMP‐7 and carboplatin with radiation therapy for children with newly diagnosed brainstem gliomas

Ninety percent of children with diffuse, intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit to these children, and a potential way to improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing; however, its delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The objective of this Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy to children with newly diagnosed, diffuse, intrinsic brainstem gliomas. RMP-7 was given prior to the end of carboplatin infusion. Local radiotherapy, in dose fractions of 180 centigrays (cGy) per day (to a total dose of 5940 cGy), was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion in cohorts of 3 patients, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, and their median age was 7 years (age range, 3-12 yrs). One child died early during treatment of progressive disease and was not assessable for toxicity. Treatment for 3 weeks, 4 weeks, and 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. One of 3 children treated at the full duration of therapy (33 doses over 7 weeks) developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival was 328 days, and 1 patient remained free of disease progression for > 400 days after the initiation of treatment. The results of this study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy to children with brainstem tumors.

Phase 1 study of concurrent RMP-7 and carboplatin with radiotherapy for children with newly diagnosed brainstem gliomas

Ninety percent of children with diffuse intrinsic brainstem tumors will die within 18 months of diagnosis. Radiotherapy is of transient benefit, and one way to potentially improve its efficacy is to add radiosensitizers. Carboplatin is antineoplastic and radiosensitizing. However, delivery to the primary tumor site is problematic. RMP-7 is a bradykinin analog that causes selective permeability of the blood-brain-tumor interface. The goal of the current Phase I study was to determine the toxicity and feasibility of delivering RMP-7 and carboplatin for 5 successive days during radiotherapy. RMP-7 was given before the end of carboplatin infusion. Local radiotherapy (5940 centigrays) was given within 4 hours of completion of drug delivery. Duration of treatment was escalated in a stepwise, weekly fashion, in cohorts of 3, until there was treatment-limiting toxicity or until radiotherapy was completed. Thirteen patients were treated, whose median age was 7 years (range, 3-14 yrs). One child died early in treatment of progressive disease and was not assessable for toxicity. Treatment for 3, 4, or 5 weeks was tolerated well, with mild flushing, tachycardia, nausea, emesis, dizziness, and abdominal pain. Of 3 children treated at the full duration of therapy (33 doses over 7 wks), 1 developed dose-limiting hepatotoxicity and neutropenia. The estimated median survival period was 328 days, and 1 patient remained disease progression free > 400 days from initiation of treatment. The results of the current study confirmed the feasibility of giving RMP-7 and carboplatin daily during radiotherapy.

Intraperitoneal carboplatin infusion may be a pharmacologically more reasonable route than intravenous administration as a systemic chemotherapy. A comparative pharmacokinetic analysis of platinum using a new mathematical model after intraperitoneal vs. intravenous infusion of carboplatin—A Sankai Gynecology Study Group (SGSG) study

Objective. To clarify the pharmacological advantage of carboplatin-based intraperitoneal chemotherapy using the three-compartment mathematical model. Methods. Eleven consecutive patients in one institution underwent intraperitoneal administration of carboplatin, and 11 consecutive patients in another institution received intravenous administration. Carboplatin (AUC = 6 mg × min/ml) was diluted in 500 ml 5% glucose and administered either as an intraperitoneal bolus infusion or intravenous drip infusion during 1 h. Patients undergoing intravenous injection also received an infusion of 500 ml 5% glucose to obtain intraperitoneal samples. Intraperitoneal fluid and blood samples were obtained, immediately and 1, 2, 4, 8, 12, and 24 h after administration. The mathematical model consisting of a three-compartment model was applied to analyze the pharmacokinetics. The model was created with simultaneous differential equations and was solved by the Runge–Kutta method. Results. The rate constants of platinum diffusion from the peritoneal cavity to serum, serum to peritoneal cavity, serum to peripheral space, peripheral space to serum, and elimination were 0.94 ± 0.79 (mean ± SD), 1.28 ± 2.50, 16.50 ± 9.26, 0.99 ± 0.62, and 4.14 ± 1.45 (h −1), respectively. When the theoretical pharmacological concentration of platinum was calculated using this mathematical model, 24-h platinum AUC in the serum was exactly the same regardless of intraperitoneal or intravenous administration of carboplatin. However, the 24-h platinum AUC in the peritoneal cavity was approximately 17 times higher when carboplatin was administered by the intraperitoneal route. Conclusion. The present pharmacological analysis suggests that intraperitoneal infusion of carboplatin is feasible not only as an intraperitoneal regional therapy but also as a more reasonable route for systemic chemotherapy.

Phase II study of prolonged ambulatory infusion carboplatin and oral etoposide for patients progressing through hormonal therapy for prostate cancer

To develop a well-tolerated outpatient chemotherapy regimen for hormone-insensitive prostate cancer. Forty patients received carboplatin 20 mg/m2 by continuous ambulatory infusion with oral etoposide 50 mg/day for 21 days repeated every 6 weeks. Four patients had a partial response and 16 patients had stable disease. Two of the partial responders and three additional patients recorded falls in prostate specific antigen of 50% or more. The median freedom from progression was 24 weeks and median survival 32 weeks. Twenty-four of 31 patients had decreasing pain scores and 20 of 34 patients recorded improved quality of life with at least one cycle of treatment. The main toxicity occurred in seven patients with World Health Organization (WHO) grade 4 neutropenia and in four patients with WHO grade 3 neutropenia. Only one patient developed febrile neutropenia. Six patients had grade 3 anaemia and three patients had grade 3 thrombocytopenia. Two patients reported grade 3 lethargy whereas 11 patients had grade 2 lethargy. This was a well-tolerated regimen that improved symptomatic control of hormone-insensitive prostate cancer.

Carboplatin Administration in Sulphur-crested Cockatoos (Cacatua galerita): Clinical Observations

To determine the clinical effect of systemic carboplatin administration in birds, 6 sulphur-crested cockatoos (Cacatua galerita) were anesthetized and infused intravenously or intraosseously with carboplatin at 5 mg/kg over 3 minutes. Four birds were euthanatized 96 hours after infusion and 2 birds given an intravenous dose were euthanatized 21 days after dosing. All birds tolerated the anesthesia and carboplatin infusion and recovered uneventfully. At 24 hours after dosing, all birds were bright and active. Within 12 hours of dosing, feed intake was reduced and 3 birds vomited, but these signs abated by 48 hours after dosing. Mean body weight decreased by 4% at 24 hours after dosing and continued to decrease, but not significantly, until 96 hours after dosing. Changes in packed cell volume (PCV) and plasma total solids reflected blood loss caused by sampling. The mean PCV decreased significantly by 6 hours after dosing, and the concentration of plasma total solids decreased significantly at 1 hour after dosing and continued to decrease until 12 hours after dosing before progressively and significantly increasing toward baseline values by 96 hours after dosing. At necropsy, myelosuppression was not observed in any bird and no evidence of carboplatin toxicity was found. These results provide veterinarians with useful data for formulating efficacious and safe protocols for platinum-containing compounds when treating neoplasia in parrots and other companion birds.

Hemapoietic, immunomodulatory, antitumor, and toxicity profiles of sequential GM-CSF and IFNγ1b biotherapy and carboplatin in recurrent ovarian carcinoma

5053 Background: Monocyte/macrophages (MO/MA) are an important population of innate immune effector cells. The goal was to develop an acceptable chemoimmunotherapy regimen for ovarian carcinoma (OC) patients based on mobilization and maturation of MO/MA. Methods: Eligibility: recurrent measurable tumors, chemo-free interval ≥ 6mos, ≤ 2 chemo regimens. Immunomodulatory regimen: GM-CSF (Leukine, Berlex) starting at 400 mcg/day SC for 7 days with IFNγ1b (Actimmune, Intermune) at 100mcg SC on days 5 and 7 administered prior to and 24 hours post chemotherapy (carboplatin Paraplatin AUC 5 IV) every cycle. Immune parameters: measured by FACS analysis of MO/MA, DC, and major subsets. MA mediated tumor cell (TC) cytotoxicity and ADCC against Her2neu+ TCs measured by 3-H thymidine incorporation. Quality of life (QOL): measured using the Functional Assessment of Cancer Therapy - General and Biologic Response Modifiers (FACT-G and FACT-BRM) at 3 time points in cycle one and at 2 time points in subsequent cycles. Results: Twenty-five patients, who completed ≥ 3 courses, were evaluated in this preliminary report. Six and 4 of 25 patients (40%) experienced CR and PR, respectively. Four patients were removed from the study due to severe carboplatin allergy (2 pts), grade 3 liver toxicity (1 pt), and grade 3 fatigue (1 pt). There were significant increases in mean absolute numbers of WBC, granulocytes, and MO from baseline to d+9 after carboplatin infusion for cycle #1 (p<0.001, p<0.001, and p=0.001, respectively). There was no change in the mean platelet levels through cycle #3 (p=0.13). The numbers of certain activated MO/MA subsets were also increased but without enhancement of direct cytotoxicity or ADCC. There was no effect on general QOL, though BRM specific symptoms were significantly suppressed (p=0.03). Conclusions: This novel regimen of GM-CSF, IFNγ, and carboplatin in OC patients has an acceptable toxicity profile, while significantly increasing absolute numbers of MO and granulocytes with a shift toward more differentiated cells. Further accrual will determine response rate, time to progression, and feasibility for future development and MO/MA functionality. No significant financial relationships to disclose.

Combined Systemic Chronotherapy and Hepatic Artery Infusion for the Treatment of Metastatic Colorectal Cancer Confined to the Liver

Background: The optimal treatment of patients with metastatic colorectal cancer is still a clinical challenge. We describe the use of combined hepatic arterial infusion (HAI) of irinotecan (CPT-11) in conjunction with systemic chronotherapy infusion of 5-fluorouracil (5FU), folinic acid and carboplatin in patients with colorectal liver metastases. Methods: Twenty-three patients with colorectal cancer and isolated liver metastases were enrolled in this trial. Intraoperative insertion of an intra-arterial catheter into the hepatic artery was accomplished during the colon operation (in cases of synchronous tumor) or as a separate procedure in colorectal cancer patients with newly diagnosed liver metastases. A systemic double-lumen double-chamber port was inserted via the subclavian vein as a separate procedure. The treatment plan included irinotecan given by intra-arterial infusion at 150 mg/m² for 1 h. After 2 weeks of rest chronomodulated 5FU (700 mg/m²; peak delivery rate at 04:00 h), leucovorin (175 mg/m²; peak delivery rate at 04:00 h) and carboplatin (40 mg/m²; peak delivery rate at 16:00 h) for 4 days was followed by 10 days’ rest and then given again. After 10 days’ rest another HAI was introduced using the same method. Each cycle of therapy included 2 HAI courses and 2 chronotherapy courses in between. After 2 complete cycles, patients were evaluated for their response with weekly accessed toxicity recording. Results: Seven women, 8 men, median age 61 years (range 46–72). Eight patients had synchronous colon and hepatic disease and 7 patients had metachronous disease. Ten patients had previously been treated with 5FU and leucovorin while 5 patients were chemonaive. The mean number of cycles were 11.6 per patient (range 8–19). Partial response was achieved in 6 patients (40%) and was followed by laparoscopic radiofrequency ablation in 5 patients (33%). Disease stabilization was observed in 2 patients (13%) and disease progression in 7 patients (47%) mainly after previous chemotherapy failure. Side effects were infrequent and mild including grade 2 GIT complaints (5 patients), RUQ pain during HAI (9 patients) and grade 2 hematological complaints in 2 patients. Conclusion: A combined chemotherapy protocol (HAI and chronotherapy) with irinotecan (CPT-11) together with chronomodulated infusion of 5FU, folinic acid and carboplatin can be used in metastatic colorectal patients with a high efficacy rate and minor side effects especially in pretreated patients.

Results of the Combined Treatment with Piroxicam and Carboplatin in Canine Oral Non‐Tonsillar Squamous Cell Carcinoma

Introduction: Over‐expression of COX‐2 has been observed in several human and animal malignancies and is implicated in carcinogenesis through the conversion of arachidonic acid to PGE‐2. Use of platinum‐containing cytostatic agents and/or (non‐)specific COX‐2 inhibitors, has been reported as a treatment option for canine oral non‐tonsillar squamous cell carcinomas (ONT‐SCC). However, no study describes the effect of a combination of carboplatin and piroxicam on this tumor type.Methods: 7 dogs with a T3 (WHO‐TNM) ONT‐SCC were treated with piroxicam and carboplatin. Five had bone involvement and no detectable metastasis. Two dogs without bone involvement had metastasis in the regional lymph nodes. Piroxicam was given orally 0.3 mg/kg s.i.d. Each dog was scheduled to receive between 6 and 12 carboplatin infusions (300 mg/m2 i.v.) at 3 week intervals. Ondansetron and metoclopramide were used as anti‐emetic agents. The dogs are planned to receive piroxicam on a lifelong basis.Results: Complete response (CR) without adjuvant surgery was achieved in 4 of the 7 dogs. Two dogs needed adjuvant surgery to achieve CR. One dog had progressive disease and was euthanised 231 days after start of therapy. All the others were still alive and in CR at date of analysis. Median follow‐up was 335 days (107–689 days).Conclusions: Our study suggests that a combination of piroxicam and carboplatin is a useful treatment option for canine ONT‐SCC. All dogs tolerated therapy well and the 57% response rate for reaching a complete and durable remission without adjuvant surgery is promising.

Long-term Effects of Carboplatin Brainstem Infusions on Hearing Thresholds in Monkeys

To isolate the central auditory neurotoxicity of carboplatin from its well-established ototoxic effects. The "best-case scenario" of targeted drug delivery to brain cancer was simulated by infusing carboplatin directly into the brainstem of cynomolgus monkeys with chronically implanted catheters. Because this manner of drug administration produced low levels of carboplatin in spinal fluid and blood, it was assumed that resulting deficits were dictated by the central auditory neurotoxicity of platinum compounds and not peripheral ototoxic effects. The magnitude of this hearing loss was estimated by comparing the auditory brainstem response thresholds of treated monkeys with results from normal controls. Six adult male cynomolgus monkeys (Macaca fascicularis) weighing 4 to 6 kg (3 received carboplatin treatment and 3 served as normal controls). Brainstem infusions of carboplatin. The average threshold of carboplatin-treated monkeys was elevated 8.8 dB (SD = 7.3 dB) relative to normal controls 6 months after the termination of drug delivery and increased to 10.7 dB with less variation between subjects (SD = 5.6 dB) 1 year after drug treatment. Although small in magnitude, the hearing loss was statistically significant (P<.05). Brainstem infusions of carboplatin induced some degree of hearing impairment in all treated monkeys. These threshold elevations were modest compared with the ototoxic effects that have been reported after systemic doses of carboplatin. Our findings suggest that the neurotoxic sensitivity of cochlear hair cells is not shared by neurons in the central auditory pathways. As a result, methods for reducing the ototoxic effects of chemotherapy remain a viable strategy for preserving auditory function in patients with brain cancer.

A Phase I and Pharmacodynamic Study of Fludarabine, Carboplatin, and Topotecan in Patients With Relapsed, Refractory, or High-Risk Acute Leukemia

A novel regimen designed to maximize antileukemia activity of carboplatin through inhibiting repair of platinum-DNA adducts was conducted in poor prognosis, acute leukemia patients. Patients received fludarabine (10 to 15 mg/m(2) x 5 days), carboplatin (area under the curve 10 to 12 by continuous infusion over 5 days), followed by escalated doses of topotecan infused over 72 hours (fludarabine, carboplatin, topotecan regimen). Twenty-eight patients had acute myelogenous leukemia (7 untreated secondary acute myelogenous leukemia, 11 in first relapse, and 10 in second relapse or refractory), 1 patient had refractory/relapsed acute lymphoblastic leukemia, and 2 patients had untreated chronic myelogenous leukemia blast crisis. Six patients had failed an autologous stem cell transplant. Patients ranged from 19 to 76 (median 54) years. Measurement of platinum-DNA adducts were done in serial bone marrow specimens. Fifteen of 31 patients achieved bone marrow aplasia. Clinical responses included 2 complete response, 4 complete response with persistent thrombocytopenia, and 2 partial response. Prolonged myelosuppression was observed with median time to blood neutrophils >/=200/microl of 28 (0 to 43) days and time to platelets >/=20,000/microl (untransfused) of 40 (24 to 120) days. Grade 3 or greater infections occurred in all of the patients, and there were 2 infection-related deaths. The nonhematologic toxicity profile was acceptable. Five patients subsequently received allografts without early transplant-related mortality. Maximum tolerated dose of fludarabine, carboplatin, topotecan regimen was fludarabine 15 mg/m(2) x 5, carboplatin area under the curve 12, and topotecan 2.55 mg/m(2) over 72 hours. An increase in bone marrow, platinum-DNA adduct formation between the end of carboplatin infusion and 48 hours after the infusion correlated with bone marrow response. Fludarabine, carboplatin, topotecan regimen is a promising treatment based on potential pharmacodynamic interactions, which merits additional study in poor prognosis, acute leukemia patients.

Pharmacokinetics of systemic versus focal Carboplatin chemotherapy in the rabbit eye: possible implication in the treatment of retinoblastoma.

To characterize the pharmacology and toxicity of intravenous versus focal carboplatin delivery in the rabbit eye. Pharmacological distribution of carboplatin was examined in New Zealand White Rabbits after a single intravenous infusion of carboplatin (18.7 mg/kg of body weight), a single subconjunctival carboplatin injection (5.0 mg/400 microL), or a single application of carboplatin delivered by Coulomb-controlled iontophoresis (CCI; 14 mg/mL carboplatin, 5.0 mA/cm(2), 20 minutes). After each treatment, animals were euthanatized, and the eyes analyzed at 1, 2, 6, or 24 hours by atomic absorption spectroscopy to determine carboplatin concentration in ocular structures. Potential toxicity of focally delivered carboplatin was assessed by histology after six cycles of 5.0 mg carboplatin delivered by subconjunctival injection or six transscleral carboplatin CCI applications at 72-hour intervals (14.0 mg/mL, 20 minutes at 2.5 mA). Determination of concentrations through atomic absorption spectroscopy in the retina, choroid, vitreous humor, and optic nerve after subconjunctival injection or iontophoretic carboplatin delivery revealed significantly higher levels than those achieved with intravenous administration. Carboplatin concentrations in the blood plasma were found to be significantly higher after intravenous delivery than after focal delivery by subconjunctival injection or CCI. No evidence of ocular toxicity was detected after focally delivered Carboplatin. Focal administration of carboplatin using subconjunctival or noninvasive CCI safely and effectively transmits this chemotherapeutic drug into the target tissues of the retina, choroid, vitreous, and optic nerve. These results suggest that focal carboplatin delivery may effectively increase intraorbital carboplatin concentrations while decreasing systemic exposure to this cytotoxic drug.

Development of a mathematical model of intraperitoneal/intravenous infusion of carboplatin. A Sankai Gynecology Study Group study

2037 Background: For ovarian cancer patients, it remains unclear whether carboplatin should be administered intraperitoneally (IP) or intravenously (IV). Because it is virtually impossible to measure the actual tissue concentration in peripheral organs, we have developed a three-compartment mathematical model for both IP and IV administration to estimate the pharmacological information in the serum (S), [the] peritoneal cavity (CV), and [the] peripheral space (PRH) Methods: Twenty two patients with ovarian cancer were enrolled in this study; two groups of 11 patients each received carboplatin IP or IV, respectively. Carboplatin (AUC 6) was diluted in 500 ml 5% glucose and administered either as an IP bolus infusion or IV drip infusion in 1 hr. Patients receiving IV injections also received an infusion of 500 ml 5% glucose to enable us to obtain intraperitoneal samples. IP fluid and blood samples were obtained, immediately, 1, 2, 4, 8, 12 and 24 hrs after administration. The free platinum was measured by a...

Development of a mathematical model of intraperitoneal/intravenous infusion of carboplatin. A Sankai Gynecology Study Group study

2037 Background: For ovarian cancer patients, it remains unclear whether carboplatin should be administered intraperitoneally (IP) or intravenously (IV). Because it is virtually impossible to measu...

Pharmacokinetic interaction study evaluating the effect of BMS-275291 on the pharmacokinetics of paclitaxel and carboplatin in patients with advanced or metastatic non-small cell lung cancer (NSCLC)

7309 Background: BMS-275291 is an inhibitor of matrix metalloproteinases. A large randomized, placebo controlled Phase II/III clinical study has been conducted to examine whether adding BMS-275291 to carboplatin plus paclitaxel therapy would improve survival in advanced NSCLC. Objective: This study was conducted to examine the effect of BMS-275291 on the plasma pharmacokinetics (PK) of paclitaxel and carboplatin when administered together to patients with advanced NSCLC. Methods/Results: Treatment with intravenous infusion of paclitaxel (200 mg/m2) and carboplatin (AUC=6) was commenced on Day 1 and repeated q 21 days. BMS-275291 1200 mg was given orally daily starting on Day 2. PK sampling for paclitaxel and carboplatin were obtained on Day 1 and 22, and for BMS-275291 on Day 22. 18 patients (11 male, 7 female) with Stage IIIB or IV NSCLC were enrolled. The median age was 61.5 yrs. 2 patients had grade 4 hypersensitivity reactions to paclitaxel including 1 patient who had a cardiac arrest. Both patients recovered. Grade 3 or 4 neutropenia was seen in 7 and 3 patients respectively and grade 3 thrombocytopenia in 4 patients. 3 patients had grade 3 arthralgia or myalgia. 6 patients developed grade 1 or 2 rash. PK samples were obtained on both Day 1 and Day 22 from 11 patients for BMS-275291, 10 patients for paclitaxel, and 9 patients for carboplatin. The peak concentration (Cmax) and exposure (AUCT) of paclitaxel and carboplatin on Day 1 was not significantly different on Day 1 compared with Day 22 (see Table). The mean (±SD) steady state parameters for BMS-275291 on Day 22 were Cmax 6.2 (±3.4) μg/mL, AUCT 23.1 (±8.9) μg.h/mL and T1/2 5.3 (±1.9) h. Conclusion: Administration of BMS-275291 1200 mg qd does not significantly affect the pharmacokinetic profile of paclitaxel or carboplatin and the combination was generally well tolerable. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb

Pharmacokinetic interaction study evaluating the effect of BMS-275291 on the pharmacokinetics of paclitaxel and carboplatin in patients with advanced or metastatic non-small cell lung cancer (NSCLC)

7309 Background: BMS-275291 is an inhibitor of matrix metalloproteinases. A large randomized, placebo controlled Phase II/III clinical study has been conducted to examine whether adding BMS-275291 to carboplatin plus paclitaxel therapy would improve survival in advanced NSCLC. Objective: This study was conducted to examine the effect of BMS-275291 on the plasma pharmacokinetics (PK) of paclitaxel and carboplatin when administered together to patients with advanced NSCLC. Methods/Results: Treatment with intravenous infusion of paclitaxel (200 mg/m2) and carboplatin (AUC=6) was commenced on Day 1 and repeated q 21 days. BMS-275291 1200 mg was given orally daily starting on Day 2. PK sampling for paclitaxel and carboplatin were obtained on Day 1 and 22, and for BMS-275291 on Day 22. 18 patients (11 male, 7 female) with Stage IIIB or IV NSCLC were enrolled. The median age was 61.5 yrs. 2 patients had grade 4 hypersensitivity reactions to paclitaxel including 1 patient who had a cardiac arrest. Both patients r...

Carboplatin pharmacokinetics following a single-dose infusion in sulphur-crested cockatoos (Cacatua galerita).

To determine the pharmacokinetics of carboplatin in sulphur-crested cockatoos, so that its use in clinical studies in birds can be considered. A pharmacokinetic study of carboplatin, following a single intravenous (IV) or intraosseus (IO) infusion over 3 min, was performed in six healthy sulphur-crested cockatoos (Cacatua galerita). Birds were anaesthetised and a jugular vein cannulated for blood collection. Carboplatin (5 mg/kg) was infused over 3 min by the IV route in four birds via the contralateral jugular vein, and by the IO route in two birds via the ulna. Serial blood samples were collected for 96 h after initiation of the infusion. Tissue samples from 11 organs were obtained at necropsy, 96 h after carboplatin administration. Total Pt and filterable Pt in plasma and tissue Pt concentrations were assayed by inductively coupled plasma-mass spectrometry. A noncompartmental pharmacokinetic analysis was performed on the plasma data. The mean +/- SD for the Cmax of filterable Pt was 27.3 +/- 4.06 mg/L and in all six birds occurred at the end of the 3 min infusion, thenceforth declining exponentially over the next 6 h to an average concentration of 0.128 +/- 0.065 mg/L. The terminal half-life (T1/2) was 1.0 +/- 0.17 h, the systemic clearance (CI) was 5.50 +/- 1.06 mL/min/kg and the volume of distribution (Vss) was 0.378 +/- 0.073 L/kg. The extrapolated area under the curve (AUC0-x) was 0.903 +/- 0.127 mg/mL x min; the area extrapolated past the last (6 h) data point to infinite time averaged only 1.25% of the total AUC0-x. The kidneys had the greatest accumulation of Pt (7.04 +/- 3.006 microg/g), followed by the liver (3.08 +/- 1.785 microg/g DM). Carboplatin infusion in sulphur-crested cockatoos produced mild, transient alimentary tract signs and the Pt plasma concentration was similar whether carboplatin was given intravenously or intraosseously. Filterable plasma Pt concentrations for carboplatin persisted longer than for cisplatin, due mostly to the difference in systemic clearance between these drugs in sulphur-crested cockatoos. The distribution of tissue Pt after carboplatin administration was similar to that reported for cisplatin in sulphur-crested cockatoos. Despite anatomical, physiological and biochemical differences among animal species, the pharmacokinetic disposition of filterable Pt in the sulphur-crested cockatoo shares some features with the kinetics reported previously in other animals and human beings.

Successful administration of carboplatin in patients with clinically documented carboplatin hypersensitivity

Objective The goal of this study was to evaluate the tolerance and effectiveness of carboplatin rechallenge using a prolonged desensitizing carboplatin infusion regimen in patients with clinically documented moderate-severe carboplatin hypersensitivity. Methods Patients admitted for carboplatin infusion were identified by computerized pharmacy records and retrospectively analyzed. Results Thirty-three patients with recurrent ovarian ( N = 27), peritoneal ( N = 4), tubal (N = 1), and cervical ( N = 1) cancer treated with a prolonged desensitizing carboplatin infusion regimen were identified. The patients had received a median of 10 courses of carboplatin (range 3–33) before developing the moderate-severe hypersensitivity reaction. Two hundred and fifteen courses (median 5, range 1–52) were administered. Twenty-nine patients (88%) were successfully rechallenged while four had a recurrent moderate-severe carboplatin hypersensitivity precluding further administration. Despite initial tolerance of the infusion schedule moderate-severe carboplatin hypersensitivity recurred in 3 additional patients (9%) after two, three, and six subsequent courses. Objective responses to therapy were seen in 22 of 28 evaluable patients (79%). Conclusions A prolonged desensitizing carboplatin infusion regimen is tolerated in the majority of patients with clinically documented moderate-severe carboplatin hypersensitivity. Objective response rates seem acceptable with this schedule.

A Surgical Technique for Safely Placing a Drug Delivery Catheter into the Pons of Primates: Preliminary Results of Carboplatin Infusion

We sought to develop a neurosurgical procedure to access the pons with a drug delivery device for chronic therapy and collect preliminary data on the toxicity of direct infusions of carboplatin in primates. We made midline incisions on five cynomolgus monkeys, identified the inion, made a burr hole 2.5 cm below the inion, and inserted a catheter through the cerebellum into the roof of the pons. Pumps that infused saline for 90 days or carboplatin solutions for 30 to 35 days at 10 microl/d were placed subcutaneously in the low cervical/high thoracic region. Monkeys were assessed by computed tomography and magnetic resonance imaging, laboratory studies, daily neurological observation, postmortem examinations, and histopathology. Monkeys infused with saline and 82 microg of carboplatin remained neurologically intact throughout the infusion periods. Serial imaging showed that the catheter tip was in the pons and revealed no evidence of hemorrhage, edema, or migration. Two monkeys infused with up to 850 microg of carboplatin showed hyperintense magnetic resonance imaging signals at Days 15 and 18 and neurological deficits at approximately Week 3. Platinum levels greater than 10 ng/mg tissue were detected over a distance of 1 cm in tissue slices. Histopathology demonstrated significant tissue necrosis around the tip of the catheter. The pons of monkeys is safely accessed with a catheter for drug delivery by using a posterior midline approach. Clinical observations, radiographic imaging, and laboratory tests of animals infused with saline for 3 months or 0.26 mg/ml of carboplatin for 1 month were unremarkable. Neurotoxicity was seen with dose levels of 2.6 mg/ml of drug for 1 month. This procedure offers opportunities for examining the toxicity of brainstem antitumor therapy in primates.