Pharmacokinetics of unchanged carboplatin (CBDCA) in patients with small cell lung carcinoma

Reece, Phillip A.; Bishop, James F.; Olver, Ian; Stafford, Irene; Hillcoat, Brian L.; Morstyn, George

doi:10.1007/bf00261482

Cited by 28 publications

(12 citation statements)

References 7 publications

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“…The volume doubling time of 2.4 days found in the non-irradiated group is in good accordance with previous data obtained for this tumour model (Busse et al, 1995). As the biological half-life of carboplatin is about 3-4 h in humans (Reece et al, 1987), and the turnover is somewhat higher in rats, it can be assumed that on the day of tumour implantation no appreciable amounts of carboplatin are present in the animals, and therefore effects of carboplatin on tumour growth in this model are not to be expected.…”

supporting

confidence: 92%

Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia

Thews

Koenig²,

Dk³

et al. 1998

Br J Cancer

130

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Summary The radiosensitivity of solid tumours in anaemic rats treated with recombinant human erythropoietin (rhEPO, epoetin beta) was studied. Anaemia was induced by a single dose of carboplatin (45 mg kg-' i.v.), resulting in a reduction in the haemoglobin concentration by 30%. In a second group, the development of anaemia was prevented by rhEPO (1000 IU kg-1) administered s.c. three times per week starting 6 days before the carboplatin application. Three days after carboplatin treatment, DS-sarcomas were implanted subcutaneously onto the hind foot dorsum. Neither carboplatin nor rhEPO treatment influenced tumour growth rate. Five days after implantation, tumours were irradiated with a single non-curative dose (10 Gy), resulting in a growth delay with a subsequent regrowth of the tumours. In the rhEPO-treated group, the growth delay lasted significantly longer (9.5 days vs. 4.5 days) and the regrowth was slower (6.0 days vs. 4.1 days) compared with the anaemic group. These data suggest that the correction of chemotherapy-induced anaemia by rhEPO (epoetin beta) treatment increases tumour radiosensitivity, presumably as a result of an improved oxygen supply to tumour tissue.

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supporting

confidence: 92%

Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia

Thews

Koenig²,

Dk³

et al. 1998

Br J Cancer

130

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“…The mean total body clearance of ultrafiltrable plasma platinum was 113 ml/min/m2 and is com parable to CBDCA plasma clearance with approximately 105 ml/min/m2 [16]. The mean steady state volume of distribution of unchanged platinum was reported for CBDCA as 17.3 L/m2 [16] which was similar to that found for ultrafilterable platinum of D-19466 in the present study being 16.6 L/m2. There is a clear relationship between the dose and the percen tage of reduction of WBC and platelets at the nadir.…”

Section: Discussionsupporting

confidence: 78%

“…Cisplatin easily binds with serum proteins, with the result that a smaller percentage of platinum is excreted in the urine after CDDP in fusions than in the case of carboplatin. In case of CDDP about 25% of the Pt is excreted into the urine during the first 24 hours whereas in case of CBDCA 60 (20)% is excreted via the urine [16]. These data indicate more similarities of D-19466 to CDDP than to CBDCA.…”

Section: Discussionmentioning

confidence: 45%

Pharmacokinetic and Pharmacodynamic Study with Lobaplatin (D-19466), a New Platinum Complex, after Bolus Administration

Mross¹,

Meyberg

Fiebig

et al. 1992

Oncol Res Treat

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Background: Lobaplatin (D-19466) is a platinum compound with greater anticancer activity in NSCLC, stomach, breast and ovarian cancer in the human tumor xeno-graft model. Preclinical studies suggested a low or absence of cross resistance to CDDP and CBDCA. Methods: During a clinical phase I trial a pharmacokinetic study was performed. The amount of platinum in plasma, plasma ultrafiltrate and urine samples was measured with atomic absorption spectometry (AAS) during a 48 hour sampling period. In total, 15 patients were studied receiving 17 treatment cycles. Pharmacokinetic parameters were determined by use of a software package TopFIT version 1.1. Toxicity data (reduction of platelets and leucocytes at the nadir) were correlated to either pharmacokinetic parameters as well as to kidney function parameters (ECC). In-vitro binding of D-19466 to plasma proteins was studied. Results: The c(t)-curves of total platinum were best described by a three compartment model. The mean residence time ranged from 5.1 to 37.8 hours in patients treated with 20 respectively 60 mg/m2. The volume of distribution was ranging from 0.64 up to 3.95 L/kg, the total plasma clearance was independent from dose with a mean of 172 ml/min. The area under the curve was increasing by dose from 2490 up to 10,000 μg h/L. The urinary excretion of total platinum during 48 hours was 27.8% of the total dose. The c(t)-curves of free platinum were best described by a two-compartment model. The mean residence time, volume of distribution as well as the total plasma clearance were independent from dose with mean values of MRT – 2.6 hours, Vdss = 0.44 L/kg and Clp = 202 ml/min. The area under the curve was increasing by dose from 2215 to 5200 μg h/L. The part of the free (unbound) platinum was calculated by comparison of the AUCs of c(t)-curves of free and total platinum and was 64% with a wide range (27-95%). In-vitro studies showed an increasing binding to proteins during time. Only a poor correlation was found between the estimated creatinine clearance and the drop of platelets and leucocytes at the nadir whereas a good correlation was found between the AUC of free as well as total platinum and reduction of platelets and leucocytes. Conclusion: In-vitro studies with D-19466 showed a slow binding to plasma proteins. This corresponds with the result that only 64% of the total platinum administered is free (= unbound) platinum. The terminal half-life of the ultrafilterable (free) platinum remains short in comparison to total platinum which includes the plasma bound platinum. There was no good correlation found between estimated creatine clearance and the drop of platelets and leucocytes at the nadir. There is no need to adjust the D-19466 dose to kidney function as far as patients are treated with normal values of creatinine.

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“…Peak plasma concentrations by this administration are typically 30-to 100-fold greater than those obtained for the same drug by continuous infusion. (For instance, for carboplatin compare Allsopp and Sewell, 1995with Harland et al, 1984and Reece et al, 1987) Thus, there is no obvious discrepancy between the LC90 values presented in this work and drug levels measured in vivo.…”

Section: Discussionmentioning

confidence: 46%

Ex vivo cytotoxic drug evaluation by DiSC assay to expedite identification of clinical targets: results with 8-chloro-cAMP

Bosanquet

Burlton²,

Bell³

et al. 1997

Br J Cancer

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Summary There is a pressing need to reduce the time and cost of developing new cytotoxic agents and to accurately identify clinically active agents at an early stage. In this study, the differential staining cytotoxicity (DiSC) assay was used to assess the efficacy of the novel antitumour cAMP analogue, 8-chloro-cAMP (8-Cl-cAMP) (and its metabolite 8-CI-adenosine) against 107 fresh specimens of human neoplastic and normal cells. Diagnoses included chronic and acute leukaemias, myeloma, non-Hodgkin's lymphoma (NHL) and miscellaneous solid tumours. The aim was to identify targets for subsequent phase 1, II and IlIl trials. 8-Cl-cAMP was tested at 4-985 gM, along with standard chemotherapeutic drugs. 8-Cl-cAMP and its metabolite caused no morphologically observable cell differentiation but induced dosedependent cytotoxicity. Compared with untreated patients, previously treated chronic lymphocytic leukaemia (CLL) patients showed no increase in ex vivo resistance to 8-Cl-cAMP (P = 0.878); minimal cross-resistance with other cytotoxic drugs was detected. Compared with normal cells (mean LC 9 = 1803 gM), 8-Cl-cAMP showed significant ex vivo activity against CLL (117.0 gM; P < 0.0001) and NHL (140.0 gM; P < 0.0001), of which eight were mantle cell NHL (84.7 gIM), and greatest activity against cells from patients with acute myeloid leukaemia (AML; mean LC 9 = 24.3 gm; in vitro therapeutic index 74-fold, P < 0.0001). Solid tumour specimens were comparatively resistant to 8-CI-cAMP. The results highlight the clinical potential of 8-Cl-cAMP, point to several new phase 1, II and IlIl trial possibilities and provide a rationale for the inclusion of ex vivo cytotoxic drug evaluation in the drug development process.Keywords: ex vivo phase 11 trial; Differential Staining Cytotoxicity assay; ex vivo cytotoxic drug evaluation; ex vivo therapeutic index Drug development is a lengthy and expensive process, costing in excess of £100 million per licensed drug. A crucial decision point in the development of any new compound is whether to take it to clinical trial, a process requiring substantial investment. Usually, indications for a new cytotoxic compound are gleaned from cell line and xenograft studies; toxicology tests are then undertaken before the drug is entered into clinical trials (Carmichael, 1994). The incorporation of a parallel series of ex vivo tests in different neoplasms at an early juncture ('ex vivo' is used to denote the determination of patient cellular response to drugs outside the body as a surrogate for treating the patient), using methodologies that predict well for subsequent patient response to known cytotoxic (Bosanquet, 1994), could increase the likelihood that drugs progressed to trials will be clinically active.Various ex vivo methods have been used to test new compounds (Nagoumey et al, 1993;Larsson et al, 1994;Martin et al, 1994; Hanauske et al, 1995). In this paper we outline a development of this approach to drug evaluation whereby new agents are tested against both fresh human neoplastic cells (from h...

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Pharmacokinetics of unchanged carboplatin (CBDCA) in patients with small cell lung carcinoma

Cited by 28 publications

References 7 publications

Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia

Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia

Pharmacokinetic and Pharmacodynamic Study with Lobaplatin (D-19466), a New Platinum Complex, after Bolus Administration

Ex vivo cytotoxic drug evaluation by DiSC assay to expedite identification of clinical targets: results with 8-chloro-cAMP

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