Pharmacokinetics of cis-dichlorodiammine platinum (II) in patients undergoing hemodialysis

The pharmacokinetics of non-protein-bound platinum (free-Pt) and protein-bound platinum derived from cisplatin [cis-dichlorodiammine platinum (II), CDDP] were studied in five patients with chronic renal failure who developed gastric cancer during long-term hemodialysis. Plasma concentrations of CDDP were determined by atomic absorption spectrophotometry. CDDP at a dose of 25 mg/m2 was given i.v. over a 30-min period every one to two weeks. When CDDP was infused simultaneously with the start of hemodialysis, free-Pt at the blood inlet decreased rapidly and free-Pt at the blood outlet remained below the level for quantitative analysis. Furthermore, the total-Pt level declined in two exponential curves at the blood inlet simultaneously with the increased level of Pt at the blood outlet after the end of dialysis. In contrast, when CDDP was infused one hour earlier before dialysis, the pharmacokinetics revealed a higher concentration of free-Pt at the blood inlet which was maintained over a longer period as compared with that occurring when infused simultaneously with the start of dialysis. In conclusion it is considered that this method is feasible for the treatment of gastric cancer in patients with chronic renal failure under long-term hemodialysis.     

Cyclophosphamide and cis-dichlorodiammine platinum (11)

Summary Fractional incorporation (FI) of ³H-thymidine (i.e., the proportion of total tissue ³H incorporated into DNA) has been used as a parameter for judging temporal scheduling of cyclophosphamide and cis-dichlorodiammine platinum (DDP). Differences in the recovery times of FI following a dose of 100 mg CY/kg, between tumor (>12 days), gut (2–3 days), and bone marrow (4 days) suggested a basis for a normal tissue-sparing drug regimen when administering double-agent CY-DDP therapy. When 100 mg CY/kg and 8 mg DDP/kg were administered simultaneously or when the doses were separated by 1 day the survival was 0/10 or 1/10, respectively. However, when the doses were separated by 4 days all rats survived. This 4-day interval was considered to allow time for gut and bone marrow recovery prior to a second insult. Such factors appear crucial to the survival of the animal. These three combinations were similar in their antitumor effect, giving a greater than additive response. Cyclophosphamide was more myelotoxic than DDP, but DDP showed greater gut toxicity. The recovery of bone marrow cellularity was delayed by 2 days compared with FI. Peripheral white blood cell counts returned to normal after a further 2-day delay.     

The gingival platinum line: a new finding following cis-dichlorodiammine platinum (II) treatment.

Cis-dichlorodiammine platinum (II) (DDP) is the salt of a heavy metal with a wide spectrum of antineoplastic activity. Its toxicity is multisystem and similar to that of other heavy metals, including lead and thallium. A young man being treated with primary adjuvant Adriamycin and DDP for osteogenic sarcoma is described who developed a gingival line which temporally was related to DDP administration. Although not chemically or histologically analyzed, we believe this to be a new finding related to DDP which corresponds to the lead line of plumbism and other heavy metal intoxication.     

Pharmacokinetics of decitabine administered as a 3-h infusion to patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS)

Purpose In this study, pharmacokinetics (PK) of decitabine administered as a 3-h intravenous infusion of 15 mg/m² every 8 h for 3 days (cycles repeated every 6 weeks) was evaluated in patients with MDS or AML. Methods The PK of this dosing regimen was evaluated in sixteen patients with MDS or AML. Plasma samples were obtained pre-dose and during the first 8-h dosing interval on each dosing day during Cycle 1, and at pre-dose and just prior to the end of infusion during Cycle 2. PK samples were assayed for decitabine by a sensitive and specific validated liquid chromatography-tandem mass spectrometry method. Results The mean maximum observed plasma concentration (C _max), 64.8–77.0 ng/ml, and the mean area under the plasma concentration-time curve (AUC_0-∞), 152–163 ng h/ml, were unchanged during dosing of decitabine for 3 days. The time to the maximum concentration (T _max) generally occurred at the end of infusion. The mean values for terminal phase elimination half-life (0.62–0.78 h), total body clearance (125–132 l/h per m²), and volume of distribution at steady state (62.7–89.2 l/m²), remained unchanged during the every 8 h dosing (P > 0.05). Cycles 1 and 2 C _max values for days 1, 2, and 3 were not significantly different as determined by paired two-tailed t test (P > 0.05). The primary toxicity of decitabine was myelosuppression, which was observed in all patients. Two deaths, from sepsis, were considered possibly related to decitabine. Conclusions Decitabine dosed at 15 mg/m² iv every 8 h for 3 days resulted in a predictable and manageable toxicity profile in patients with MDS/AML. The repeated dosing did not result in systemic accumulation of the drug, and decitabine PK remained unchanged from cycle to cycle.     

Pharmacokinetics and metabolism of docetaxel administered as a 1-h intravenous infusion

Docetaxel, a taxane antitumor agent, was administered to 24 patients by a 1-h intravenous infusion at a dose level of 100 mg/m² with pharmacokinetic monitoring. The plasma concentration-versus-time data were fitted with a three-compartment model. The mean area under the curve (AUC) for docetaxel was 3.1 ± 0.9 h · mg/l and the clearance was 34.8 ± 9.3 l/h per m². There was considerable interpatient pharmacokinetic variability. In 33% of the patient population, metabolites were detected in plasma samples collected 5–30 min after the end of the infusion. The cyclized oxazolidinedione metabolite M4 was most frequently present and was detected in 8 out of 24 patients with maximal concentrations between 0.022 and 0.23 mg/l. Logistic regression analysis was performed to predict M4 docetaxel metabolism. In the final model, alanine aminotransferase and alkaline phosphatase levels were the strongest predictors. No relationship was found between M4 metabolism and percentage decrease in neutrophil count in this study. Three patients with high M4 concentrations in plasma during course 1 suffered from most pronounced fluid retention (grade 2–3) after two to five courses. Received: 26 March 1999 / Accepted: 7 September 1999     

A comparative study of the distribution in the male rat of platinum-labelled cis-dichlorodiammine platinum (II), cis-trans-dichlorodihydroxy-bis-(isopropylamine) platinum (I), and cis-dichloro-bis-cyclopropylamine platinum (II)

Summary Three platinum derivatives, cis-dichlorodiammine platinum (II), (DDP), cis-trans-dichlorodihydroxy-bis-(isopropylamine)platinum (IV) (CHIP) and cis-dichloro-bis-cyclopropylamine platinum (II) (CP), have been prepared with a gamma-emitting platinum label. The distribution of these complexes was studied in male rats.The results are presented as fractions of the administered radiolabel per gram of tissue and per total organ. Accumulation in the liver was highest initially following CP and lowest after DDP, but by 14 days the levels in kidney and liver were highest with CP. The concentration in the skin was relatively high after all the compounds, but was the most conspicuous after DDP at the early times. In general, patterns of distribution between the other organs were similar with DDP and CP.CHIP, however, exhibited a different pattern of distribution. Over the first 24 h the level of platinum in most tissues declined more rapidly than after either of the other two compounds but the residual label persisted for a longer period. In the kidney there appeared to be a secondary uptake of labelled material, presumably from other tissues. The level present at 14 days after CHIP was also significantly higher in a number of other organs than after the other two drugs. The increase in label in the spleen at the later times may be due to the removal of circulating damaged cells and consistent with the higher levels of residual platinum in the blood. There was also a higher level of residual platinum in the blood especially after IV administration of the labelled agent.The results show that CHIP was cleared at a faster rate from blood and kidney than the other two complexes, results which closely resembled clinical findings with these three agents, to be published elsewhere.The greater retention time of label after CHIP also suggests that longer-term toxicity may follow its repeated administration. Present address: Radiochemical Centre, Amersham International     

Proliferative defects in renal and intestinal epithelium after cis-dichlorodiammine platinum (II).

The effects of cis-dichlorodiammine platinum II (DDP) on the intestinal mucosa and the kidney were studied after single and multiple treatments with intervals of 7-45 days. After a single treatment, the jejunal epithelium underwent a transient interruption of cell proliferation followed by a hyperplastic recovery and return to control proliferative rate on Day 7. Subsequent treatments led to suboptimal recovery for all treatment intervals. In contrast, DDP induced a 6-fold increase in [3H]dT incorporation in the kidney by Day 7 which remained high until Day 21, and returned to near-control values by Day 45. After a single DDP treatment, the "recovery potential" of kidneys, measured by the proliferative response to folic-acid stress, demonstrated suboptimal proliferative reserve compartments for up to 45 days. The distinction between acute and delayed sensitivity to subsequent drug treatment was more apparent in the DDP-treated kidney than in the intestinal epithelium.     

Blood clearance of three radioactively labelled platinum complexes: cis-dichlorodiammine platinum II,cis, trans-dichlorodihydroxy-bis-(isopropylamine) platinum IV,and cis-dichloro-bis-cyclopropylamine platinum II,in patients with malignant disease

Summary The blood clearances of three platinum compounds, cis-dichlorodiammine platinum II (DDP), cis, trans-dichlorodihydroxy-bis-(isopropylamine) platinum IV (CHIP), and cis-dichloro-bis-cyclopropylamine platinum II (CP), were determined in nine patients with malignant disease. The complexes were prepared using radioactive platinum (¹⁹¹Pt and ¹⁹³Pt). A 10-Ci dose of each complex, containing the equivalent of 1–2 mg elemental platinum, was injected IV into groups of three patients. Serial blood and urine samples were collected over 72 h.No obvious difference was found between the three complexes for blood clearance, median t_1/2 being 16.8 (range 11.2–23.5) min and median t_1/2 89 (range 63.7–127) h. The urinary excretion was greatest for CHIP, 60% of injected dose as against 42.6% for CP and 38.8% for DDP.Differences in renal excretion of DDP analogues could indicate potentially less nephrotoxic agents. The use of radioactive Pt will allow in vivo dynamic imaging of the distribution of platinum compounds in areas of interest.     

Pharmacokinetics of phenylacetate administered as a 30-min infusion in children with refractory cancer

Purpose Phenylacetate (PAA), a deaminated metabolite of phenylalanine, suppresses tumor growth and induces differentiation in preclinical tumor models. We performed a pharmacokinetic study, as part of a phase I trial, of PAA in children with refractory cancer.Methods PAA was administered as a 30-min i.v. infusion at a dose of 1.8 or 2.5 g/m². Serial plasma samples were collected for up to 24 h after the end of the infusion in 27 children. The concentrations of PAA and its inactive metabolite, phenylacetylglutamine (PAG), were measured using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection.Results PAA and PAG concentrations were best described by a two-compartment model (one compartment for each compound) with capacity-limited conversion of PAA to PAG. The half-life of PAA was 55±18 min at the 1.8 g/m² dose and 77±22 min at the 2.5 g/m² dose. The half-life of PAG was 112±53 min at the 1.8 g/m² dose and 135±75 min at the 2.5 g/m² dose. The clearance of PAA was 66±33 ml/min per m² at the 1.8 g/m² dose and 60±24 ml/min per m² at the 2.5 g/m² dose. The Michaelis-Menten constants describing the conversion of PAA to PAG in the model (V_m and K_m) were (means±SD) 18.4±13.8 mg/m² per min and 152±155 g/ml, respectively. The volumes of distribution for PAA and PAG (V_d-PAA and V_d-PAG) were 7.9±3.4 l/m² and 34.4±16.1 l/m², respectively. The first-order elimination rate constant for PAG (k_e-PAG) was 0.0091±0.0039 min^–1.Conclusions The capacity-limited conversion of PAA to PAG has important implications for the dosing of PAA, and the pharmacokinetic model described here may be useful for individualizing the infusion rate of the drug in future clinical trials.This work was supported in part by the National Institutes of Health (M01-RR00188), and the General Clinical Research Center, Baylor College of Medicine.     

Pharmacokinetics of cis-diammine (glycolato) platinum (254-S), a new platinum antitumor agent, following an intravenous and intraperitoneal infusion bioactive platinum concentration profile

The pharmacokinetics of cis-diammine (glycolato) platinum (254-S) was investigated in cancer patients following intravenous and intraperitoneal infusion. The serum concentrations of total and unbound 254-S were determined by bioassay and chemical assay as platinum. Platinum detected by bioassay was thought to be active and unchanged 254-S. Almost all of platinum in plasma were found to be active and unbound to protein because of no differences in the concentrations determined by bioassay and chemical assay and in plasma and plasma filtrate. In abdominal ascites, platinum concentrations determined by bioassay corresponded with those determined by chemical assay, suggesting that 254-S was stable in abdominal ascites. The Cmax and AUC of active 254-S in plasma determined by bioassay following an intraperitoneal infusion were about 60% and 60-80% of those following an intravenous infusion, respectively. These results showed that 254-S was well absorbed into systemic circulation from abdominal ascites as an active form. It is concluded that antitumor effect may be obtained following an intraperitoneal infusion of 254-S as well as for the reduction of abdominal ascites.     

DNA binding of iproplatin and its divalent metabolitecis-dichloro-bis-isopropylamine platinum(II)

Summary The quadrivalent second-generation platinum complex iproplatin and an in vivo divalent metabolite of iproplatin,cis-dichloro-bis-isopropylamine platinum (CIP) were tested for binding to DNA in vitro. DNA binding was determined according to radioactivity measured using [¹⁴C]-iproplatin and [¹⁴C]-CIP and also by platinum content. Results indicate that (a) iproplatin shows negligible binding to DNA, (b) CIP binds to DNA in a time-dependent fashion, and (c) the isopropylamine ligand is intact when CIP is bound to DNA. Glutathione (GSH) inhibits the binding of CIP to DNA, possibly by inhibiting binding to DNA of the aquated form of CIP.     

Pharmacokinetics and plasma protein binding of two platinum cytostatics CHIP and CBDCA in rats

Summary Twenty-three specimens (biopsied tissue, resected specimens, and resected pulmonary metastases were obtained during biopsy, radical surgery, or thoracotomy from patients with osteosarcoma. Using these specimens, human tumor clonogenic assay (standard HTCA) and cultivated HTCA (HTCA using single-cell suspensions obtained from short-term cultures) were carried out. The percentage of colony-forming ability, which was very small for standard HTCA, increased significantly when cultivated HTCA was performed. With cultivated HTCA, sensitivity tests were possible in 87% of the specimens in contrast to only 28.6% using standard HTCA. We retrospectively analyzed the relationship between the results of HTCA and the clinical efficacy of agents such as methotrexate, adriamycin, cis-platinum, and vincristine, which are frequently prescribed for the treatment of osteosarcoma. This analysis revealed that if drugs are show to be ineffective by this test, they can be regarded as clinically ineffective against that specific tumor target, i. e., the tumor cells are refractory to those drugs. Thus, clinical use of such drugs should be avoided.     

Phase II clinical trial of cis-dichlorodiammine platinum (cis-DDP) for antitumorigenic activity in previously untreated patients with metastatic breast cancer

Cancer Chemotherapy and Pharmacology - A phase II clinical trial was set up in metastatic breast cancer patients who had not received previous cytotoxic drug therapy, involving the administration...     

Phase II study of XR5000 (DACA) administered as a 120-h infusion in patients with recurrent glioblastoma multiforme.

BACKGROUND: XR5000 is a tricyclic carboxamide that intercalates DNA and inhibits both topoisomerase I and II. The aim of this study was to evaluate the efficacy and tolerability of XR5000 in patients with recurrent glioblastoma multiforme previously untreated with chemotherapy at relapse. PATIENTS AND METHODS: Patients received XR5000 at a dose of 3010 mg/m2 as a 120-h central venous infusion every 3 weeks. An independent panel assessed response every two cycles using McDonald's criteria (tumour size, steroid intake and neurological status); toxicity was graded according to the National Cancer Institute-Common Toxicity Criteria, version 2.0. RESULTS: Sixteen patients were enrolled (one ineligible patient was excluded from efficacy evaluation). Performance status was zero (five patients), one (nine patients) or two (one patient). They received 30 cycles of XR5000 (median 2, range 1-5). Haematological toxicity was mild, with only one patient experiencing grade 3 neutropenia. Other related grade 3/4 adverse events included chest pain (one patient), axillary vein thrombosis (one patient) and rigors/fever in the absence of neutropenia (one patient). There were no objective responses, 14 patients progressing on XR5000 and one having stable disease. CONCLUSIONS: Although XR5000 was generally well tolerated, these results do not support further evaluation in patients with glioblastoma multiforme using this dose and schedule.     

Pharmacokinetics of cis-diamminedichloroplatinum (II) given as low-dose and high-dose infusions

A pharmacokinetic analysis of cis-diamminedichloroplatinum (II) (DDP) was conducted comparing low-dose daily bolus infusions, and high-dose drip infusions. Eight patients with gastric cancer were treated with low-dose daily bolus infusions of DDP to a total daily dose of 75 mg/m² bid for 5 days. Four patients with esophageal cancer and one patient with gastric cancer were treated with high-dose drip infusions of DDP to a total daily dose of 70–80 mg/m². Side effects were assessed in all the patients, and the platinum concentration in plasma was determined by an atomic absorption method. The peak plasma concentration (C_max) and area under the curve (AUC) were calculated in four cases of the low-dose therapy, and three cases of the high-dose therapy. The side effects of DDP were evaluated according to the World Health Organization (WHO) grading, paying particular attention to nausea/vomiting, appetite loss, renal toxicity, and bone marrow suppression. The incidence of nausea/vomiting and appetite loss was significantly reduced with low-dose daily bolus infusions when compared to the high-dose drip infusions. Bone marrow toxicity and renal toxicity were similar with both administration methods, although hydration was required for the high-dose drip infusions to prevent renal toxicity. The peak plasma concentration (C_max) of total and free platinum, and the area under the curve (AUC) of total platinum, were similar with both administration methods, while the AUC of free platinum was higher with the low-dose daily bolus infusions compared to the high-dose drip infusions. The time when the concentration of total platinum was >1 μg per ml (holding time) was significantly longer with the high-dose drip infusions than with the low-dose daily bolus infusions. The present study suggests that low-dose daily bolus infusions of DDP would be useful in reducing gastrointestinal toxicity, without reducing the area under the curve which is important for antitumor activity. © 1996 Wiley-Liss, Inc.     

Pharmacokinetics of cis-dichlorodiammineplatinum (II)

The pharmacokinetics of cis-dichlorodiammineplatinum (II) have been studied in 8 patients with advanced head and neck cancer. Plasma and urine platinum concentration were determined by atomic absorption spectrometry. Three different infusion methods were compared: 1) 24 hour continuous i.v. infusion; 2) 2 hour i. a. infusion and; 3) equally divided 5 daily i. a. infusion. In 4 patients receiving the 24 hour infusion, plasma platinum level had declined with second peak, which appeared 0.5-6 hours after end of infusion. Slow phase of half-life time of total platinum was very long ranged 86-197 hours. Non-protein bound platinum was rapidly cleared below the measurable level within 2 hours. At the end of 24 hour infusion, about 90% of plasma platinum was bound with plasma proteins. In a case of 2 hour infusion only one-half of platinum was bound. A patient receiving 2 hour infusion exhibited biphasic clearance of total platinum. In the 3 patients receiving divided daily infusion platinum concentration increased day by day. The level at 5th day was about 3 times higher than that of level at first day. In a patient with renal dysfunction slow phase half-life time prolonged markedly; however, his accumulative urinary excretion in first 24 hours did not diminish as compared with the patients with normal renal function.     

Nin one binding protein expression as a prognostic marker in prostate carcinoma

Background

To investigate the prognostic value of expression levels of nin one binding protein (Nob1) in prostate carcinoma.

Methods

Nob1 protein levels were evaluated by Western blot in samples from 40 prostate carcinomas and matched adjacent non-neoplastic prostate tissues. Nob1 expression was also assessed by immunohistochemistry in samples from 300 prostate carcinoma and matched adjacent non-neoplastic prostate tissues, as well as 20 benign prostatic hyperplasia samples. The findings were compared with clinical and pathologic parameters and patient outcome.

Results

Nob1 protein analysis showed significant differences between the prostate carcinomas and control groups tested. Immunohistochemical analysis showed that Nob1 positivity was higher in prostate carcinoma than that in paired adjacent non-cancerous tissues (58 vs 7 %, P < 0.001). Nob1 positivity was significantly associated with high Gleason scores and metastasis in patients. Nob1 expression was significantly associated with shorter biochemical recurrence-free survival (BCRFS). Multivariate analysis revealed that Nob1 is an independent marker for BCRFS.

Conclusions

These findings provide evidence that Nob1 is an indicator of poor prognosis in prostate carcinoma.     

Phase I clinical and pharmacokinetic study of hexamethylene bisacetamide (NSC 95580) administered as a five-day continuous infusion

Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was tested in patients with refractory, solid tumors. Twenty patients received 25 evaluable courses. HMBA was given by continuous i.v. infusion for 5 consecutive days with courses repeated every 4 wk, provided there was acceptable, reversible toxicity. The starting dose was 4.8 g/m2/day for 5 days with escalations in subsequent cohorts of patients to 43.2 g/m2/day for 5 days. The patients included 12 females and eight males with median age of 56 yr (range 35 to 75 yr) and a median performance status of 80% (range, 60 to 100%). All except two patients had received prior chemotherapy, radiation therapy, or both. Metabolic acidosis and neurotoxicity, consisting of agitation, hallucinations, confusion, and alteration of consciousness, were dose dependent and dose limiting. The one patient treated with 43.2 m/m2/day became acidotic, agitated, and disoriented but recovered to his previous mental and electrolyte status by 8 days after the end of the HMBA infusion. One patient treated with 33.6 g/m2/day became severely acidotic (pH 7.07) and obtunded and also developed myocardial and cerebral infarctions during the HMBA infusion. The other two patients treated with 33.6 g/m2/day became mildly agitated during drug infusion. Six patients were treated at 24 g/m2/day without neurotoxicity. Transient renal insufficiency was seen in the two patients with severe neurotoxicity and in three other patients. Dose-related, mild to moderate nausea and vomiting were observed in ten patients. Four patients developed cutaneous herpes infections during treatment. White blood cell depression was not dose related, and at 24 g/m2/day, the median white blood cell nadir was 4,500/microliter (range, 2,000 to 7,900/microliter). Thrombocytopenia was dose related. At 24 g/m2/day, the median platelet count nadir was 207,000/microliter (range, 66,000 to 542,000/microliter). No objective tumor regressions were noted. HMBA pharmacokinetics was studied at all dosages. Plasma and urine samples from 20 patients were analyzed by gas-liquid chromatography for parent compound. HMBA plasma steady-state concentrations (Css) were achieved in all patients by 12 to 24 h into infusion. Once Css was achieved, daily variation was generally less than or equal to 10% from the mean Css. HMBA plasma Css increased linearly with dose, but there was variation in the Css achieved in individual patients at each dose. Doses of 24 to 33.6 g/m2/day consistently produced plasma HMBA Css of 1 to 2 mM matching concentrations required for differentiation in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)