Pharmacokinetic study of mitomycin C with emphasis on the influence of aging.

Mitomycin C (MMC) at a dose of 8 mg/m2 was administered by short intravenous infusion to 14 cancer patients. All patients had normal renal, hepatic, cardiac and bone marrow functions. The plasma level of MMC, which was determined by high-performance liquid chromatography over a 24-h period after the infusion, fitted the 2-compartment model curve except for one patient. There was a significant correlation between the area under the time versus concentration curve (AUC) of MMC and the age of patients (r = 0.558, P < 0.05). Pharmacokinetic parameters in one of the older (a 69-year-old male) patients were extremely different from those of the other 13 patients. This patient experienced severe myelosuppression, probably due to the markedly increased AUC of MMC. Our results suggest that a patient's age has a significant influence on the pharmacokinetics of MMC in patients with normal major organ functions and that in some patients, MMC pharmacokinetics may be altered, possibly due to interpatient variation in the activation or metabolic pathway of MMC.     

The influence of ageing on cisplatin pharmacokinetics in lung cancer patients with normal organ function

This study was performed to identify any relationship between age and cisplatin (CDDP) pharmacokinetics in lung cancer patients. CDDP was given at a dose of 80 mg/m² by 1-h intravenous infusion to 23 lung cancer patients. All patients had normal renal, hepatic, and bone marrow functions. We measured ultrafilterable platinum (U-Pt) and total plasma platinum (T-Pt) using atomic absorption spectrometry. There was significant correlation between the age of the patients and U-Pt pharmacokinetic parameters such as the area under the plasma concentration versus time curve (AUC), total clearance (Cl), and peak plasma concentration (Cmax) as well as the AUC of T-Pt (P<0.05). We performed univariate regression analysis to examine the influence of factors aside from age on the AUC of U-Pt and T-Pt. Creatinine and GPT levels were significantly related to the AUC of U-Pt, and creatinine clearance and creatinine concentrations were significantly related to the AUC of T-Pt. Therefore, stepwise multiple-regression models for the AUC of U-Pt and T-Pt were developed to assess an age effect. Age was consistently an independent and significant predictor of the AUC of U-Pt and T-Pt.     

Doxorubicin clearance in the obese

A study was carried out to examine the effect, if any, of obesity on doxorubicin pharmacokinetics. Body weight was found to be significantly related to doxorubicin clearance (r = -.75; P less than .001) and elimination half-life (r = .62; P = .003). Thus, the contribution of obesity on pharmacokinetics of antineoplastic agents should be taken into consideration in the analysis of clinical data with respect to toxicity and tumor response. Twenty-one patients were studied with their first course of doxorubicin (50 to 70 mg/m2) administered as a 60-minute intravenous (IV) infusion. Patients were divided into three groups on the basis of percentage of ideal body weight (IBW): normal (less than 115% IBW), mildly obese (115% to 130% IBW), and obese (greater than 130% IBW). Blood samples were collected up to 48 hours after the infusion and analyzed for doxorubicin and its metabolite, doxorubicinol, by high performance liquid chromatography. Doxorubicin area under the curve (AUC) was greater in obese than in normal patients (2,209 v 1,190 ng h/mL; P less than .05), yielding correspondingly reduced systemic clearance of the agent in obese patients (891 v 1,569 mL/min; P less than .001). The mean elimination half-life (T1/2) was 20.4 hours in the obese patients and 13.0 hours in the normal patients. The apparent volume of distribution (Vss) was not significantly different among the three groups of patients, indicating that the prolonged T1/2 in the obese patients is due to the reduction in clearance. The AUC and T1/2 of doxorubicinol were similar among all patient groups.     

Pharmacokinetics and pharmacodynamics of serum platinum of gynecologic cancer patients treated with nedaplatin

Nedaplatin (cis-diammine glycolate platinum) is one of the effective platinum agents for gynecologic carcinoma. In order to assess the pharmacokinetics and pharmacodynamics of serum platinum of gynecologic cancer patients treated with nedaplatin, we calculated 10 course AUCs (area under the curve) of the free and total platinum from blood samples of 4 patients. Peak serum platinum concentrations were dependent on infusion times. In the case of a patient with renal dysfunction or ascites, the concentration of serum platinum tended to stay at a high level for a long time. Serum-free platinum ratios were maintained longer than cisplatin. Low dose nedaplatin administration and divided administration were effective, but total AUC was not so great. The relation between AUC ratio (free platinum AUC/total platinum AUC) and dose/m(2) was not clarified.     

Five-day continuous infusion of vindesine in the treatment of non-small cell lung cancer--clinical pharmacokinetics of vindesine]

We administered vindesine (VDS) as a single agent at a dose of 1.2 mg/m2/day for 5 days by continuous infusion in 6 patients with inoperable non-small cell lung cancer, and studied the pharmacokinetics of VDS. The maximum concentration (Cmax) of VDS was 6.9 ng/ml and the area under the curve (AUC) was 803 ng.hr/ml. The AUC achieved for VDS was 2.5 times higher after continuous infusion than that observed when 3 mg/m2 of VDS was given by bolus iv injection. Among six patients were 2 PR, including one PR achieved using a 5-day continuous infusion of VDS after failure to respond to cisplatin plus VDS (bolus injection). Severe leukopenia was observed, but it was clinically manageable. The AUC exposure of VDS is greater with the longer infusion periods, and this might improve efficacy compared to conventional bolus injection treatments. The need for further studies appears warranted.     

Phase I and pharmacokinetic study of 7-hydroxystaurosporine and carboplatin in advanced solid tumors.

PURPOSE: Based on preclinical data showing synergy between 7-hydroxystaurosporine (UCN-01) and platinum agents, a phase I trial of carboplatin with UCN-01 administered as a 3 h infusion in patients with advanced solid tumors was done. The primary goals of this trial were to evaluate the tolerability of this combination and the pharmacokinetics of UCN-01 when administered over 3 h and to compare the tolerability and pharmacokinetics with previously described schedules. Patients and Methods: Patients with advanced solid tumors, good performance status, normal organ function, and no potentially curative therapy were eligible for the trial. Carboplatin was escalated from an area under the curve (AUC) of 3 to an AUC of 5. UCN-01 was escalated from 50 to 90 mg/m(2). RESULTS: Twenty-three patients with advanced solid tumors (20 with prior platinum treatment) received a total of 60 cycles of therapy. Full doses of both agents (carboplatin AUC 5, UCN-01 90 mg/m(2) in cycle 1, 45 mg/m(2) in subsequent cycles) could be administered. The major toxicity noted was hypotension, which could be abrogated with the use of saline prehydration and posthydration. No responses were seen; however, seven patients were able to receive more than two courses of therapy. Of note, two of three patients with refractory, progressive small cell lung cancer were able to receive six cycles of therapy without evidence of progression. One patient experienced resolution of paraneoplastic syndrome of inappropriate antidiuretic hormone. The pharmacokinetic variables C(max) and t(1/2) of the 3 h infusion were essentially identical to those previously observed when UCN-01 was administered over 72 h. The average t(1/2) for cycle 1 was 506 +/- 301 h, and the mean C(max) for all dose levels was >30 micromol/L. The mean AUC over the dosing interval for each dose level ranged from approximately 6,000 to 9,000 micromol/L h. Thus, the AUC of UCN-01 after the 3 h infusion was lower than was observed after a 72 h infusion. CONCLUSION: The regimen of carboplatin and UCN-01 (administered as a 3 h infusion) was well tolerated. Further development of this combination, particularly in small cell lung cancer, is warranted.     

Subcutaneous infusion of cytosine arabinoside

The administration of cytosine arabinoside (araC) by continuous IV infusion requires the patient to be in hospital and have prolonged IV cannulation. In this study the pharmacokinetics of araC during continuous IV infusion were compared with those of continuous SC infusion in six patients with acute myelogenous leukaemia. Each patient acted as his own control. The mean plasma levels of araC reached a plateau within 2 h and the plasma concentrations and the area under the curve were similar for both methods of administration. The mean area under the curve (AUC) was 1147 +/- 230 ng/ml for the IV infusion and 1017 +/- 238 ng/ml for the SC infusion. The plasma araC concentrations showed wide interpatient variation, and there was also considerable variability in the plasma concentrations of araC within the individual patients after a plateau had apparently been reached. Subcutaneous infusion was well tolerated by the patients without any local discomfort or excoriation and SC infusion of araC is thus a feasible alternative to IV infusion. It allows the patients the benefits of being at home, while avoiding unnecessary thrombophlebitis.     

Pharmacokinetics and toxicity of mitomycin C in rodents,given alone,in combination,or after induction of microsomal drug matabolism

Summary The pharmacokinetics of mitomycin (MMC) was studied in Wistar rats. Up to five half-lives, the plasma concentration-time curve was biphasic. The AUC changed linearly with increasing doses between 0.5 and 7.5 mg/kg, which corresponds to 0.2 and 3 times the LD₅₀ value in rats. Most of the drug was metabolized, and only 1%–2% and 10%–15% of the dose was eliminated unchanged by biliary and urinary excretion, respectively. The AUC of MMC at the LD₅₀ is slightly less than that reported for the human MTD. Inoculation of MMC together with 5-fluorouracil and doxorubicin did not change the terminal half-life of MMC but decreased the total body clearance and the volume of distribution. The lack of significant influence of phenobarbital and 3-methylcholanthrene pretreatment on the terminal elimination half-life suggests that microsomal drug-metabolizing enzymes inducible by these compounds do not play a decisive role in the in vivo biotransformation of MMC.     

Effects of impaired renal function on the pharmacokinetics of raltitrexed (Tomudex ZD1694).

This open-label, non-randomized, parallel-group trial investigated the pharmacokinetics of raltitrexed (Tomudex, formerly ZD1694) after a single intravenous dose of 3.0 mg m(-2), comparing eight cancer patients with mild to moderate renal impairment (creatinine clearance 25-65 ml min(-1)) with eight cancer patients with normal renal function (creatinine clearance >65 ml min(-1)). The primary end points were area under the plasma raltitrexed concentration-time curve from the start of the infusion to the last determined concentration (AUC(0-tldc)) and AUC to infinity (AUC(0-infinity)); secondary end points were peak concentrations of raltitrexed (Cmax) and elimination half-life (t(1/2gamma)). The groups were compared statistically using analysis of covariance. The AUCs were greater for patients with renal impairment than for patients with normal renal function (2452.2 compared with 1247.3 ng h ml(-1) for AUC(0-tldc) (ratio 1.97; 95% CI 1.36-2.84); 2961.5 compared with 1457.0 ng h ml(-1) for AUC(0-infinity) (ratio 2.03; 1.25-3.29). These differences were statistically significant (P = 0.002 and P = 0.008 for AUC(0-tldc) and AUC(0-infinity) respectively. Terminal half-life was longer for the renally impaired patients (271.2 compared with 143.3; P = 0.030). There was no significant statistical difference between the groups for Cmax (652.9 compared with 564.7 ng ml(-1) for patients with impaired and normal renal function respectively: ratio 1.16; 0.91-1.46; P = 0.204). There was a clear relationship between raltitrexed clearance and creatinine clearance. Adverse events, severe (WHO grade 3 or 4) toxicity and hospitalization due to adverse events were more frequent in the group with renal impairment. Therefore, a reduction in raltitrexed dose and increased interval between doses is recommended for patients with mild to moderate renal impairment.     

Pharmacokinetics of oxaliplatin in patients with severe hepatic dysfunction

Purpose Data are lacking on the pharmacokinetics of oxaliplatin in patients with severe hepatic dysfunction. The aim of this study was to determine the pharmacokinetic parameters of platinum after administration of oxaliplatin in cancer patients with severe hepatic impairment due to extended metastases into the liver. Patients and methods Two female breast cancer patients and one male colon cancer patient were treated with oxaliplatin monotherapy at 130 mg/m2 given as a 3-h intravenous infusion. The patients exhibited bilirubin concentrations of 9.6, 22.5 and 41.1 mg/dl indicating severe hepatic dysfunction. Serial blood samples were collected immediately before treatment, and at fixed intervals up to 27 h after start of therapy. Platinum concentrations in plasma, ultrafilterable plasma, and whole blood were determined using a validated flameless atomic absorption spectrometry (FAAS) method. Pharmacokinetic data analysis was performed assuming a two-compartment model. Individual pharmacokinetic parameters were compared with a reference population with normal hepatic function. Results The area under the curve (AUC from 0 to infinity) as well as the elimination half-life of platinum in ultrafilterable plasma were substantially increased and clearance accordingly decreased in the three patients with severe hepatic dysfunction. In plasma and whole blood, the deviations from the reference population were less pronounced. However, partial AUC from 0 up to 2 h after end of infusion reflecting better the exposure with cytotoxic platinum species was not different or only slightly altered. Moreover, no acute oxaliplatin-associated neurotoxicity was observed. Conclusions The comparable platinum exposure early after administration in conjunction with the lack of acute toxicity do not support a dose reduction of oxaliplatin in patients with markedly elevated bilirubin concentrations. However, a larger number of patients must be examined before valid dose recommendations can be derived.     

Pharmacokinetics of mitomycin C in humans

This paper describes an investigation into the pharmacokinetic behavior of mitomycin C (MMC) in 36 patients receiving either single-agent chemotherapy (10 to 20 mg/sq m), or a combination regimen including MMC (5 to 10 mg/sq m). A high-performance liquid chromatographic assay of MMC was applied for the analysis of plasma, urine, bile, and ascites fluid samples. The detection limit is 1 ng/ml sample. Most patients were given short-term i.v. infusion, although other methods of administration were used as well. Most plasma concentration-time curves fit a two-compartment model. Pharmacokinetic parameters revealed large interindividual variations. Median terminal half-lives in single-agent chemotherapy and combination chemotherapy were 50 and 42 min, respectively. The apparent volume of the central compartment was 7 liters/sq m in both groups. The volume of distribution was 22 liters/sq m in single-agent chemotherapy, and 25 litres/sq m in combination chemotherapy. Linear regression analysis of the area under the plasma concentration-time curve versus the dose did not produce any evidence that the pharmacokinetics was dose dependent. However, differences were observed between patients receiving MMC alone and those on combination chemotherapy, in particular with regard to the total body clearance: 18 liters/hr/sq m for single-agent chemotherapy and 28 liters/hr/sq m for combination chemotherapy. Urinary recovery was limited to a maximum of 15% of the administered dose. In one patient studied, MMC was found to be present in the bile. There is evidence for enterohepatic circulation of MMC, and MMC was also found to penetrate into the ascites fluid.     

Pharmacokinetics of bolus 5-fluorouracil: relationship between dose, plasma concentrations, area-under-the-curve and toxicity

The pharmacokinetics of 5-fluorouracil (5FU) have been related to toxicity and antitumor activity, in particular for continuous infusion schedules, but to a lesser extent for frequently used bolus injections. The use of intensive sampling schedules limits the application of pharmacokinetics to optimize individual dosing or to define the ideal combination with other drugs. We therefore reanalyzed a pharmacokinetic study in order to develop a limited sampling schedule. Patients received escalating doses of 5FU at 500, 600 and 720 mg/m2 as a bolus until toxicity developed. Blood samples were analyzed until 24 h after administration. The area under the concentration time curve from 0-90 min (AUC(0-90)) was strongly correlated with dose and also with toxicity (p = 0.0009). The 5FU concentrations at 30 and 60 min were correlated to the AUC(30-240) and to that of the AUC(0-90) (r2 = 0.970). The use of limited sampling (30, 60, 90 min) in a patient given 353 mg/m2 5FU with severe toxicity at initial dosing at 500 mg/m2 revealed that the AUC(0-90) at 353 mg/m2 was higher than the normal AUC(0-90) for 500 mg/m2. This patient appeared to have an 8-fold lower activity of the 5FU degradation enzyme dihydropyrimidine dehydrogenase. Limited sampling will allow us to define potential aberrant kinetics of pharmacokinetic interaction of 5FU with other drugs being developed for treatment of colorectal cancer.     

Validation of the pharmacodynamics of BMS-247550, an analogue of epothilone B, during a phase I clinical study.

The primary aims of this study were to evaluate the timecourse and dose response of microtubule bundle formationin peripheral blood mononuclear cells (PBMCs) and to correlate these data with BMS-247550 pharmacokinetics. The data presented here were obtained from 17 patients enrolled in a Phase I trial who received five dose levels of BMS-247550 (7.4-59.2 mg/m(2)), given as a 1-h infusion once every 3 weeks. Plasma drug exposure or area under the curve (AUC), and tubulin bundle formation in PBMCs were assessed in cycles 1 and 2. Similar analyses were also performed on tumor biopsies from one eligible patient. PBMCs exhibited dramatic microtubule bundle formation 1 h after infusion that declined by 24 h, showing a positive correlation with AUC((0-24)) for cycles 1 and 2. A similar pattern of tubulin bundle formation also was observed in a smaller proportion of breast tumor cells from one patient who exhibited a partial response to BMS-247550. This patient's tumor expressed multidrug resistance (MDR1) and MDR-associated protein (MRP1), and in addition poly(ADPribose) polymerase cleavage, a marker of cell death, was observed within 23 h after drug infusion. This patient was also heterozygous for a novel polymorphism at the extreme COOH terminus of beta-tubulin (Gly 437 Gly/Ser), although the relevance of the polymorphism to the response is unknown. In summary, microtubule bundle formation in PBMCs occurs within 1 h of treatment with BMS-247550 and is related to plasma AUC. Similar bundle formation was seen in one tumor sample, despite expression of MDR1 and MRP1. Cell death occurred 23 h after peak microtubule bundle formation in these tumor cells. These findings validate in vitro pharmacodynamic observations.     

Pharmacokinetics and pharmacodynamics of protein-unbound docetaxel in cancer patients

Alpha(1)-acid glycoprotein, a plasma protein that binds docetaxel, is a significant determinant of the clearance and activity of docetaxel, but its serum levels in cancer patients are variable. This emphasizes the importance of investigating the pharmacokinetics of unbound drug rather than total drug in the plasma. In the present study, the pharmacokinetics and pharmacodynamics of unbound docetaxel were investigated in cancer patients. Docetaxel was infused over a 1-h period in 69 patients. The concentration of unbound docetaxel was measured in the plasma ultrafiltrate at the end of infusion and the unbound fraction (fu) was calculated. The pharmacokinetics of total docetaxel in the plasma was investigated. The area under the concentration-time curve (AUC) of unbound docetaxel was calculated by multiplying fu by the AUC of total docetaxel. The peak concentration at the end of infusion (Cmax) and AUC of total and unbound drug were compared between patients who did or did not experience grade 4 neutropenia. The median of fu was 4.0%, ranging from 1.2 to 22.6% (5-95% percentile; 1.4-10.5%). Grade 4 neutropenia was observed in 24 patients. Although Cmax and AUC of total drug were not different in patients with or without grade 4 neutropenia, patients who experienced grade 4 neutropenia had significantly greater Cmax (92.3 vs 63.3 ng/mL, P=0.01) and AUC (0.137 vs 0.104 microgxh/mL, P=0.05) of unbound docetaxel. In a logistic regression analysis, the unbound Cmax and alpha1-acid glycoprotein were determinants of grade 4 neutropenia. Pharmacokinetics of unbound drug rather than total drug is a better predictor of neutropenia for docetaxel.     

Phase I bioequivalency study of MitoExtra and mitomycin C in patients with solid tumors

BACKGROUND: This study compares serum pharmacokinetics, urinary excretion patterns, and relative bioequivalencies of single doses of MitoExtra (ME; SuperGen, San Ramon, CA) and mitomycin C (MMC). METHODS: Thirty-five patients were entered into this open-label, single-institution, crossover study with 2 treatment arms. Each patient received alternating courses of ME and MMC as 15 mg/m(2) single intravenous doses via a short intravenous infusion. Patients were sequentially assigned to receive either ME or MMC as their first treatment course. The courses were given in 6-week intervals and could be repeated up to 4 times in patients with responding disease. Pharmacokinetic parameters were analyzed during the first two courses of therapy. RESULTS: The noncompartmental pharmacokinetic analysis conducted on serum and urine data obtained from patients who received both ME and MMC indicates that the kinetic disposition of these two formulations is similar. This is evident when the mean (+/- standard deviation) values of the various pharmacokinetic parameters are compared. There were no significant differences in any of the kinetic parameters obtained between treatments in all patients examined. The statistical evaluation conducted on the 25 patients that completed both arms of the 2-way pharmacokinetic crossover demonstrates that ME is bioequivalent to MMC. Hematologic and nonhematologic toxicities were similar between the two treatments. There were three clinically significant infusion-related complications associated with MMC administration and none associated with ME. CONCLUSIONS: The similar pharmacokinetics of MMC and ME suggest complete release of MMC from the hydroxypropyl-Beta-cyclodextrin carrier contained in the ME formulation. Further studies are needed to define the pharmacodynamics, toxicity, and efficacy of this drug-carrier complex.     

A case of large-cell lung cancer responding remarkably to combination chemotherapy with vinorelbine, mitomycin C and carboplatin

The patient was a male who started to show symptoms at age 59. He was a smoker until age 40. In October 1998 he came to the hospital complaining of hemosputum and hoarseness. There was already swelling of the supraclavicular lymph nodes. Through lymph node aspiration cytology and bronchofiberscopy, large-cell carcinoma (T2N3M0, stage IIIB) was diagnosed. Chemotherapy with vindesine (VDS, 3 mg/m2), mitomycin C (MMC, 8 mg/m2) and carboplatin (CBDCA, 300 mg/m2) was conducted in three stages. Thanks to a partial response (PR) the patient was released in January 1999. However, in September 1999 he was readmitted when dysphagia, loss of body weight and dyspnea appeared. After bronchoscopy, chemotherapy combining vinorelbine (VNB, 25 mg/m2), (MMC, 8 mg/m2), CBDCA and the Calbert method calculated at AUC = 4.5 (AUC = area under the concentration-time curve) was completed in 4 stages. Upon PR and an abatement of symptoms he was released from the hospital. It is thought that treatment combining VNB is effective.     

Chemotherapy with nedaplatin for an oral floor cancer patient undergoing chronic hemodialysis

Since pharmacokinetics in patients undergoing hemodialysis differs from that in patients with normal renal function, the administration of chemotherapeutic drugs to a patient with renal failure should be sufficiently considered beforehand to avoid adverse effects. A case of carcinoma of the oral floor in a 69 year-old male receiving ongoing hemodialysis due to chronic renal failure is reported. Chemotherapy was given using nedaplatin and 5-FU; surgery was performed as well. To investigate the pharmacokinetics and determine the optimal dose of nedaplatin during ongoing hemodialysis, the concentrations of free-platinum and total-platinum in serum from the patient were measured periodically. The patient received approximately one half of the dose of nedaplatin for a patient with normal renal function. Hemodialysis was performed 3 hours after the start of the administration of nedaplatin and continued for 4 hours. As a result, the maximum concentration of nedaplatin (Cmax) was about one half of the normal range. However, the value of the area under the blood concentration time curve (AUC), which is considered a target index of administration, was close to the value in patients with normal renal function. No severe side effects were observed after chemotherapy. A Grade IV pathological effect on Ohboshi-Shimosato's classification was obtained from the specimen after radical resection.     

Pharmacokinetic analysis in intraperitoneal hyperthermic perfusion using mitomycin C in far-advanced gastric cancer

Postoperative intraperitoneal hyperthermic perfusion (IPHP) using MMC was performed with marked success on 15 gastric cancer patients with peritoneal dissemination or serosal invasion (first surgery group) and on 5 recurrent gastric cancer patients with ascitic retention (recurrent cancer group), and the MMC concentrations was studied in the perfusate and circulating blood. The perfusate contained MMC 10 micrograms/ml at the onset of IPHP, except one recurrent case of 20 micrograms/ml, and IPHP was performed for 120 minutes except in one case given 20 micrograms/ml of MMC. There was little difference in the hepatorenal functions and perfusate temperatures between the first surgery group and the recurrent cancer group. The drug levels were measured by HPLC method with minimal assay levels of 2 ng/ml. Perfusate drug levels in the first surgery group reduced by half at 12 minutes after the start of IPHP, whereas in the recurrent cancer group, they decreased by half about 60 minutes later. Perfusate drug levels in the first surgery group decreased twice as rapidly as in the recurrent cancer group. The area under the curve (AUC) and average drug levels in the first surgery group were 7,900 micrograms.hr/l and 3.3 micrograms/ml, respectively, and those in the recurrent cancer group were 12,620 micrograms.hr/l and 5.3 micrograms/ml, respectively. On the other hand, the drug levels in peripheral blood were almost the same between the two groups. These data suggest that although recurrent gastric cancer is well suited for IPHP because of high AUC, it is worthwhile performing IPHP combined with surgery for gastric cancer with peritoneal seeding, with due consideration for AUC of 7,900 micrograms.hr/l and the average drug level of 3.3 micrograms/ml.     

Pharmacokinetic study of etoposide in aged patient with non Hodgkin lymphoma receiving hemodialysis

A 78 year old patient with non Hodgkin Lymphoma receiving hemodialysis was treated with etoposide at a dose of 50 mg per body and its plasma pharmacokinetics were studied. The patient was dialyzed for 4 hours three times weekly. Etoposide was given by 60 minutes infusion on day 1 and 3, and hemodialysis was performed on day 2. The pharmacokinetic curve was found to fit to two compartment model. T 1/2 beta was 11.29 hours. Total body clearance was 13.65 mg/min/m2 on day 1 and 12.83 mg/min/m2 on day 3 respectively. AUC was 41.53 micrograms.h/ml on day 1 and 44.18 micrograms.h/ml on day 3 respectively. When these results were compared to those reported in patients with normal renal function, half life were longer while total body clearance was lower. In addition, AUC was higher. Hematologic toxicities were severe at this low dose. Hemodialysis did not influence on the decay of concentration during the elimination phase. These results suggest that it is necessary to reduce the dose of etoposide in hemodialysis patients.     

A randomized cross-over trial to determine the effect of Cremophor EL on the pharmacodynamics and pharmacokinetics of carboplatin chemotherapy

Purpose Paclitaxel, when combined with carboplatin, exhibits a platelet-sparing effect. Paclitaxel is formulated in Cremophor EL (CrEL), which has been shown in preclinical models to reduce haematological toxicity from radiotherapy and chemotherapy. We sought to determine the effect of a 3-h infusion of 20 ml/m² (equivalent to 175 mg/m² paclitaxel) CrEL on myelosuppression following carboplatin chemotherapy, and the effect of CrEL on carboplatin pharmacokinetics.Methods A total of 16 patients with locally advanced or metastatic cancer were randomized to receive either CrEL or saline over 3 h prior to carboplatin (area under the curve, AUC, 5–7). Each patient was subsequently crossed over to the other treatment. Blood samples were collected at selected time-points for estimation of platinum AUC and 24-h platinum levels. Full blood counts were obtained three times per week.Results Of the 16 patients randomized, 15 were evaluable. Myelosuppression was measured by percentage fall at nadir and nadir levels. No significant differences were obtained when comparing CrEL and saline with respect to the above end-points after adjusting for multiple testing. There was no evidence to indicate that CrEL altered the pharmacokinetics of carboplatin.Conclusion CrEL at this dose and schedule does not appear to be a major contributory factor to the platelet-sparing effect of paclitaxel when combined with carboplatin, nor does it alter the pharmacokinetics of carboplatin.