Population pharmacokinetics of cisplatin in adult cancer patients

Purpose To characterize the pharmacokinetics of the anticancer agent cisplatin, and explore the influence of patient covariates and interoccasion variability on drug disposition.Methods Data were obtained from 285 patients (519 complete curves; 3483 plasma samples) who received the drug as a 3-h intravenous infusion at a mean dose of 144 mg (range 75–210 mg). The population model was built with the use of NONMEM, performing generalized-additive modeling to identify candidate covariates including body-surface area (BSA), age, sex, height, weight, hematocrit, total protein, albumin, serum creatinine, and creatinine clearance, and using a backward deletion protocol to obtain the final models for clearance (CL) and volume of distribution (V).Results The final model was a one-compartment linear model with BSA (in meters squared) as the only significant covariate that impacted on both CL and V: TVCL (in liters per hour)=51.7+26.3×(BSA–1.855) and TVV (in liters)=41.1+24.6×(BSA–1.855), where TVCL and TVV are referred to as typical values that could be used a priori in dosage regimen design. The interindividual and interoccasion variability estimates for CL and V were 16.82 and 20.35%, and 13.93 and 22.91%, respectively.Conclusion A population pharmacokinetic model for cisplatin has been developed that incorporates measures of body size to predict clearance. In this patient population, cisplatin pharmacokinetics were not associated with age, sex, or measures of renal dysfunction.Presented previously in part at the 92nd Annual Meeting of the American Association for Cancer Research, 24–28 March 2001, in New Orleans, LA, USA.     

DNA adducts of cisplatin and carboplatin in tissues of cancer patients

An enzyme-linked immunosorbent assay (ELISA) has been developed with an antiserum elicited against cisplatin-modified DNA and used to quantify the intrastrand bidentate d(GpG)- and d(ApG)-diammineplatinum adducts in DNA samples prepared from nucleated blood cells and tissues of cancer patients receiving cisplatin or carboplatin chemotherapy. In nucleated blood cell DNA, adducts accumulated with increasing dose administered over a period of months, and a correlation was observed between the ability of a patient to form high levels of adduct and the frequency of tumour remission. Thus, many patients who did not form adducts also did not respond to therapy. Adduct distribution was shown to be widespread in many human tissues, and similar quantities of adducts were formed in peripheral blood cell DNA and tumour tissue. In addition, evidence suggests that residues of persistent adducts remain in many tissues weeks and even months after treatment. All of the above observations were obtained with the cisplatin-DNA ELISA; however, in comparison with other published data, the adduct levels reported are low. It now appears certain that the cisplatin-DNA ELISA results in an underestimation of adduct values in biological samples, since some human samples have been assayed by both this and two other procedures--the G-Pt-GMP ELISA and atomic absorbance spectroscopy. Values obtained with the two other procedures compare well with each other, but those obtained with the cisplatin-DNA ELISA for three human samples are 10-300-fold lower. The factors that result in this discrepancy are still under investigation.     

以双铂为主方案治疗晚期恶性肿瘤41例报告

目的：评价双铂为主方案的耐受性,毒性和初步疗效。方法：自1998年10月起,以双铂为主方案治疗晚期恶性肿瘤41例。化疗方案以CBP＋PDD分别与Vp-16,Vm-26,CF,5-FU,CTX及ADM配伍。其中CBP 200－300mg iv第1天,PDD 40－50mg iv第3,4,5天。15例同时合并放疗。结果：全组共完成101个周期,中位周期数2。可评价疗效31例,可评价毒性41例。总有效率67．74％（21／31）。常见的毒副反应为骨髓抑制,发生率85．37％（35／41）。其中I度19．51％（8／41）,Ⅱ度41．46％（17／41）,Ⅲ度21．95％（9／41）。结论：双铂为主方案的疗效较好,耐受,毒副反应轻微。     

Influence of the cisplatin hydration schedule on topotecan pharmacokinetics

The study described here was designed to investigate the influence of the hydration schedule of cisplatin on the pharmacokinetics of topotecan. To test this hypothesis, 13 adult cancer patients were treated with intravenous (i.v.) cisplatin followed by i.v. topotecan for 5 days every 3 weeks using a short hydration schedule (SHS) for cisplatin in the first course and a hyper-hydration schedule (HHS) in the second course or vice versa. Topotecan pharmacokinetic analysis was performed in plasma, whole blood and red blood cells in both courses on days 1, 2 and 5. 11 patients received both courses and were pharmacokinetically evaluable. No significant differences between the two studied schedules were noted in the clearances of topotecan on day 1 in the different matrices. However, in both hydration schedules, on average, slightly lower topotecan clearances were observed on both days 2 and 5 compared with day 1 in all of the matrices, while no differences were noted between days 2 and 5. This alteration was independent of the schedule used and was less pronounced than that which has been initially reported for SHS and, overall, will not have clinical consequences.     

含紫杉醇化疗方案治疗晚期头颈部恶性肿瘤

目的：探讨紫杉醇类药物分3周疗法治疗晚期头颈部恶性肿瘤的价值和毒性。方法：对51例临床Ⅲ-Ⅳ期的头颈部恶性肿瘤患者（初治19例,复治32例）选用紫杉醇与卡铂或顺铂联合治疗：紫杉醇75－100mg/m^2,静滴,第1、8、15天,卡铂300－350mg/m^2,静滴,第2天,(或顺铂20mg/m^2,静滴,第1－5天）。每4周重复,共展3－6周。结果：51例患者完全缓解（CR）4例（7．8％）,部分缓解（PR）15例（29．4％）,无变化（NC)18例（35．3％）,进展（PD）14例（27．4％）,总有效率（RR）37．2％。疗程中出现耐药复发或转移的11例（21．6％）。其中初治的19例患者中,CR2例（10．50）,PR6例（31．6％）,RR为42．1％,较复治患者的RR有显著性差异（P＜0．05）。主要不良反应：骨髓抑制、肢体感觉异常、面色潮红、发热、脱发、消化道反应,并出现可疑过敏性休克死亡1例（2．0％）。结论：含紫杉醇的化疗方案治疗晚期头颈部恶性肿瘤有较好的疗效,即使在治疗对常规化疗耐药的患者也能取得一定的疗效,多数毒副作用处于可以耐受范围,但可能有严重的过敏性反应。     

Randomized trial in advanced ovarian cancer comparing cisplatin and carboplatin

The aim of this multicenter randomized trial was to compare carboplatin (400 mg/m2) and cisplatin (100 mg/m2) in patients with untreated advanced epithelial ovarian cancer. Toxicity and treatment efficacy assessed by pathological response rate, progression-free survival, and survival were the endpoints of the study. One hundred seventy-three patients with advanced epithelial ovarian cancer, F.I.G.O. (International Federation of Gynecology and Obstetrics) stage III and IV were accrued in the trial. The median follow-up time was 15 months (maximum, 34); three patients in each treatment arm were not eligible (four, nonepithelial ovarian cancer type; one, no data, and one, stage II). Patient characteristics were similar in the two groups. In the carboplatin-treatment arm, the overall pathological response rate was 57.3% and the complete pathological response rate was 26.8%. In the cisplatin-treatment arm, the overall pathological response rate was 71.6% and the complete pathological response rate was 24.7%. There was no statistical difference in the two arms in survival or progression-free survival. Cisplatin was more nephrotoxic while carboplatin induced a higher degree of myelosuppression, especially thrombocytopenia; however, severe hematological toxicity was seldom observed. Carboplatin is a cisplatin analog with definite activity in ovarian cancer, but it is more active than the parent compound. Because of less nonhematological toxicity, carboplatin is undoubtedly a useful substitute in patients who cannot be given cisplatin. Further experience is needed to indicate whether or not carboplatin should completely displace cisplatin in the clinical treatment of ovarian cancer.     

Prognostic results of cisplatin IP and carboplatin IV with G-CSF in patients with ovarian cancer

We performed a dose-escalation study of carboplatin combined with a fixed dose of intraperitoneal cisplatin and G-CSF in patients with epithelial ovarian cancer, and analyzed the progression-free and overall survival. Six of the patients who entered the study with stage IC and II disease are still alive with no evidence of disease. The five-year survival rate was 61% for the 18 patients with stage III and IV disease; progression-free survival over 5 years was 32%. Our results show this to be an effective treatment regimen for epithelial ovarian cancer. Prognosis is good with this combined carboplatin/cisplatin/G-CSF therapy, especially for those patients with microscopic or no residual disease.     

Relationship between pharmacokinetics of unchanged cisplatin and nephrotoxicity after intravenous infusions of cisplatin to cancer patients

 Purpose: The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80 mg/m²) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor). Methods: Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary β₂-microglobulin (BMG_p and BMG_u), urinary N-acetyl-β-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration. Results: The maximum plasma concentration (C_max), maximum urinary excretion rate (dAe/dt_max), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t_1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m²) caused nephrotoxicity. The C_max of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. C_max was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model. Conclusion: In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the C_max or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 μg/ml in a standard continuous infusion schedule over 2 h and 4 h. Received: 2 May 1995/Accepted: 25 March 1996     

吉西他滨联合顺铂或卡铂治疗晚期非小细胞肺癌的近期疗效

目的 :观察吉西他滨 (gemcitabine)联合顺铂与吉西他滨联合卡铂治疗晚期非小细胞肺癌的疗效和毒性反应。方法 :10 6例经病理组织学或细胞学证实的晚期非小细胞肺癌患者分为GP和GC两组 ,GP组应用吉西他滨 10 0 0mg/m2 ,静滴 ,第 1、8天 ;顺铂 30mg/m2 ,静滴 ,第 1～ 3天。GC组应用吉西他滨 10 0 0mg/m2 ,静滴 ,第 1、8天 ;卡铂ACU =5 ,静滴 ,第 1天。 2 1天为 1个周期 ,连用 2个周期评价疗效。结果 :GP组和GC组有效率 (CR PR)分别为 4 8.1%和 4 4 .2 % (P >0 .0 5 ) ;中位疾病进展时间分别为 6 .8个月和 6 .2个月 (P >0 .0 5 ) ;毒性反应中GP组消化道毒副反应较GC组大 ,差异有显著性 ;骨髓毒性两组相当 ,差异无显著性。结论 :吉西他滨联合顺铂及吉西他滨联合卡铂两方案治疗晚期非小细胞肺癌疗效均较好 ,毒性反应轻微 ,患者耐受良好 ,尤其吉西他滨联合卡铂的消化道反应轻 ,患者易于接受 ,值得临床进一步研究。     

Vinblastine pharmacokinetics in patients with non-small cell lung cancer given cisplatin.

The pharmacokinetics of vinblastine were studied in 16 patients with non-small cell lung cancer after a bolus intravenous dose of 3 mg/m2 given before or after cisplatin (100 mg/m2). Venous blood was collected at 0, 10, and 36 hr for analysis by radioimmunoassay. The mean plasma vinblastine concentration at 10 hr was similar when vinblastine was given before (4.8 ng/ml; 95% CI, 3.2-6.3) or after cisplatin (4.9 ng/ml; 95% CI, 2.7-7.1). Plasma vinblastine concentrations in patients given cisplatin were higher than previously reported in patients given vinblastine alone. Patients with plasma vinblastine concentrations less than 2.75 ng/ml at 10 hr experienced less severe neutropenia (37% fall in neutrophil count; 95% CI, 18-55) than those with levels greater than 2.75 ng/ml (69% fall in neutrophil count; 95% CI, 62-77). In conclusion, the pharmacokinetics of vinblastine predict the severity of neutropenia and may be altered when given in conjunction with cisplatin.     

Influence of the antacid Maalox on the pharmacokinetics of capecitabine in cancer patients

Purpose: In the present study the possible influence of the antacid Maalox on the pharmacokinetics of capecitabine (Xeloda) and its metabolites was investigated in cancer patients. Methods: A total of 12 patients with solid, predominantly metastatic tumors of various origin received a single oral dose of 1250 mg/m² of capecitabine (treatment A), a single oral dose of 1250 mg/m² of capecitabine followed immediately by 20 ml of Maalox (treatment B), and a single oral dose of 1250 mg/m² of capecitabine followed 2 h later by 20 ml of Maalox (treatment C) in an open, randomized, three-way cross over fashion. Serial blood and urine samples were collected for up to 24 h after each administration. Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chromatography/mass spectrometry and in urine using nuclear magnetic resonance spectroscopy. Results: Administration of Maalox either concomitantly with capecitabine or delayed by 2 h did not influence the time to peak plasma concentrations (C_max) or the elimination half-lives of capecitabine and its metabolites. Unexpectedly, moderate increases in the C_max and AUC_0–∞ values obtained for capecitabine and 5′-deoxy-5-fluorocytidine were observed when Maalox was given together with capecitabine. However, these increases, which ranged between 10% and 31%, were not statistically significant (P > 0.05) and are not of clinical significance. There was no indication of consistent changes in the plasma concentrations of the other metabolites 5′-deoxy-5′-fluorouridine (5′-DFUR), 5-fluorouracil, and α-fluoro-β-alanine. The C_max and AUC_0–∞ values recorded for these three metabolites increased and decreased in a stochastic manner. The magnitude of these changes was low (<13%) and not statistically significant. The primary statistical analysis of the AUC_0–∞obtained for 5′-DFUR provided a P value of 0.4524 and clearly indicated no significant difference between the treatments. The addition of Maalox had no influence on the overall urinary recovery or the proportion of the dose recovered as capecitabine or its metabolites from urine. Conclusion: At the dose used in this study, the effect of concomitantly delivered Maalox on the extent and rate of gastrointestinal absorption of capecitabine is not clinically significant. Therefore, there is no need to adjust the dose or timing of capecitabine administration in patients treated with Maalox. Received: 11 May 1998 / Accepted: 17 August 1998     

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.     

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy.

Platinum (Pt)-DNA adducts were measured in peripheral blood leucocytes (PBLs) from 24 children with solid tumours after standard cisplatin and/or carboplatin treatment. The relationship between Pt-DNA adduct levels and pharmacokinetics of cisplatin and carboplatin was investigated. Adduct measurements were performed by competitive enzyme-linked immunosorbent assay (ELISA) and plasma unbound Pt concentrations were measured by atomic absorption spectrophotometry (AAS). There was considerable interindividual variation in Pt-DNA adduct level that was weakly correlated (r2 = 0.32) with the area under the unbound drug concentration vs time curve (AUC) at 6 h after the start of cisplatin infusion, indicating that the variation in Pt-DNA adduct levels was primarily determined by factors other than AUC. No clear relationship between AUC and adduct levels was seen at 24 and 48 h after cisplatin or at 6, 24 or 48 h after carboplatin. Carboplatin produced lower levels of immunoreactive adducts than did cisplatin (1.3 +/- 0.6 nmol Pt g-1 DNA vs 3.2 +/- 1.7 nmol Pt g-1 DNA), despite a 20-fold higher unbound drug AUC for carboplatin (8.0 +/- 3.5 mg ml-1 min vs 0.4 +/- 0.2 mg ml-1 min). This study demonstrates that, after cisplatin and carboplatin treatment the drug-target interaction is determined by both pharmacokinetic and, predominantly, cellular factors. Intrinsic differences between the two complexes, primarily reactivity, probably explain the lower adduct levels observed after carboplatin treatment.     

DHMEQ enhances the cytotoxic effect of cisplatin and carboplatin in ovarian cancer cell lines

Ovarian cancer (OvCa) is one of the most lethal gynaecological malignancies. It is diagnosed mostly in advanced stages. Due to a lack of appropriate early detection markers and non-ambiguous symptoms, the five-year survival rate is significantly reduced. Despite a primary good response to platinum-based therapy, approximately 70% of patients will develop a chemoresistance phenotype. The activation of the NF-κB signalling pathway plays a crucial role in this process. It is responsible for increasing cell viability, cell cycle progression and induces growth and migration of neoplastic cells. A few independent studies have yet suggested a high correlation between activation of NF-κB and poor outcome in OvCa patients. Thus, developing inhibitors of the NF-κB pathway has become a new target of cancer therapies. One of the promising compounds is DHMEQ (dehydroxymethylepoxyquinomicin). Our preliminary studies indicated that DHMEQ combined with cisplatin (CDDP) or carboplatin (CBP) enhanced apoptosis in the A2780 cell line and caused cell cycle arrest in the G2/M phase in the SKOV3 cell line, but not in the normal cell line MRC-5 pd19. Moreover, the combination of those agents caused decreased motility of cells, especially with the CBP. However, the invasion of cells was not changed significantly. The analysis of drug interactions using CompuSyn software has revealed that observed effect of the doses used in the study was antagonistic, but the DRI guidelines and in vitro observation of biological response indicate that a combination of DHMEQ with CDDP or CBP could be a novel proposal in ovarian cancer treatment.     

CPE和CE方案治疗小细胞肺癌的疗效比较

目的　评价CPE(卡铂、顺铂、足叶乙甙)和CE(卡铂、足叶乙甙)方案治疗小细胞肺癌(SCLC)的疗效和毒性。方法　应用CPE和CE方案治疗32例SCLC患者,每组16例,CPE组和CE组中的复治病例分别为10例和7例。结果　CPE组和CE组的有效率分别为81.3%(13/16)和87.5%(14/16)(P>0.05)。CPE组与CE组中的复治病例有效率分别为60%(6/10)和42.9%(3/7)(P<0.05)。CPE组与CE组的骨髓抑制率分别为71.9%和93.8%(P<0.05)。两组间其它毒性反应差异无显著性(P>0.05)。结论　CPE方案治疗SCLC的疗效与CE方案相近,但CPE的骨髓抑制明显较CE轻;CPE对复治病例的疗效优于CE。     

High-dose platinum consisting of combined carboplatin and cisplatin in previously untreated ovarian cancer patients with residual disease

A phase II trial of carboplatin, 300 mg/m2 day 1, and cisplatin, 50 mg/m2 days 2 and 3 every 4 weeks for six cycles, was performed in 42 previously untreated patients with residual disease after primary laparotomy. Overall, 79% of patients had primary residual tumor larger than 2 cm. The overall pathologic response rate (pathologic complete response [PCR] plus partial response [PPR]) in 37 evaluable patients was 62%, and in PCRs was 22%. Of the responding patients, 78% had primary residual tumor larger than 2 cm. The toxicity was cumulative but manageable, with thrombocytopenia being the main reason for dose reduction. Dose-limiting nephrotoxicity and neurotoxicity occurred in 22% and 7% of the patients, respectively. Combined high-dose platinum as a "single agent" appears to be as active as combination chemotherapy containing cisplatin, and the treatment is feasible. Further clinical trials of this combination alone or combined with other drugs are warranted.     

Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates.

PURPOSE: Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species. EXPERIMENTAL DESIGN: Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration x time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC(0-24)/plasma ultrafiltrate AUC(0-24) ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites. RESULTS: The mean +/- SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 +/- 22, 18 +/- 6, and 211 +/- 64 micromol/L hour, respectively. The AUCs in CSF were 1.2 +/- 0.4 micromol/L hour for oxaliplatin, 0.56 +/- 0.08 micromol/L hour for cisplatin, and 8 +/- 2.2 mumol/L hour for carboplatin, and CSF penetration was 2.0%, 3.6%, and 3.8%, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29%, 79%, and 81% of platinum in plasma ultrafiltrate, respectively, and 25%, 89%, and 56% of platinum in CSF, respectively. The CSF penetration of active drug was 1.6% for oxaliplatin, 3.7% for cisplatin, and 2.6% for carboplatin. CONCLUSIONS: The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF.     

Combined high-dose carboplatin and cisplatin, and ifosfamide in previously untreated ovarian cancer patients with residual disease

Carboplatin 200 mg/m2 day 1, cisplatin 50 mg/m2 days 2 and 3, ifosfamide 1,500 mg/m2 days 1 to 3, and mesna 900 mg/m2 days 1 to 3 every 4 weeks for six cycles were given to 37 previously untreated ovarian cancer patients with residual disease after the primary laparotomy. The median observation time was 17+ months (range, 9+ to 24+ months). Of all the patients, 81% had primary residual disease larger than 2 cm. The overall pathologic response rate (pathologic complete response [PCR] plus partial response [PPR]) in 36 assessable patients was 58%, PCR was 42%. Of the PCR patients, 53% had primary residual tumor larger than 5 cm. The substantial hematologic toxicity was manageable, but also the main reason for dose modifications. During treatment, 92% and 100% of the patients developed WBC and platelet nadir values corresponding to World Health Organization (WHO) grades 3 to 4. Dose-limiting encephalopathy, nephro- and neurotoxicity each occurred in 6% of the patients. The high PCR rate warrants further investigations of combined high-dose platinum and ifosfamide.