高剂量表阿霉素在肿瘤患者中的药物动力学和药效学研究

目的：研究高剂量表阿霉素（ＥＰＩ）在肿瘤化疗患者体内的药物动力学过程,并初步探讨药效学特点。方法：１１例肿瘤患者接受了包含１００ｍｇ／ｍ＾２高剂量ＥＰＩ的联合化疗,高效液相色谱法（ＨＰＬＣ）测定血药浓度,ＰＬＮＯＮＬＩＮ程序进行药动力学房室模型数据拟合和参数计算;血液学毒性指标作为药效学参数,进行药动力学和药效学相关性及剂量调整因素的研究。结果：高剂量ＥＰＩ的消除具有典型的三室特征,患者对ＥＰＩ的     

A limited sampling strategy for the study of pirarubicin pharmacokinetics in humans

Pirarubicin (4-O-tetrahydropyranyldoxorubicin, THP-Adriamycin) is a new anthracycline antibiotic that has recently been developed because its reduced cardiac toxicity is associated with an antitumour efficacy similar to that of doxorubicin. Pirarubicin is characterised by strong haematological toxicity, which has been shown to be correlated with pharmacokinetic parameters, especially the area under the time-concentration curve. To obtain routine pharmacokinetic evaluations of pirarubicin for dose monitoring we developed a limited sampling strategy relying on three blood samples taken at the end of the infusion and at 12 and 24 h post-infusion. The characteristics of interindividual variability were assessed on the first courses of treatment performed in 18 patients; the model was then validated on 10 independent first courses of treatment performed in 10 other patients. The main pharmacokinetic parameters (half-lives, total volume of distribution, total plasma clearance) were estimated in the test group by maximum-likelihood estimation using all samples and by Bayesian estimation using three samples. The concordance between the two estimates was correct (the bias and precision for clearance were 2.3% and 12.1%, respectively), which shows that this limited sampling strategy can be used in routine drug monitoring.     

Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks

Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ringopened hydroxy acid, is essential for this activity. The open form predominates at physiological pH. We performed a pharmacokinetic, study as part of a phase I study in patients with various types of solid tumors, where topotecan was administered in a 30-min infusion daily on 5 consecutive days every 3 weeks. The plasma kinetics of topotecan could be described best using an open two-compartment model with t1/2() and t1/2() of 8.1 (range 0.3 to 40.7) min and 132 (range 49 to 286) min, respectively. The plasma concentration-time profiles of the metabolite, however, could be described using a one-compartment model with t1/2(formation) of 29.0 (range 5.6–99.5) min and t1/2 (elimination of 123.2 (range 32–265) min, respectively. The lactone was the predominate form during the first hour from the start of infusion, but was rapidly converted into its ring-opened structure. The elimination rate of topotecan was independent of the dose. There were linear relationships between the dose (mg m^–2 day^–1), the area under the plasma concentration versus time curve (AUC) of topotecan and its metabolite, the total AUC, peak plasma lactone concentrations, and the time period that the topotecan concentrations remained above 10 nM. Different models were used to correlate pharmacokinetic and pharmacodynamic parameters. The percentage decrease in absolute neutrophil count (ANC) was related to these parameters and plots were well fitted by linear and sigmoidal E_max models.     

Pharmacokinetics and pharmacodynamics of irinotecan and its metabolites from plasma and saliva data in patients with metastatic digestive cancer receiving Folfiri regimen

Purpose: Irinotecan is extensively metabolized into at least four compounds and previous pharmacokinetic–pharmacodynamic studies have given varying results. We hypothesized that saliva, a noninvasive, safe and painless biological sampling process, could be a good predictor of the behavior of irinotecan and its metabolites. Methods: Thirty-five patients with metastatic digestive cancer were treated with a Folfiri regimen every 2 weeks. The irinotecan-administered dose was 180 mg/m²; 17 patients participated in a dose-escalating study. Irinotecan and its metabolites (SN-38, SN-38G, APC, NPC) were quantified in plasma and saliva by high-performance liquid chromatography with fluorescence detection. Results: The mean irinotecan systemic clearance and steady-state volume of distribution values were 14.3 l/h/m² and 211 l/m², respectively. The intrapatient variability (22–28%) was far lower than the interindividual variability (33–88%). Age and weight were the two physiological parameters that influenced drug disposition. For irinotecan, SN-38, APC and NPC, similar pharmacokinetic profiles were observed from plasma and saliva data. The saliva/plasma AUC ratios averaged 1 for irinotecan, 0.3 for SN-38, 0.17 for APC and 0.27 for NPC. Neutropenia, diarrhea and nausea were the main toxicities encountered. From both plasma and saliva data, the percentage decrease in neutrophil count appeared to be related to irinotecan and SN-38 AUCs. Conclusions: All these findings provide a rationale for an individual adaptation of irinotecan dosing. In case of difficult venous access, the titration of irinotecan and of its active metabolite SN-38 in saliva may prove relevant.     

Pharmacokinetics and pharmacodynamics of a novel protein kinase inhibitor, UCN-01

Purpose: 7-Hydroxystaurosporine (UCN-01) is a potent protein kinase inhibitor and is being developed as a novel anticancer agent. We describe here its pharmacokinetics and pharmacodynamics in experimental animals. Methods: The pharmacokinetics of UCN-01 were studied following intravenous (i.v.) administration to mice, rats and dogs at doses of 1–9, 0.35–3.5 and 0.5 mg/kg, respectively. We also studied the pharmacodynamics of UCN-01 (9 mg/kg per day) during and after five consecutive i.v. administrations to nude mice bearing xenografted human pancreatic tumor cells (PSN-1). The concentrations of UCN-01 in plasma and tumor were measured by HPLC using a fluorescence detector. Results: UCN-01 in plasma after i.v. administration was eliminated biphasically in mice and rats, and triphasically in dogs. The elimination half-lives in mice, rats and dogs were 3.00–3.98, 4.02–4.46 and 11.6 h, respectively. The total clearance (Cl_total) values in mice, rats and dogs were high (1.93–2.64, 2.82–3.86 and 0.616 l/h per kg, respectively). The hepatic clearance (Cl_hepatic) in rats represented 54.0–81.3% of Cl_total. The volumes of distribution at steady-state in mice, rats and dogs were large (7.89–8.42, 13.0–16.9 and 6.09 l/kg, respectively). These pharmacokinetic parameters were dose-independent in mice and rats. UCN-01 produced significant inhibition of tumor growth during five consecutive i.v. administrations in mice bearing the xenografted PSN-1 cells, and the inhibitory effect continued for 3 days after the final administration. UCN-01 concentrations in tumor tissue were much higher than those in the plasma, and the ratio of tumor to plasma concentrations was about 500 at 24 h after five consecutive doses. Conclusions: The pharmacokinetic studies showed that UCN-01 has a high clearance and large distribution volume in various experimental animals, and its disposition is linear over the range of doses tested. The pharmacodynamic study showed that UCN-01 is distributed at much higher concentrations in tumor than those in plasma and that it significantly inhibits tumor growth. The high distribution of UCN-01 into tumor cells may contribute to the potent inhibition of tumor growth in vivo. Received: 29 April 1998 / Accepted: 28 October 1998     

Pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine, and effects of CYP3A5 and MDR1 polymorphisms in patients with urogenital cancers

Background We investigated the pharmacokinetics and pharmacodynamics of paclitaxel with carboplatin or gemcitabine in patients with urogenital cancer to clarify the significance of monitoring of the serum concentration of paclitaxel. Methods Paclitaxel was administered at 175 mg/m² or 150 mg/m² to patients with hormone-refractory prostate cancer (n = 10) or advanced transitional cell carcinoma (n = 6) along with carboplatin or gemcitabine, respectively. The relationships between pharmacokinetic parameters and hematological adverse effects, as well as pharmacological effects, were examined. The effects of patient characteristics, including single-nucleotide polymorphisms of MDR1(ABCB1), CYP2C8, CYP3A4, and CYP3A5, on the total body clearance of paclitaxel were evaluated. Results Total body clearance and volume of distribution at a steady-state after the intravenous infusion of paclitaxel were not significantly different between patients with carboplatin or gemcitabine. The percent decreases in neutrophils and platelets for the regimen with gemcitabine were significantly greater than those with carboplatin, and showed a significant positive relationship with the observed concentration at the end of infusion or time above 0.1-μM concentration of paclitaxel. Post-therapy decreases in prostate-specific antigen were not positively correlated with the extent of paclitaxel exposure in the prostate cancer patients. Neither the polymorphisms at exon 26 (C3435T) and at exon 21 (G2677A/T) in MDR1 nor the CYP3A5*1 allele significantly affected the total body clearance of paclitaxel. Conclusion The hematological side effects of paclitaxel were intensified by gemcitabine, and were correlated with paclitaxel pharmacokinetics. Monitoring of the serum concentration of paclitaxel will facilitate the therapy, with less myelosuppression and without any loss of therapeutic efficacy.     

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     

Pharmacokinetics and pharmacodynamics of the new podophyllotoxin derivative NK 611 A study by the AIO groups PHASE-I and APOH

 NK 611 is a new podophyllotoxin derivative in which a dimethyl amino group replaces a hydroxyl group at the sugar moiety of etoposide. This results in profound physico-chemical differences: NK 611 is much less hydrophobic than etoposide. Preclinical studies have shown that NK 611 is advantageous in terms of bioavailability and of the potency of its anticancer activity. A clinical phase I study was performed in cancer patients within the framework of the AIO. Additionally, its pharmacokinetics and pharmacodynamics were investigated. NK 611 was given to 26 patients at doses ranging from 60 to 140 mg/m² [maximum tolerated dose (MTD) 120 mg/m²] in a 30-min infusion. Plasma and urine samples were collected from 25 patients and analyzed using a validated high-performance liquid chromatography (HPLC) assay procedure. The concentration versus time curve of total NK 611 in plasma samples was best described by a three-compartment model. The overall median pharmacokinetic values were as follows (ranges are given in parantheses): mean residence time (MRT) 16.5 (5.4– 42.3)h, terminal half-life 14.0 (8.2–30.5)h, volume of distribution at steady state (V_ss) 11.4 (7.9–18.1) l/m², and plasma clearance (Cl_p) 15.1 (3.6–36.4) ml min^-1 m ^-2. The total systemic drug exposure, represented by the area under the curve (AUC), varied between 53.4 and 532.0 μg ml^-1 h. The mean AUC (±SD) increased with the dose from 78.7±3.7 μg ml^-1 h at 60 mg/m² up to 202.8±157.2 μg ml^-1 h at 120 mg/m². The mean urinary excretion (UE) fraction of unchanged drug at 48 h after the end of the infusion varied between 3.0% and 25.8% of the total dose delivered. Analysis of ultrafiltrate samples showed a protein binding of approx. 99%. The percentage reduction in white blood cells (WBC) and neutrophils (ANC) correlated with the dose, AUC, and AUC_free. The best relationship between the percentage of reduction in ANC and a pharmacokinetic parameter (AUC) took a nonlinear Hill-type form. The laboratory parameter for kidney or liver function did not correlate with the AUC. The variation of pharmacokinetic parameters within each dose level was profound. The reason for this pharmacological behavior remains unclear and should be investigated in further studies. Received: 8 May 1995/Accepted: 27 October 1995     

Pharmacokinetics of doxorubicin and epirubicin in mice during chlorpromazine-induced hypothermia

Blood concentrations of doxo- and epirubicin were studied in mice after i.v. or i.p. administration under normal and hypothermic conditions. The animals either were pretreated i.p. with chlorpromazine at 15 mg/kg and allowed to cool to a rectal temperature of 28 °C or were given saline i.p. with their rectal temperature remaining at 37 °C. The anthracyclines were 14-¹⁴C-labeled and were given at a dose of 0.85 mg/kg. Blood samples were taken at 5, 15, and 25 min and 2, 6, 24, and 48 hours after injection and were analyzed by liquid scintillation counting. The blood concentration related to time was similar for the two anthracyclines. The peak concentration was highest for i.v. administration and was higher for the hypothermic groups. The peak concentration and the area under the curve were highest under hypothermic conditions. The terminal half-life was longer after i.p. administration. The ratio calculated for the blood concentration under hypothermic/normothermic conditions over time was substantially increased after i.p. administration, the increase being most pronounced for epirubicin. The pharmacokinetic characteristics found might be related to the anthracycline toxicity encountered in tumor-inoculated mice treated at different body temperatures. Received: 27 May 1996 / Accepted: 8 February 1997     

Pharmacokinetics and pharmacodynamics of topotecan given on a daily-times-five schedule in phase II clinical trials using a limited-sampling procedure

 Topotecan is a novel semisynthetic derivative of the anticancer agent camptothecin and inhibits the intranuclear enzyme topoisomerase I. The lactone structure of topotecan, which is in equilibrium with the inactive ring-opened hydroxy acid, is essential for this activity. We performed a pharmacokinetics study as part of phase II clinical trials in patients with various types of solid tumors, giving topotecan at 1.5 mg/m² per day by 30-min infusion for 5 consecutive days, with courses being repeated every 3 weeks. Previously validated limited-sampling models, using concentration measurements in samples obtained 2 h after infusion, were used to calculate the area under the plasma concentration-time curves (AUCs) for both chemical forms. Samples were obtained from a total of 36 patients over 136 treatment days. The mean AUC of the closed-ring form (AUC_closed) was 8.74 (range 2.3–16.3)  μM min per day, and the mean AUC of the ring-opened form (AUC_open) was 11.5 (range 3.2–46.0)  μM min per day (interpatient variability 34–61%). In each patient the AUC values achieved on the 1st day of administration were similar to and, thus, predictive for those achieved during the following days, with a day-to-day variation of 7.39% being recorded for the AUC_closed and that of 12.6%, for the AUC_open. There was no drug accumulation during the 5 consecutive treatment days of each cycle. However, despite the large interpatient pharmacokinetic variability, the importance of regular drug monitoring on this schedule can be questioned, as the pharmacodynamic variability was relatively small. Received: 15 June 1995/Accepted: 19 October 1995     

Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts

Purpose 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) is a water-soluble analogue of 17-(allylamino)-17-demethoxygeldanamycin (17AAG), a compound currently in clinical trials. These preclinical studies: (1) characterized 17DMAG concentrations in plasma, normal tissues, and tumor after i.v. delivery to mice; and (2) correlated tumor and normal tissue 17DMAG concentrations with alterations in heat shock protein 90 (HSP90) and selected HSP90-chaperoned proteins.Methods At specified times after i.v. administration of 75 mg/kg 17DMAG, SCID mice bearing s.c. MDA-MB-231 human breast xenografts were killed and plasma and tissues were retained. 17DMAG concentrations were determined by HPLC. Raf-1, heat shock protein 70 (HSP70), and HSP90 in tissues were determined by Western blotting.Results Peak plasma 17DMAG concentration was 15.4±1.4 g/ml. The area under the plasma 17DMAG concentration versus time curve was 1072 g/ml min, corresponding to a total body clearance of 70 ml/kg/min. Peak 17DMAG concentrations in liver (118.8±5.7 g/g), kidney (122.9±10.6 g/g), heart (81.3±8.1 g/g), and lung (110.6±25.4 g/g) occurred at 5–10 min, while peak concentrations in spleen (70.6±9.6 g/g) and tumor (9.0±1.0 g/g) occurred at 30–45 min. At 48 h, 17DMAG was detectable in tumor but not in any normal tissue. Raf-1 in tumors of 17DMAG-treated mice killed at 4, 7, 24 and 48 h was about 20% lower than in tumors from vehicle-treated mice. HSP90 and HSP70 in tumors of 17DMAG-treated animals were significantly lower than in tumors of control animals at 4, 7, and 24 h. Hepatic Raf-1 was decreased by more than 60% at all times after 17DMAG treatment; however, hepatic HSP90 was not affected. HSP70 was undetectable in livers of vehicle-treated mice or mice killed at 2 or 4 h after 17DMAG treatment, but was detected in livers at 7, 24 and 48 h. 17DMAG did not affect renal Raf-1. In contrast, renal HSP70 and HSP90 were decreased by more than 50% at 2 and 4 h after 17DMAG treatment. Renal HSP70 increased approximately twofold above that in kidneys from vehicle-treated control mice at 7 and 24 h, while HSP90 relative protein concentration was no different from that in controls.Conclusions Plasma pharmacokinetics of 17DMAG in tumor-bearing mice were similar to those previously reported in nontumor-bearing mice. 17DMAG was distributed widely to tissues but was retained for longer in tumors than normal tissues. Raf-1, HSP90, and HSP70 were altered to different degrees in tumors, livers, and kidneys of 17DMAG-treated animals. These data illustrate the complex nature of the biological responses to 17DMAG.This work was supported by contract NO1-CM07106 and Grant 2P30 CA47904, awarded by the National Cancer Institute.     

Pharmacokinetics of a HER2 tyrosine kinase inhibitor CP-724,714 in patients with advanced malignant HER2 positive solid tumors: correlations with clinical characteristics and safety

Purpose CP-724,714 is an orally available, small molecule, potent HER-2 tyrosine kinase inhibitor under development for the treatment of advanced HER2-overexpressing cancers. In this study, the influence of baseline clinical characteristics and pathophysiological variables on the pharmacokinetics (PK) of CP-724,714, and the correlation between PK exposure and safety were examined in patients treated in the First-in-Human trial. PK and safety were also simulated for a Phase 2 trial at the recommended Phase 2 dose (RP2D) to assess if the simulated PK exposures of CP-724,714 covered the preclinically predicted efficacious concentrations, and if the predicted incidence of hepatic toxicities (≥CTC grade 3) was acceptable. Methods Patients (n = 30) with advanced malignant HER2 positive solid tumors were enrolled in this open label dose-escalation study, and treated with daily oral dosing of CP-724,714 in 21-day cycles at the following dose levels: 250 mg QD, 250 mg BID, 400 mg BID, and 250 mg TID. PK parameter values were estimated using noncompartmental techniques. PK exposure parameters were correlated with the baseline pathophysiological variables, clinical characteristics, and safety. The simulations of PK exposures and the incidence of ≥grade 3 liver toxicity at the recommended Phase 2 dose were performed by nonparametric bootstrap (n = 1,000). Results C _max and AUC increased in an approximate dose proportional manner. The terminal t _1/2 was approximately 4.5 h, and was constant across the dose range from 250 to 400 mg. There was some accumulation with BID and TID dosing with a mean AUC accumulation ratio ∼1.2–1.5, consistent with the t _1/2. Inter-patient variability in PK parameters was 31–65%, resulting in a considerable overlap of systemic exposure parameters (C _max and AUC) at higher doses (i.e., 250 mg TID and 400 mg BID), as expected for the narrow dose range. Significant correlations were observed for body size and oral clearance (CL/F) (r = 0.574, P = 0.001) and oral steady-state volume of distribution (V _dss/F) (r = 0.669, P = 0.0001). The most frequently encountered toxicities were elevated ALT and AST, hyperbilirubinemia, rash, asthenia, and nausea/vomiting (N/V). The steady-state AUC0-24 h was significantly correlated with the elevation of total bilirubin (r = 0.670, P = 0.001), ALT (r = 0.548, P = 0.002), and AST (r = 0.461, P = 0.010). The simulation of the Phase 2 trial at 250 mg BID predicted that the 95% confidence interval of the simulated mean concentrations of CP-724,714 were above the preclinically predicted efficacious concentrations throughout the majority of the dosing interval. The probability for ≥33% incidence of grade 3 or greater elevations of liver function test (LFT) was low (1.1%). Conclusions CP-724,714 demonstrates linear single-dose and multiple-dose PK. Both CL/F and V _dss/F correlate with body size. Elevations of ALT, AST, and total bilirubin positively correlate with the steady-state AUC0-24 h. The Phase 2 trial simulation suggests that CP-724,714 will be well tolerated and that PK exposures will exceed the preclinically predicted efficacious level at the recommended Phase 2 dose (250 mg BID), supporting further evaluation of CP-724,714 in the Phase 2 trial.     

Pharmacokinetics of once and twice daily dosing of intravenous tobramycin in paediatric patients with cystic fibrosis

The optimal dosing of intravenous tobramycin for treatment of pulmonary exacerbations in paediatric cystic fibrosis (CF) patients has not been completely delineated. We performed a retrospective study evaluating the pharmacokinetics and pharmacodynamics of once daily dosing (ODD) of IV tobramycin compared to twice daily dosing (TDD). Fifty-nine and 44 patients were included in the ODD and TDD groups, respectively. Once daily dosing achieved higher C_max as compared to TDD (29.5?±?11.0 vs 19.0?±?4.9, P?P?P?C_max:MIC for MICs >1.0?mg/l. Twice daily dosing may be a viable alternative to ODD in treating organisms with MICs ≤?1.0?mg/l; however, with MICs >1.0?mg/l, ODD is likely necessary to achieve goal C_max:MIC ratios.     

紫杉醇联合吡柔比星治疗晚期乳腺癌临床观察

目的观察紫杉醇联合吡柔比星(THP)治疗晚期乳腺癌患者的临床疗效和毒性反应。方法26例晚期乳腺癌患者采用THP 40 mg/m2,静注,d1;紫杉醇135 mg/m2,静滴3 h,d1。21 d为1个周期,连用2个周期以上评价疗效。结果26例患者中CR 4例(15.4%),PR 14例(53.8%),SD 7例(26.9%),PD 1例(3.8%),总有效率为69.2%(18/26)。主要不良反应为骨髓抑制和脱发。结论紫杉醇联合吡柔比星治疗晚期乳腺癌疗效较高,不良反应可耐受,是治疗晚期乳腺癌安全、有效的方案。     

多西他赛联合吡柔比星在乳腺癌新辅助化疗中的应用

目的观察多西他赛联合吡柔比星(THP)治疗局部晚期乳腺癌的近期疗效和毒性反应。方法48例局部晚期乳腺癌患者接受多西他赛75mg/m2,静滴,第1天;THP40mg/m2,第1天,静滴。21d为1个周期,完成3个周期。结果总有效率(CR PR)为79.2%。主要不良反应有骨髓抑制和脱发(发生率分别为95.8%和97.9%)。结论多西他赛联合THP治疗局部晚期乳腺癌疗效显著,不良反应可耐受,是局部晚期乳腺癌新辅助化疗的有效方案。     

Pharmacokinetics and pharmacodynamics of MX2 hydrochloride in patients with advanced malignant disease

The purpose of the present study was to investigate the pharmacokinetics and pharmacodynamics of the new morpholino anthracycline drug MX2. A total of 27 patients with advanced cancer participated in a dose-escalation study in the first cycle of treatment with drug given i.v. at doses of 10–50 mg/m² (total dose 16.8–107.5 mg). The mean total systemic plasma clearance (CL) of MX2 was 2.98 ± 1.68 l/min, the mean volume of distribution at steady state was 1460 ± 749 l and mean elimination half-life was 10.8 ± 5.1 h. The area under the plasma concentration-time curve (AUC) of MX2 was linearly related to the dose per kilogram and the dose per body surface area (r ² = 0.43, P < 0.01 and r ² = 0.44, P < 0.01, respectively). CL did not correlate with total body weight, lean body mass or body surface area. The mean elimination half-lives of the metabolites M1, M2, M3 and M4 were 11.8 ± 5.0, 21.9 ± 11.8, 19.0 ± 11.3 and 12.3 ± 6.3 h, respectively. The fractional E _max model produced a much better fit to the relative nadir neutrophil count versus dose data (r ² = 0.42) than to the relative nadir neutrophil count versus AUC or peak concentration (C _max) data (r ² = 0.15 and 0.09, respectively). There seemed to be a threshold dose of about 65 mg of MX2 at or above which a large proportion of patients had a nadir neutrophil count of less than 0.5 × 10⁹/l. This study shows that the pharmacokinetics of MX2 are similar to those of other anthracyclines. With other anthracyclines the degree of myelosuppression seems to depend more on the AUC and C _max than on the delivered dose; however, with MX2 the degree of myelosuppression depends more on the dose given than on drug exposure expressed as the AUC or C _max. Received: 18 February 1996 / Accepted: 20 December 1996     

Age‐Related Changes in Nanoparticle Albumin‐Bound Paclitaxel Pharmacokinetics and Pharmacodynamics: Influence of Chronological Versus Functional Age

Purpose.

This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with metastatic breast cancer.

Methods.

Forty patients received nab-paclitaxel (100 mg/m² weekly for 3 weeks followed by a 1-week break) as first- or second-line chemotherapy. Blood samples were collected for analysis, and response was assessed every two cycles. Planned statistical analyses included linear regression to examine the relationship between age and pharmacokinetic variables (ln clearance [CL] and ln area under the curve [AUC]) and two-sided two-sample t tests to evaluate age differences in pharmacodynamic variables. The association between chemotherapy toxicity risk scores and pharmacokinetic and pharmacodynamic variables including grade ≥3 toxicity were examined post hoc.

Results.

Of 40 patients enrolled, 39 (98%) were evaluable (mean age: 60 years; range: 30–81 years). A partial response was achieved in 31%, and 38% had stable disease. There was a borderline positive association between age and 24-hour ln AUC (slope = 0.011; SE = 0.006; p = .055). Grade 3 toxicity was experienced by 26% (8% hematologic, 18% nonhematologic). There were no differences in age based on the presence of grade 3 toxicity (p = .75), dose reductions (p = .38), or dose omissions (p = .15). A significant association was noted between chemotherapy toxicity risk score category and presence of grade 3 toxicity (toxicity rate by risk score category: low, 5 of 30 patients; medium, 3 of 6 patients; high, 2 of 3 patients; p = .041).

Conclusion.

A borderline significant relationship exists between age and 24-hour AUC, but no differences were noted for pharmacodynamic variables (grade 3 toxicity, dose reductions, or dose omissions) based on age. There is an association between toxicity risk score and grade ≥3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups.     

Phase I trial of chloroguinoxaline sulfonamide,with correlation of its pharmacokinetics and pharmacodynamics

To define a maximum tolerable dose, chloroquinoxaline sulfonamide (CQS) was given as a 1-h infusion every 28 days to cancer patients for whom no effective standard therapy was available. Doses were escalated in cohorts of at least three patients each. Plasma for characterization of the pharmacokinetics of free and total CQS was obtained during and after the initial infusion and, when possible, during and after subsequent infusions of CQS if the dose had been reduced. A total of 101 courses of CQS in 55 patients were evaluated. Dose levels ranged from 18 to 3,700 mg/m². The dose-limiting toxicity was hypoglycemia, first recognized at the 3,700-mg/m² dose. When dose-limiting hypoglycemia was recognized, patients were entered at successively lower doses, with close monitoring of plasma glucose and insulin concentrations being done in 26 patients. grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m² Concomitant administration of 5% gyciosion being done in 26 patients. Grade 1–3 hypoglycemia close monitoring of plasma glucose and insulin concentrations being done in 26 patients. Grade 1–3 hypoglycemia occurred within 4 h of the termination of CQS infusion and cleared by 24 h. Symptomatic hypoglycemia was more frequent at doses of CQS above 1,000 mg/m². Concomitant administration of 5% glucose did not ameliorate the hypoglycemia associated with CQS doses of >1,000 mg/m². The total calorie intake, percentage of ideal body weight, or percentage of weight lost did not explain the incidence or severity of hypoglycemia in 12 patients in whom these data were obtained. Cardiac tachyarrhythmias occured in 7 patients who received CQS at doses of 1,000 mg/m², and tachyarrhythmia was associated with hypoglycemia in 3 patients. Other toxicities were sporadic, but the frequency of toxicity was higher at CQS doses of 1,000 mg/m². These toxicities included fever, rash, lightheadedness, leukopenia, thrombocytopenia, alopecia, diarrhea, nausea, and vomiting. All toxicities were reversible. Mean peak plasma [CQS] and AUC increased with dose, with a suggestion that peak plasma [CQS] plateaued at higher doses. The decline in plasma [CQS] was fitted to a three-compartment, open linear model. The terminal half-life ranged from 28 to 206 h. Total body clearance ranged from 44 to 881 ml/h with no evidence of saturation. Urinary excretion of the parent compound in 24 h averaged <5%. CQS not bound to plasma protein (free CQS) comprised 1%–17% of total plasma CQS and was not related to dose. A relationship was defined between the magnitude of hypoglycemia and CQS pharmacokinetic parameters. The percentage of decrease in plasma [glucose], i.e., (predose [glucose]-nadir [glucose]/predose [glucose])×100, correlated with both free and total peak plasma [CQS]. The relationship was described by the Hill equation:Effect=(Emax) (peak) ^H/(peak ₅₀)^H+(peak)^H, where the maximal effect (Emax) equals the maximal possible percentage of decrease in plasma [glucose] equals 100%,peak ₅₀ is the peak total [CQS] at whichE is half-maximal (326 mg/l), andH is the Hill constant, a measure of the sigmoidicity of the relationship (1.06). The relationship fit the data precisely with a mean absolute error (MAE) of 10.42 and was unbiased with a mean error (ME) of –0.06. The recommended phase II dose of CQS is 1,000 mg/m². Because the magnitude of hypoglycemia after CQS administration is related to peak plasma [CQS], repetitive CQS doses of 1,000 mg/m² would probably be tolerated better than single large doses of equivalent intensity.Abbreviations CQS Chloroquinoxaline sulfonamide - AUC area under the plasma concentration x time curve - CLTB total body clearance - MAE mean absolute error - ME mean error - DNA deoxyribonucleic acid - BCNU carmustine [N, N-bis(2-chloroethyl)-N-nitrosourea] - ECOG Eastern Cooperative Oncology Group - WBC white blood cell count - PLT platelet count - ALT alanine aminotransferase - AST aspartate aminotransferase - PT prothrombin time - PTT partial thromboplastin time - EKG electrocardiogram - D5W 5% dextrose in water - HPLC high-performance liquid chromatography - BEE basal energy expenditure This work was supported in part by contract N-01-CM-07303 awarded by the National Cancer Institute, Department of Health and Human Services. One of the authors (B.A.C.) is the recipient of American Cancer Society Clinical Oncology Career Development Award 90-127     

Effect of high-dose cyclosporine on etoposide pharmacodynamics in a trial to reverse P-glycoprotein (MDR1 gene) mediated drug resistance

Purpose: The consequences of using cyclosporine (CsA) therapy to modulate P-glycoprotein-mediated multidrug resistance include increased myelosuppression, hyperbilirubinemia, and altered disposition of the cytotoxin. The purpose of this study was to analyze further the relationship between the degree of leukopenia, and etoposide pharmacokinetic factors. Methods: Each patient initially received intravenously-administered etoposide alone (150–200 mg/m²/d × 3). Later it was given in combination with CsA administered at escalating loading doses (range 2–7 mg/kg) as a 2 hour intravenous (IV) infusion followed by a 3 day continuous infusion, at doses ranging from 5 to 21 mg/kg/day. Serial plasma etoposide concentration-time samples were assayed by high-performance liquid chromatography (HPLC). The area under the curve (AUC) of unbound etoposide was calculated from the total plasma etoposide AUC using a previous published equation [22] where % unbound etoposide = (1.4 × total bilirubin) – (6.8 × serum albumin) + 34.4. The percent decrease in white blood cell (WBC) count and the total or unbound etoposide AUC relationship was fitted to a sigmoid Emax model adapted for paired observations, where: In this equation, Z was the variable describing the two treatment groups (0=no CsA and 1=CsA). The fitted parameters were PDRV₅₀, the pharmacodynamic response variable (PDRV) producing 50% of the maximal response; parameter β, which describes the effect of the treatment group on the PDRV₅₀; parameter H (Hill constant), which defines the slope of the response curve and parameter δ, which describes the effect of the treatment group on parameter H. Results: CsA at a median concentration of 1,938 μg/ml resulted in a median increase in the total plasma etoposide AUC by 103% and the calculated unbound plasma etoposide AUC by 104%. This paralleled a 12% greater median percent decrease in WBC count during etoposide + CsA treatment (72% vs. 84%, P=0.03). The percent decrease in WBC count and total or unbound etoposide AUC relationship was fitted to the sigmoid Emax model. The model using the unbound etoposide AUC described the data adequately (r=0.790) and was precise, with a mean absolute error of 6.4% (95% confidence interval: −4.9, 7.8). The fitted parameter-estimates suggested that at equivalent unbound etoposide AUC values above 10 μg × h/ml, the sigmoid Emax model predicted a 5% greater WBC count suppression when CsA was added to the treatment regimen. Conclusion: These findings suggest that a small degree of the enhanced myelosuppression observed with CsA combined with etoposide might be attributable to inhibition of P-glycoprotein in bone marrow precursor cells. However, the majority of the effect observed appears to be due to pharmacokinetic interactions, which result in increases in unbound etoposide. Received: 14 December 1998 / Accepted: 15 September 1999     

紫杉醇联合吡喃阿霉素一线治疗转移性乳腺癌临床分析

目的观察紫杉醇联合吡喃阿霉素一线治疗转移性乳腺癌的近期疗效和毒副作用.方法经病理组织学或细胞学证实的19例转移性乳腺癌应用紫杉醇135 mg/m2静脉滴注,第1天;吡喃阿霉素40 mg/m2,静脉推注,第1天,3周为1周期.所有患者至少接受2周期治疗.结果可评价疗效19例,总有效率为68.4%,其中CR 2例,占10.5%.主要毒副作用是骨髓抑制、恶心、呕吐、脱发、关节肌肉痛和心脏毒性反应,但均可耐受.结论紫杉醇联合吡喃阿霉素一线治疗转移性乳腺癌疗效较好,毒性可以耐受.