The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity

Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.     

Pharmacokinetics and pharmacodynamics of combination chemotherapy with paclitaxel and epirubicin in breast cancer patients

AIMS: To investigate the pharmacokinetics and pharmacodynamics of epirubicin and paclitaxel in combination, as well as the effects of paclitaxel and its vehicle Cremophor EL on epirubicin metabolism. METHODS: Twenty-seven female patients with metastatic breast cancer received epirubicin 90 mg m-2 i.v. followed 15 min or 30 h later by a 3 h i.v. infusion of paclitaxel 175, 200 and 225 mg m-2. Plasma concentrations of paclitaxel, epirubicin and epirubicinol were measured and the relationship between neutropenia and drug pharmacokinetics was evaluated using a sigmoid maximum effect (Emax) model. Finally, the influence of paclitaxel and Cremophor EL on epirubicin metabolism by whole blood was examined. RESULTS: An increase in epirubicinol plasma concentrations occurred after the start of the paclitaxel infusion, resulting in a significant increase in the area under the plasma concentration-time curve (AUC) of epirubicinol (+0.5 micromol l-1 h [95% CI for the difference: 0.29, 0.71],+0.66 micromol l-1 h [95% CI for the difference: 0.47, 0.85] and +0.82 micromol l-1 h [95% CI for the difference: 0.53, 1.11] at paclitaxel doses of 175, 200 and 225 mg m-2, respectively), compared with epirubicin followed by paclitaxel 30 h later (0.61+/-0.1 micromol l-1 h). A significant increase in epirubicin AUC (+0.74 micromol l-1 h [95% CI for the difference: 0.14, 1.34] and +1.09 micromol l-1 h [95% CI for the difference: 0.44, 1.74]) and decrease in drug clearance (CLTB) (-25.35 l h-1 m-2[95% CI for the difference: -50.18, -0.52] and -35.9 l h-1 m-2[95% CI for the difference -63,4,-8,36]) occurred in combination with paclitaxel 200 and 225 mg m-2 with respect to the AUC (3.16+/-0.6 micromol l-1 h) and CLTB (74.4+/-28.4 l h-1 m-2) of epirubicin followed by paclitaxel 30 h later. An Emax relationship was observed between neutropaenia and the time over which paclitaxel plasma concentrations were equal to or greater than 0.1 micromol l-1 (tC0.1). The tC0.1 value predicted to yield a 50% decrease in neutrophil count was 7.7 h. Finally, Cremophor EL markedly inhibited the metabolism of epirubicin to epirubicinol in whole blood. CONCLUSIONS: Paclitaxel/Cremophor EL affects the disposition of epirubicinol and epirubicin. Furthermore, the slope factor of the Emax relationship between neutropenia and tC0.1 of paclitaxel suggests that the drugs might also interact at the pharmacodynamic level.     

Population pharmacokinetic model of fluvoxamine in rats: utility for application in animal behavioral studies.

The limitations of blood sampling in pharmacokinetic (PK)/pharmacodynamic (PD) studies in behavioral animal models could in part be overcome by a mixed effects modeling approach. This analysis characterizes and evaluates the population PK of fluvoxamine in rat plasma using nonlinear mixed effects modeling. The model is assessed for its utility in animal behavioral PK/PD studies. In six studies with a different experimental setup, study site and/or sampling design, rats received an intravenous infusion of 1, 3.7 or 7.3mg/kg fluvoxamine. A population three-compartment PK model adequately described the fluvoxamine plasma concentrations. Body weight was included as a covariate and mean population PK parameters for CL, V(1), V(2), Q(2), V(3) and Q(3) were 25.1 ml/min, 256 ml, 721 ml, 30.3 ml/min, 136 ml and 1.0 ml/min, respectively. Inter-individual variability was identified on CL (39.5%), V(1) (43.5%), V(2) (50.1%) and Q(2) (25.7%). A predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates. Body weight was identified as a significant covariate of the inter-compartmental clearance Q(2). The pharmacokinetics was independent of factors such as dose, surgery (for instrumentation) and study site. The utility of the model in animal behavioral studies was demonstrated in a PK/PD analysis of the effects on REM sleep in which a sparse PK sampling design was used. By using the pertinent information from the population PK model, individual PK profiles and the PK/PD correlation could be adequately described.     

Pharmacokinetics of Teicoplanin in An ICU Population of Children and Infants

PURPOSE: Better dosing is needed for antibiotics, including teicoplanin (TEI), to prevent emergence of resistant bacterial strains. Here, we assess the TEI pharmacokinetics (PK) related to a 10 mg/l minimum inhibitory concentration (MIC) target in ICU children (4 to 120 months; n = 20) with gram+ infections. METHODS: Standard administration of TEI was with three 10 mg/kg Q12h, loading infusions, and maintainance with 10 mg/kg or 15 mg/kg Q24h. During maintenance, 9 samples (3/day) were collected per patient and the PK analyzed with Nonlinear Mixed Effects Model (NONMEM). RESULTS: Thirty-five percent of concentrations in older children (> or =2 months) vs. 8% in younger infants (<12 months) were below the target MIC. The global bicompartmental population PK parameters were [mean (interindividual CV%)] CL = 0.23 l/h [72%], V = 3.16 l [58%], k12 = 0.23 h(-1), and k21 = 0.04 h(-1). Two PK subpopulations were identified. The older children had CL = 0.29 [23%] l/h, V = 3.9 l and the younger infants, CL = 0.09 [37%] l/h, V = 1.05 l. Residual error was reduced from 52% to around 30% in the final models. CONCLUSIONS: Older children in the ICU may require relatively higher doses of teicoplanin. However, a study in a larger population is needed.     

Population pharmacokinetics and pharmacodynamics of oral etoposide

AIMS: To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours. METHODS: A prospective, open label, cross-over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P-Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints. RESULTS: Mean clearance was 1.14 l h(-1) (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r(2) = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l(-1) h; CV 64%; range 0.4-9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l(-1) h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l(-1) h) than in patients with stable (2.1 mg l-1 h) or progressive disease (2.3 mg l-1 h) (P = 0.01). CONCLUSIONS: Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.     

Pharmacokinetics and pharmacodynamics of propofol in patients undergoing abdominal aortic surgery

Available propofol pharmacokinetic protocols for target-controlled infusion (TCI) were obtained from healthy individuals. However, the disposition as well as the response to a given drug may be altered in clinical conditions. The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol during total intravenous anesthesia (propofol/fentanyl) monitored by bispectral index (BIS) in patients scheduled for abdominal aortic surgery. Population nonlinear mixed-effect modeling was done with Nonmem. Data were obtained from ten male patients. The TCI system (Diprifusor) was used to administer propofol. The BIS index served to monitor the depth of anesthesia. The propofol dosing was adjusted to keep BIS level between 40 and 60. A two-compartment model was used to describe propofol PK. The typical values of the central and peripheral volume of distribution, and the metabolic and inter-compartmental clearance were V(C) = 24.7 l, V(T) = 112 l, Cl = 2.64 l/min and Q = 0.989 l/min. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment with the rate constant for the distribution to the effector compartment equal to 0.240 min(-1). The BIS index was linked to the effect site concentrations through a sigmoidal E(max) model with EC(50) = 2.19 mg/l. The body weight, age, blood pressure and gender were not identified as statistically significant covariates for all PK/PD parameters. The population PK/PD model was successfully developed to describe the time course and variability of propofol concentration and BIS index in patients undergoing surgery.     

Multi-centre Phase II trial of the polyamine synthesis inhibitor SAM486A (CGP48664) in patients with metastatic melanoma

Summary Purpose: To determine the activity and tolerability of SAM496A, an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), in patients with metastatic melanoma who had not received prior chemotherapy. Selected patients were offered participation in two sub-studies examining early changes in tumor metabolism with FDG-PET and changes in tumor polyamine content.Patients and methods: Fifteen patients with measurable metastatic melanoma, normal cardiac function, and no known CNS metastases were eligible and received SAM486A by 1-hour IV infusion daily for 5 days every 3 weeks. Response was assessed by SWOG criteria.Results: No patient had a confirmed partial response. Fatigue/lethargy, myalgia and neutropenia were the main toxicities but no febrile neutropenia or grade 4 non-hematological toxicity occurred. Five patients had PET scans pre-treatment and on days 8–12 of cycle 1. No patient had reduction of tumor metabolism. Serial biopsy in one patient showed alterations in polyamines consistent with SAMDC inhibition.Conclusions: Using the present dose and schedule of administration, SAM486A does not have significant therapeutic potential in patients with metastatic melanoma.     

A population pharmacokinetic/pharmacodynamic model of methotrexate and mucositis scores in osteosarcoma

Methotrexate, when used in high doses (12 g/m2) in the treatment of osteosarcoma, shows wide between-subject variability (BSV) in its pharmacokinetics. High-dose methotrexate is associated with severe toxicity; therefore, therapeutic drug monitoring (TDM) is carried out to guide rescue therapy and monitor for nephrotoxicity. Mucositis is a commonly encountered dose-limiting toxicity that often leads to delays in subsequent courses of chemotherapy. This, in turn, results in a reduction in the dosing intensity, which is essential in the treatment of osteosarcoma. The aims of this study were to develop a population pharmacokinetic (PK) model from TDM using physiologically relevant covariates and to investigate the correlation between mucositis scores and methotrexate pharmacokinetics. In total, 46 osteosarcoma patients (30 men and 16 women; age, 4-51 years) were recruited, and blood samples were collected for routine TDM once every 24 hours. Mucositis scores, graded according to the National Cancer Institute Common Toxicity Criteria, were recorded for 28 of the patients (18 men and 10 women; age, 8-51 years) predose and postdose. A population PK model was developed in NONMEM VI. A 2-compartment PK model was chosen, and clearance (CL) was divided into filtration and secretion/metabolism components. All parameters were scaled with body weight, and, in addition, total CL was scaled with age- and sex-adjusted serum creatinine. Between-subject variability was modeled for all parameters, and between-occasion variability was included in CL. For a typical 70 kg man of 18 years or older, the parameter estimates for the final model were CL(filt) = 2.69 L/h/70 kg, CL(sec) = 10.9 L/h/70 kg, V? = 74.3 L/70 kg, Q = 0.110 L/h/70 kg, and V? = 4.10 L/70 kg. Sequential pharmacodynamic modeling consisted of mucositis scores as 5-point ordered categorical data. A significant linear relationship between individual area under the curve (AUC) and mucositis score probability was found, and the probability of having mucositis score ≥ 1 increased with increasing AUC and was almost 50% at the average cumulative AUC after 2 consecutive methotrexate doses.     

No evidence that amifostine influences the plasma pharmacokinetics of topotecan in ovarian cancer patients

OBJECTIVE: This aim of this study was to compare the pharmacokinetics of topotecan in the presence and absence of preceding amifostine to reduce the risk of side effects in patients with advanced ovarian cancer.METHODS: Ten patients with advanced ovarian cancer received topotecan, 1.5 mg/m(2) for 5 days, as second-line therapy in an open phase-II study after previous platinum-containing first-line therapy. Patients were randomised to receive intravenous (IV) amifostine at a daily dose of 300 mg/m(2) prior to topotecan in the first cycle and topotecan alone in the second cycle or vice versa. Thereafter all patients were given amifostine and topotecan for additional four cycles. Topotecan was given as a 30-min IV infusion. On day 1 of the first and second treatment cycles, venous blood samples were collected up to 24 h after the start of topotecan infusion. Plasma concentrations of total topotecan and its active lactone form were determined using high-performance liquid chromatography.RESULTS: There was a rapid decline in total topotecan plasma concentrations after the end of the infusion followed by a slower decay. The initial decline was even faster for the lactone form. The inter-individual variability was pronounced and the area under the plasma concentration-time curve from time zero to infinity (AUC(0-infinity)) of the total topotecan plasma concentration ranged from 182 nmol/l h to 725 nmol/l h for topotecan alone and from 188 nmol/l h to 574 nmol/l h for topotecan and amifostine. The geometric mean of AUC(0-infinity) values were 326 nmol/l h and 297 nmol/l h, respectively ( P=0.41). In the cycles when the patients received topotecan alone, the plasma AUC of the lactone averaged 40% of the AUC of the total concentration compared with 39% in the cycles when topotecan was given after amifostine. The peak plasma concentration (C(max)) of the lactone averaged 72% of the C(max) of the total topotecan concentration in the topotecan-only group. The corresponding figure after topotecan and amifostine was 80% ( P=0.11). A large intra-individual pharmacokinetic of topotecan between cycles 1 and 2 was also observed.CONCLUSION: Amifostine, 300 mg/m(2), does not significantly affect the pharmacokinetics of topotecan and there are pronounced intra- and inter-individual variabilities in the topotecan pharmacokinetics.     

Pharmacokinetic optimisation of treatment schedules for anthracyclines and paclitaxel in patients with cancer.

The integration of paclitaxel into chemotherapy regimens with anthracyclines offers a new opportunity for devising effective therapy for patients with breast cancer. High response rates have been obtained by combining epirubicin or doxorubicin with paclitaxel. The pharmacokinetic analysis of paclitaxel and anthracyclines, as well as the identification of relationships with their pharmacodynamics, represents a rational approach for treatment optimisation. A schedule-dependent interaction between paclitaxel and anthracyclines has been demonstrated in clinical pharmacokinetic studies. In patients given paclitaxel 125 to 200 mg/m2 as 3- to 24-hour infusions in combination with doxorubicin 48 to 60 mg/m2 as a 48-hour infusion or intravenous bolus, the peak plasma drug concentration (Cmax) of doxorubicin increased significantly and drug clearance was reduced in the sequence paclitaxel-->doxorubicin as compared with doxorubicin-->paclitaxel. The schedule paclitaxel-->doxorubicin was more toxic as compared with doxorubicin-->paclitaxel, and an incidence of 18 to 20% of congestive heart failure was observed in patients with breast cancer given doxorubicin 60 mg/m2 followed by paclitaxel 125 to 200 mg/m2. Likewise, patients given epirubicin 90 mg/m2 had a sudden rebound of epirubicinol plasma concentrations shortly after the start of infusion of paclitaxel 200 mg/m2, with a significant increase in the area under the concentration-time curve (AUC) of epirubicinol as compared with epirubicin alone (1.27 +/- 0.2 vs 0.61 +/- 0.1 mumol/L.h). Moreover, the severity of the myelosuppression induced by paclitaxel, as defined by a sigmoid maximum effect (Emax) relationship between the decrease in neutrophil count and the duration of drug plasma concentrations above the threshold value of 0.1 mumol/L, was significantly enhanced by epirubicin. Finally, chemotherapy with paclitaxel and anthracyclines may be improved by designing pharmacologically guided regimens in order to control the extent of pharmacokinetic interaction and reduce the risk of severe toxicity while maintaining the therapeutic efficacy of the combination. Future protocols should explore the activity of a prolonged paclitaxel infusion in association with an anthracycline separated from the taxane by a washout time interval in order to minimise the inhibitory effects exerted by paclitaxel on P-glycoprotein-mediated biliary clearance of anthracyclines, the most likely cause of pharmacokinetic interaction.     

Phase I trial of vinorelbine and diphenylhydantoin in patients with refractory carcinoma

The anti-epileptic diphenylhydantoin (DPH; Dilantin) selectively enhances the in vitro cytotoxicity of vinca microtubule poisons in both parent sensitive and multi-drug resistant (MDR) human tumor cells. The in vivo clinical activity of this combination has not been fully evaluated. Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicities, and preliminary antitumor activity of the combination of intravenous (IV) bolus vinorelbine (VRL) and oral diphenylhydantoin (DPH) in patients (pts) with refractory solid tumors. Methods: Cohorts of 3-6 pts with refractory cancer were treated with escalating doses of weekly IV bolus VRL (I -20.0 mg/m(2); II -22.5 mg/m(2); III -25.0 mg/m(2); IV -27.5 mg/m(2); V -30.0 mg/m(2); VI -32.5 mg/m(2)) combined with a fixed oral dose of DPH (400 mg/day) until MTD or progression. During each 35 day cycle, pts received DPH 400 mg/day administered orally on Days -6 to Day +22 and weekly IV bolus infusion of VRL on Days +1, +8, +15, and +22. The cohort treated at the MTD was expanded to further define toxicity. Results: A total of 25 evaluable pts. (9 men; 16 women) were treated with VRL and DPH at dose levels I ( n = 5), II ( n = 3), III ( n = 2), IV ( n = 3), V ( n = 7) and VI ( n = 5) in 5 week cycles over a 16 month period. Dose limiting toxicity occurred at dose level VI (VRL 32.5 mg/m(2)) and included grade 3 leukopenia ( n = 2), grade 3 neutropenia ( n = 1) and grade 4 neutropenia ( n = 1) occurring within the first cycle of treatment. There were no responses, however 9 pts had stable disease of variable duration (8-56 weeks) and received a median of 2 cycles of treatment (range 2-14). Conclusion: Intravenous bolus administration of VRL and oral administration of a fixed dose of DPH was well tolerated according to the schedule reported here. Although there were no responses, several patients had prolonged disease stabilization. The recommended phase II dose of VRL when used in this combination is 30 mg/m(2).     

阿莫西林-舒巴坦联用替硝唑相关中性粒细胞减少

1例76岁男性患者,因丹毒给予阿莫西林-舒巴坦2.25 g溶于0.9%氯化钠注射液100 ml,2次/d静脉滴注;0.4%替硝唑100 ml,1次/d静脉滴注。6 d后血常规检查:白细胞计数1.86×109/L,中性粒细胞0.21,淋巴细胞0.55,单核细胞0.23,中性粒细胞计数0.39×109/L。立即停用阿莫西林-舒巴坦和替硝唑,并给予对症治疗。停药3 d后,血常规检查:白细胞计数3.20×109/L,中性粒细胞0.32,淋巴细胞0.54,单核细胞0.12,中性粒细胞计数1.04×109/L。     

应用蒙特卡洛模拟优化哌拉西林他唑巴坦在血液肿瘤化疗后中性粒细胞缺乏伴发热患者中的给药方案

目的：优化哌拉西林他唑巴坦在血液肿瘤化疗后中性粒细胞缺乏伴发热（FN）患者中经验性给药方案。方法：根据哌拉西林他唑巴坦临床药动学和药效学参数,分别以50% f_T>MIC和100% f_T>MIC为目标靶值,用Crystal Ball 11.1.1.3软件对哌拉西林他唑巴坦7种给药方案（3 g q4h、3 g q6h、4 g q6h、4 g q8h,给予0.5 h输注;4 g q6h、4 g q8h,给予3 h输注;16 g持续24 h输注）进行蒙特卡洛模拟,以获得不同治疗方案的达标概率（PTA）,从而优化出最佳的抗感染方案。结果：以50% f_T>MIC为目标靶值,当MIC=16 mg·L^-1时,3 g q4h 0.5 h输注、4 g q6h 3 h输注和16 g 24 h连续输注给药方案的PTA均能达到90%以上;以100% f_T>MIC为目标靶值,当0.5≤MIC≤2 mg·L^-1时,3 g q4h 0.5 h输注、4 g q6h 3 h输注和16 g 24 h连续输注给药方案的PTA均能达到90%以上;当MIC=4 mg·L^-1和MIC=8 mg·L^-1时,仅16 g 24 h连续输注给药方案的PTA能达到90%以上。结论：对于血液肿瘤化疗后FN患者,推荐使用哌拉西林他唑巴坦4 g q6h 3 h输注或16 g 24 h连续输注的给药方案。     

Integrated pharmacokinetic/pharmacodynamic model of XV459, a potent and specific GPIIb/IIIa inhibitor,in healthy male volunteers

Roxifiban is an oral prodrug of XV459, a potent and specific inhibitor of the glycoprotein (GP) IIb/IIIa receptor previously under investigation for the treatment of peripheral arterial disease and acute coronary care syndrome. The objective of the present analysis was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that would be used to guide dose selection in Phase 2. This was a randomized, sequential, rising multiple-dose study in 41 healthy male volunteers given doses of 0.5 to 1.25 mg daily for 7 to 10 days. Total XV459 was measured in plasma by a sensitive and specific LC/MS/MS method. The percent inhibition of platelet aggregation (%IPA) was evaluated in citrated plasma in response to 10 microM ADP using the initial slope of the response. The resulting PK data were fit to a two-compartment model with first-order absorption and saturable oral absorption. The pharmacodynamics was modeled using a direct sigmoidal Emax model. Modeling was performed using NONMEM V. Intersubject variability was moderate in both PK and PD (15.3%-18.5%), except for V2/F (64.8%). Residual variability was low at 11.8%. Platelet count influenced both CL/F and EC50. Age and weight did not explain any additional variability in either PK or PD. The model was shown to produce realistic data when used for simulation. Overall, the results suggest that XV459 concentrations in the range of 10 to 20 ng/ml will yield %IPA values in the range of 40% to 80% inhibition. Because of the pharmacodynamically mediated PK of XV459 (due to platelet binding), the EC50 and CL/F are negatively correlated, limiting the utility of plasma concentration monitoring.     

Pharmacokinetics of paclitaxel and cisplatin in a hemodialysis patient with recurrent ovarian cancer

This is the first report that the combination of paclitaxel and cisplatin is feasible in a patient with recurrent ovarian cancer undergoing hemodialysis. Paclitaxel at a dose of 150 mg/m(2) was administered as a 3-h continuous i.v. infusion. Thirty minutes after paclitaxel administration, cisplatin was administered at a dose of 30 mg/m(2) for 30 min. Hemodialysis was started 30 min after completion of the cisplatin infusion and performed for 5 h. The maximum plasma concentrations of paclitaxel, total platinum and free platinum were 3.26, 2.44 and 1.84 microg/ml, respectively. The AUC of paclitaxel and free platinum were 15.3 and 1.76 microg x h/ml, respectively. The pelvic tumor size was reduced by 42% on MRI after the second course of this therapy. Grade IV neutropenia and grade III thrombopenia were observed. We conclude that paclitaxel and cisplatin combination chemotherapy is efficacious and feasible for an ovarian cancer patient under hemodialysis.     

Effect of cyclosporin A on protein binding of teniposide in cancer patients

We investigated the effect of cyclosporin A (CSA) on protein binding of teniposide (VM26) in 16 patients with metastatic renal cell carcinoma receiving i.v. VM26 alone over 24 h (total dose, 200 mg/m2) and in association with CSA (5 mg/kg/2 h followed by 30 mg/kg/48 h i.v.). CSA was used in an attempt to overcome multidrug resistance. The unbound fraction (%fu) of VM26 was significantly (p=0.04) higher in the cycles with CSA (median 0.8; range 0.4-1.9) than in the cycles with VM26 alone (median 0.5; range 0.1-1.6). Both total VM26 area under curve concentration (AUC0-infinity) and free VM26 AUC0-infinity increased after treatment with CSA, but the median increase in free AUC0-infinity was higher (2.7-fold) than total AUC0-infinity (1.5-fold) (p = 0.04). Bilirubin was significantly (p<0.01) increased after CSA but no association was observed between bilirubin level and %fu of VM26. Albumin was in the normal range after both VM26 alone and VM26 plus CSA. The nadir of absolute neutrophil count (ANC) after VM26 plus CSA (median 700/microl, range <100-2860/microl) was lower than after VM26 alone (median 1900/microl, range 200-6000/microl) (p = 0.0007). The median percentage of ANC compared to the pretreatment value (ANC nadir/ANC pretreatment x 100) was 39.0% (range 3.1-98.8%) in the cycles with VM26 alone and 16.9% (range 1.4-97.9%) (p = 0.007) after VM26 plus CSA. Percentage change of neutrophils significantly correlated with free AUC0-infinity VM26 in the cycles with VM26 alone and VM26 plus CSA (p = 0.04, r = -0.53 and p = 0.04, r = -0.52, respectively). Only a trend which failed to reach significance was observed between total AUC0-infinity VM26 and percentage change of neutrophils in the cycles with VM26 alone and in association with CSA (p = NS, r = -0.33 and p = 0.055, r = -0.49, respectively). In conclusion, patients treated with CSA had higher systemic exposure to unbound VM26.     

Population pharmacokinetics-pharmacodynamics of alemtuzumab (Campath) in patients with chronic lymphocytic leukaemia and its link to treatment response

AIMS: To characterize alemtuzumab pharmacokinetics and its exposure-response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL). METHODS: Nonlinear mixed effects models were used to characterize plasma concentration-time data and WBC count-time data from 67 patients. Logistic regression was used to relate summary measures of drug exposure to tumour response. RESULTS: Alemtuzumab pharmacokinetics were best characterized by a two-compartment model with nonlinear elimination where V(max) (microg h(-1)) was [1020 x (WBC count/10 x 10(9) l(-1))(0.194)], K(m) was 338 microg l(-1), V(1) was 11.3 l, Q was 1.05 l h(-1) and V(2) was 41.5 l. Intersubject variability (ISV) in V(max), K(m), V(1) and V(2) was 32%, 145%, 84% and 179%, respectively. The reduction in WBC over time was modelled by a stimulatory loss indirect response model with values of 18.2 for E(max), 306 microg l(-1) for EC(50), 1.56 x 10(9) cells l(-1) h(-1) for K(in) and 0.029 per h for K(out). The probability of achieving a complete or partial response was >/=50% when the maximal trough concentration exceeded 13.2 microg ml(-1) or when AUC(0-tau) exceeded 484 microg h(-1) ml(-1). CONCLUSIONS: Alemtuzumab displayed time- and concentration-dependent pharmacokinetics with large interpatient variability, both in pharmacokinetics and pharmacodynamics, which was probably reflective of differences in tumour burden among patients. A direct relationship between maximal trough concentrations and clinical outcomes was observed, with increasing alemtuzumab exposure resulting in a greater probability of positive tumour response.     

Pharmacokinetics and pharmacodynamics of erythropoietin receptor in healthy volunteers

The purpose of this study was to apply the target-mediated drug disposition (TMDD) pharmacokinetic (PK) model to describe binding, internalization, and turnover of erythropoietin receptor (EPOR). This model allows one to determine from free drug (C) PK data not only parameters describing linear disposition of EPO such as the elimination rate constant (k (el)) and volume of distribution (V (c)), but also the total receptor concentration (R (tot0)), drug-receptor complex (RC) internalization rate constant (k (int)), as well as synthesis and degradation rate constants (k (syn) and k (deg)) for the receptor turnover. The previously published data on PK of recombinant EPO (rHuEPO) in humans and the results of EPOR binding studies were used for analysis. The estimated PK parameters were used to simulate time courses of free and bound EPOR after IV administration of clinically relevant rHuEPO doses. The estimates of k (el) = 0.106 h(-1) and V (c) = 0.032 l/kg are consistent with reported in the literature values of rHuEPO linear disposition parameters. The determined value of R (tot0) was 66.35 pM and the half-life for EPOR degradation was 8.8 h. Computer simulations showed a very rapid binding phase in the EPOR time profile followed by a decline to a nadir, and a subsequent return to the baseline. The nadir values decreased with increasing doses and resulted in the maximum values of the bound fractions of the total EPOR in the ranges 33-99%. At the baseline conditions, only 3.1% of EPOR were occupied. The saturation of EPOR was correlated with the time C remained above the K (D) level. In conclusion, the time courses of serum rHuEPO concentrations contain information about internalization and turnover of EPOR. Kinetics of EPOR can be utilized to determine the relationship between the pharmacologic effect and exposure to rHuEPO.     

万古霉素相关白细胞减少1例

目的 报道１例使用万古霉素过程中出现白细胞与中性粒细胞严重减少的不良反应并总结国内外文献分析。方法 1例72岁男性患者因脑脓肿合并败血症,给予万古霉素0.5 g, Q8H,静脉滴注。治疗15d后,患者血常规:WBC 1.6×10-9 L-1, 中性 粒 细 胞 百 分 比44.9%,中性粒细胞0.7×10-9 L-1。结果 停用万古霉素3d后血白细胞及中性粒细胞恢复正常。结论 万古霉素所致白细胞与中性粒细胞严重减少需引起临床高度重视,在较长疗程中须定期监测血常规,以避免和减少此类不良反应的发生。     

A limited sampling schedule to estimate mycophenolic Acid area under the concentration-time curve in hematopoietic cell transplantation recipients

Mycophenolate mofetil (MMF) is a key component of postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSSs) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2-hour MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of 1 and 2 compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSSs were derived using a simulation approach based on the scaled mean squared error. A 5-sample schedule of 2, 2.5, 3, 5, and 6 hours from the start of the infusion precisely estimated MPA AUC(0-12 h) for Q12-hour IV MMF. A comparable schedule (2, 2.5, 3, 4, and 6 hours) similarly estimated MPA AUC(0-8) (h) for Q8-hour dosing.