Quantification of antiangiogenic and antivascular drug activity by kinetic analysis of DCE-MRI data.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to quantify the response of tumors to vascular targeting agents. Tumor response is frequently assessed using mathematical models that describe the distribution of contrast agents over time as a function of fundamental characteristics of vascular physiology. Generally, mathematical models of biological systems are abstractions that attempt to retain fundamental physiologic characteristics, thereby allowing for multiple potential modeling approaches and structures. Various DCE-MRI modeling techniques are discussed in this article.

Investigations in vivo of the effects of carbogen breathing on 5-fluorouracil pharmacokinetics and physiology of solid rodent tumours.

PURPOSE: We have shown previously that carbogen (95% 0(2), 5% CO(2)) breathing by rodents can increase uptake of anticancer drugs into tumours. The aim of this study was to extend these observations to other rodent models using the anticancer drug 5-fluorouracil (5FU). 5FU pharmacokinetics in tumour and plasma and physiological effects on the tumour by carbogen were investigated to determine the locus of carbogen action on augmenting tumour uptake of 5FU. METHODS: Two different tumour models were used, rat GH3 prolactinomas xenografted s.c. into nude mice and rat H9618a hepatomas grown s.c. in syngeneic Buffalo rats. Uptake and metabolism of 5FU in both tumour models with or without host carbogen breathing was studied non-invasively using fluorine-19 magnetic resonance spectroscopy ((19)F-MRS), while plasma samples from Buffalo rats were used to construct a NONMEM pharmacokinetic model. Physiological effects of carbogen on tumours were studied using (31)P-MRS for energy status (NTP/Pi) and pH, and gradient-recalled echo magnetic resonance imaging (GRE-MRI) for blood flow and oxygenation. RESULTS: In both tumour models, carbogan-induced GRE-MRI signal intensity increases of approximately 60% consistent with an increase in tumour blood oxygenation and/or flow. In GH3 xenografts, (19)F-MRS showed that carbogen had no significant effect on 5FU uptake and metabolism by the tumours, and (31)P-MRS showed there was no change in the NTP/Pi ratio. In H9618a hepatomas, (19)F-MRS showed that carbogen had no effect on tumour 5FU uptake but significantly ( p=0.0003) increased 5FU elimination from the tumour (i.e. decreased the t(1/2)) and significantly ( p=0.029) increased (53%) the rate of metabolism to cytotoxic fluoronucleotides (FNuct). The pharmacokinetic analysis showed that carbogen increased the rate of tumour uptake of 5FU from the plasma but also increased the rate of removal. (31)P-MRS showed there were significant ( p

Dynamic contrast-enhanced MRI using Gd-DTPA: interindividual variability of the arterial input function and consequences for the assessment of kinetics in tumors.

Gd-DTPA kinetics in arterial blood was investigated by dynamic MRI in 47 patients with malignant and benign mammary tumors. Signal enhancement was monitored for 10 min after the beginning of a 1-min infusion of 0.1 mmol/kg Gd-DTPA. Kinetics in blood was biexponential with median half-lives of 21 sec and 11.1 min, respectively. Peak signal enhancement and the area under the signal enhancement-time curve varied 2.5- and 3.7-fold between patients. The shortest mean residence time in one of up to three tumor compartments, MRT*, was estimated using either the individual (reference) or a mean population (surrogate) arterial input function (AIF). MRT* (reference estimate) was 1.0 (0-1.5), 1.9 (1.5-2.3), and 2.5 (2.3-2.8) min in carcinomas, fibroadenomas, and mastopathies, respectively (median and interquartile distance). Surrogate estimates were unbiased but differed from the reference estimates 1.5-fold or more in 23% of cases. AIFs should be monitored individually if accurate estimates of individual MRT* are desired.

Estimating kinetic parameters from dynamic contrast-enhanced T(1)-weighted MRI of a diffusable tracer: standardized quantities and symbols.

We describe a standard set of quantity names and symbols related to the estimation of kinetic parameters from dynamic contrast-enhanced T(1)-weighted magnetic resonance imaging data, using diffusable agents such as gadopentetate dimeglumine (Gd-DTPA). These include a) the volume transfer constant K(trans) (min(-1)); b) the volume of extravascular extracellular space (EES) per unit volume of tissue v(e) (0 < v(e) < 1); and c) the flux rate constant between EES and plasma k(ep) (min(-1)). The rate constant is the ratio of the transfer constant to the EES (k(ep) = K(trans)/v(e)). Under flow-limited conditions K(trans) equals the blood plasma flow per unit volume of tissue; under permeability-limited conditions K(trans) equals the permeability surface area product per unit volume of tissue. We relate these quantities to previously published work from our groups; our future publications will refer to these standardized terms, and we propose that these be adopted as international standards.

Multicompartment analysis of gadolinium chelate kinetics: blood-tissue exchange in mammary tumors as monitored by dynamic MR imaging.

The blood-tissue exchange kinetics of gadopentetate were studied in 49 malignant and benign mammary tumors. Signal enhancement was monitored simultaneously in the aorta and in tumor for 10.5 minutes after the beginning of a 1 minute i.v. infusion of the contrast medium (CM). Kinetic analysis was based on a model with two compartments for systemic pharmacokinetics and up to three kinetically distinct compartments for tumor. Kinetic heterogeneity, ie, two or more compartments with different exchange rate constants in a given tumor, was found in 85% of carcinomas, 38% of fibroadenomas, and 14% of mastopathic tumors. The within-tumor average of CM exchange rates was 1.22 (0.62-1.65) min(-1) in carcinomas, 0.38 (0.26-0.60) min(-1) in fibroadenomas, and 0.16 (0. 12-0.20) min(-1) in mastopathies (median and interquartile distances). The area under the signal enhancement-time curve of the aorta varied 4.5-fold between individuals. It is concluded that individual CM kinetics in arterial blood should be taken into account when CM exchange rates between blood and tumor are to be determined and that a kinetic model for potentially malignant tumors should allow for kinetic heterogeneity.

Noninvasive determination of the arterial input function of an anticancer drug from dynamic PET scans using the population approach.

For the application of a kinetic model to PET data, it is generally necessary to obtain the arterial input function (AIF). It was the aim of the present study to introduce a method suitable for the determination of the AIF of a substance that undergoes biochemical transformation from noisy PET data: the population approach. F-18 labeled 5-fluorouracil (5-[18F]FU) was administered i.v. to eight patients suffering from liver metastases of colorectal carcinoma. Radioactivity concentrations in liver and aorta were dynamically measured with PET over 120 min. Pharmacokinetic analysis was carried out by applying a five-compartment model to individual activity-time data for the eight patients or to the mean activity-time data among the eight patients. The mean values of all parameters describing 5-FU transport and catabolism, i.e., volumes of distribution and clearances, as well as interindividual coefficients of variation (CV) were calculated according to both approaches. With our model, we were able to separate the concentration-time course of 5-FU in plasma, i.e., the AIF, from that of its major catabolite alpha-fluoro-beta-alanine (FBAL). As far as the mean parameter estimates are concerned, the differences between both approaches are not significant. For the liver data, the CV's are almost the same for both approaches. For the parameters concerning the aorta, however, there is a decrease in the CV's by using the population approach. For example, the CV of the central distribution volume of 5-FU was 30% for the individual approach and 18% for the population approach. With the population approach, it is possible to determine the AIF of drugs that undergo metabolic conversion, such as anticancer drugs, from the abdominal aorta visualized on PET images. The population approach helps to overcome noise in individual data. Since no measurements are needed in addition to the PET examination, the suggested method helps to reduce risk and pain for the patients as well as cost and thus facilitates large scale patient studies.

Predicting the time course of haemoglobin in children treated with erythropoietin for renal anaemia.

AIMS: To establish a pharmacodynamic model that allows one to predict the haemoglobin (Hb) response to EPO in children as a function of dose and time, and to derive recommendations for initial dosing and subsequent dose adjustment. METHODS: Haemoglobin was monitored in eight children aged 8-15 years with anaemia due to renal failure during treatment with EPO. All patients were free of conditions known to impair the response to EPO. Pretreatment Hb was 4.9-9.0 g dl(-1). The drug was administered once weekly by subcutaneous injection; doses ranged from 1700 to 6800 U week (-1). Hb was monitored for 4-38 months. The Hb-time data were analysed by applying a population pharmacodynamic model proposed for EPO in adult haemodialysis patients. Internal model validation was carried out by using a bootstrap procedure. RESULTS: The increase of Hb during treatment with EPO was linear until steady state was reached after 103+/-33 days (mean +/- interindividual s.d.). The weekly gain in Hb from the onset of therapy to steady state was 0.0805+/-0.026 g dl(-1) (mean +/- interindividual s.d.) for every 1000 U EPO week (-1); it did not exhibit a dependence on body weight. Estimated mean prediction errors are +/-1.53 g dl(-1) for predictions that are based on the mean population parameters and +/-0.83 g dl(-1) for predictions that take into account the complete individual Hb-time data up to and including steady state. CONCLUSIONS: The model describes the time course of the Hb response to EPO in children with renal anaemia. The required weekly EPO dose should initially be calculated from the individual pretreatment Hb and the desired Hb at steady state by using the mean population estimates of the weekly gain in Hb per dose unit before steady state (beta) and the time needed to reach steady state (tau). A reduction of the initial dose according to body weight is not justified by the available evidence. beta should be re-estimated individually after 6 weeks of treatment and dose should be adjusted accordingly. A final dose adjustment should be made when steady state has been reached based on individual estimates of beta and tau.

Monitoring local disposition kinetics of carboplatin in vivo after subcutaneous injection in rats by means of 195Pt NMR.

The anticancer drug carboplatin has been monitored in rats during treatment by means of in vivo 195Pt NMR spectroscopy at 2.0 T. The purpose of the study was to assess local disposition kinetics in intact tissue following subcutaneous injection of a platinum-containing drug. Serial 195Pt NMR measurements have been carried out in four animals after administration of carboplatin solutions with doses ranging from 37.1 to 59.4 mg per kg body weight. A surface coil of 2 cm diameter tuned to 18.3 MHz was placed over the injection site (back of the neck of the animals). To optimize measurement parameters of the single-pulse-acquire sequence and to determine chemical shifts and the detection threshold, in vitro 195Pt NMR experiments have been performed on model solutions of potassium tetrachloroplatinate(II), carboplatin, and cisplatin with different solvents such as H2O, DMSO, and DMF. Resonances of PtCl2-4, carboplatin, cisplatin, and cis-[Pt(NH2)Cl(DMSO)]+ were observed at chemical shift positions delta = -1623 ppm, -1705 ppm, -2060 ppm (cisplatin in DMSO), and -3120 ppm, respectively, relative to the reference signal of Na2PtCl6 at delta = 0 ppm. A spin-lattice relaxation time of carboplatin of T1 = (0.103 +/- 0.02) s was measured. The threshold for NMR detection of platinum-containing compounds estimated from the in vitro experiments was 10 micromol (corresponding to approximately 4.8 mM). In vivo 195Pt NMR spectra obtained in four rats after administration of carboplatin showed a broad resonance at delta = -(1715 +/- 8) ppm. The signal-to-noise ratio of this peak (starting 2 min after the injection) was approximately 9:1 for a measurement time of 6 min (TR= 13 ms, 28672 transients). The elimination rate constant of local disposition of carboplatin was kel = 0.017 (0.008-0.025) min-1 (median and range).

A population model for the leukopenic effect of etoposide.

We present a new model-dependent approach to quantify hematologic toxicity in a patient population after anticancer therapy. The population model consists of three submodels that are simultaneously fit to the data: (1) a cubic spline function describing the average response of the population versus time ("structural model"), (2) a covariate model, which relates parameters of the structural model to measured demographic or therapeutic variables that are found to be of predictive value (in this study: white blood cell (WBC) count baseline, drug concentration, serum albumin, and serum bilirubin concentration), and (3) a variance model, which estimates the contribution to the response from random variability between patients and from variability within patients, both between courses and within courses, between days. To demonstrate the approach, previously reported data from 118 courses of etoposide therapy in 71 patients with cancer were used to model the decrease in WBC count after 3-day continuous infusions of drug. The estimated typical response profile is characterized by (1) a lag-time of 4 1/2 days before any WBC count decline is observed, (2) a duration of time below baseline of 22 days, and (3) half-maximal effect (i.e., decrease to 50% of baseline WBC count) after exposure to C50 = 3 mg/L etoposide (mean) over 3 days. Lower serum albumin concentrations, higher bilirubin concentrations, or both are associated with greater effects at a given etoposide exposure. Large variability in the estimated response was found between individuals and within individuals, between courses. The total variabilities (SD) in lag-time, duration of the decrease, and C50 were 1 day, 6 days, and 1.8 mg/L, respectively. The population model can also be used to predict the consequence of as-yet untested therapy and sampling strategies, as well as to relate acceptable risks of toxicity to target drug exposure.

Influence of tetrachlorodecaoxide (Ryoxon) on the development of leukemia after total-body gamma-irradiation.

The effect of tetrachlorodecaoxide (TCDO) treatment after total-body irradiation (TBI) with gamma-rays (single dose, about LD 50) on the development of radiation-induced leukemia was tested in rats. TCDO was applied intravenously from day 4 through day 11. The control group was exposed to the same dosage of X-rays (TBI), but received physiological saline solution instead of TCDO. Compared to the control group, TCDO therapy initially markedly increased the survival rate: 72 versus 44% (6 months after TBI) and 36 versus 20% (1-year survival rate). The overall survival, however, was not significantly prolonged. TBI caused leukemia in 36% of the rats in the irradiation control group without TCDO treatment, however, none of 24 rats treated with TCDO after X-ray exposure developed leukemia. Since in this study TCDO was only administered for 8 days during the acute phase of radiation syndrome, we suppose that additional TCDO treatment at various times later on would lead to even better results.

Anticarcinogenic effect of tetrachlorodecaoxide after total-body gamma irradiation in rats.

Tetrachlorodecaoxygen (TCDO) therapy of acute radiation syndrome was tested for a possible influence on the development of X-ray-induced malignancies. BD IX rats were exposed to total-body irradiation (TBI, gamma rays, 9 or 11 Gy) and received daily intravenous injections of either TCDO or physiological saline solution from days 4 through 11 after TBI. The short-term TCDO therapy reduced the acute death rate markedly, but survival rates after 4 months were similar with and without TCDO. The first malignancy after TBI occurred on day 103, and over the lifetime of the animals the tumor incidence in the group given TBI (11 Gy) without TCDO treatment was 73% vs 20% in animals with short-term TCDO therapy after TBI. In particular, there was a highly significant prevention of radiation-induced leukemia [P (one-sided) < 0.001] by TCDO, and a significantly reduced incidence of malignant epithelial tumors [P (one-sided) < 0.05]. The development of sarcomas was not affected by TCDO. Long-term survival was not enhanced by TCDO due to the occurrence of bronchopneumonial infections about 1 year after TBI. In conclusion, TCDO is not only a potent therapeutic agent in acute radiation syndrome, but it also significantly reduced the carcinogenic risk in rats after exposure to ionizing radiation.

Pharmacokinetic analysis of sparse in vivo NMR spectroscopy data using relative parameters and the population approach.

NMR spectroscopy in vivo when applied to studying drugs and their metabolites usually measures relative concentration in a tissue over time. Only ratios of clearance and volume parameters can be estimated from these data. Low drug dosages (relative to the sensitivity of in vivo NMR) or rapid drug elimination create the additional problem of data sparsity where a pharmacokinetic model cannot be fitted individually. We have investigated whether relative and absolute pharmacokinetic parameters can be estimated from such data by applying a population model. The data analysed were relative concentrations of 5-fluorouracil (FU) and of the sum of its catabolites alpha-fluoro-beta-ureido-propanoic acid (FUPA) and alpha-fluoro-beta-alanine (FBAL) in the liver, as monitored in 16 cancer patients by [19F]-NMR spectroscopy during and after a 10-min intravenous infusion of 650 mg FU.m-2. The "structural" part of the population model was a non-linear, two-compartment model featuring one FU compartment with volume VFU, a saturable clearance of FU by conversion into the catabolites where CL = vmax/(kM+CFU), a catabolite compartment with volume Vcat, and a concentration-independent clearance of the catabolites, CLcat. The parameters actually fitted were: gamma, vmax, kM.VFU, Vcat/VFU, and CLcat/Vcat where gamma is a proportionality factor relating the NMR signal intensity of FU to the amount of FU in the body and, therefore, has no purely pharmacokinetic interpretation. All parameters were checked for random interindividual variation: gamma and vmax were also tested for inter-occasion variation. The program system NONMEM was used for model fitting.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of ciclotropium on human heart rate.

Ciclotropium is a recently developed parasympathicolytic agent. Plasma concentration and heart rate increase (the most prominent anticholinergic effects) were measured in 12 healthy subjects before, during and after a 15-min intravenous infusion of 10 mg ciclotropium. The effect was described by using either a linear or a nonlinear (Emax) effect model linked to a linear three-compartment kinetic model via an effect compartment. Maximum heart rate increase was 33 (10) beats.min-1, and half-value duration of effect was 41 (9) min. Total plasma clearance was 0.51 (0.13) l.min-1, and mean terminal elimination half-life was 12(4) h, whereas the equilibration half-lives of drug removal from the effect compartment ranged from 2 to 14 min.

Kinetic modeling of in vivo--nuclear magnetic resonance spectroscopy data: 5-fluorouracil in liver and liver tumors.

Kinetic modeling has been applied to the time course of the nuclear magnetic resonance signal intensities of 5-fluorouracil and the sum of its catabolites, alpha-fluoro-beta-ureido propanoic acid and alpha-fluoro-beta-alanine, as monitored in liver tumors of seven patients with cancer after brief intraarterial infusion of 5-fluorouracil. Because these data represent only relative tissue concentrations, only ratios of clearance and volume parameters can be estimated (e.g., clearance/central volume of distribution or central volume of distribution/steady-state volume of distribution). On the other hand, parameters that do not refer to volumes, such as half-lives or maximal velocity of metabolic conversion of a nonlinear model, can be estimated in absolute terms. A nonlinear three-compartment model gave satisfactory fits with all of the individual data sets. Kinetics of 5-fluorouracil and catabolites were similar in five patients with metastases of colorectal adenocarcinomas but differed from those of two patients with cholangiocarcinoma and metastases of an anaplastic carcinoma of unknown origin, respectively.

Pharmacokinetics of 5-fluorouracil after short systemic infusion: plasma level at the end of the distribution phase as an indicator of the total area under the plasma concentration-time curve.

The correlation between single plasma concentration (CP) values of 5-fluorouracil (FU) after a 10-minute i.v. infusion and the total area under the plasma concentration-time curve (AUC) has been studied in 26 cancer patients. FU dose was either 320-550 mg/m2 (seven patients, 13 treatments) or 610-960 mg/m2 (19 patients, 30 treatments). Linear single CP-AUC relationships were found in both dose groups with the CPs at 1, 5, 10, 15, and 30 minutes after the end of infusion. Parameters of linear regression of AUC on single CP differed between the two dose groups. For the high-dose group, the single CPs at repeated treatments were tested as estimators of the total AUC at these treatments, using calibration lines relating total AUC to single CP, which were derived from the data of the first (or only) treatments of all patients. The "best" AUC estimators of the total AUC were the CPs at 10 and 15 minutes after the end of infusion, with a bias of only 2% and an imprecision of only 11% of the AUC values directly determined from the complete concentration-time profiles of the repeated treatments. Because of the close correlation between these single CPs and the total AUC, these CPs should be considered equivalent to the AUC as an overall index of individual FU kinetics after brief infusion of high doses.

Relative importance of dose, body surface area, sex, and age for 5-fluorouracil clearance.

The pharmacokinetics of 5-fluorouracil (FU) has been investigated in 26 cancer patients; 15 of these patients were pretreated with methotrexate (MTX). FU was given by a constant rate intravenous infusion within 10 min, at doses of 320-960 mg/m2. Total plasma clearance, beta-half-life, and steady-state distribution volume were determined with 43 treatments, based on plasma level measurements up to 90 min after the end of the infusion. Average clearance decreased from 1.3 l/min for 320 to 0.7 l/min for 960 mg FU/m2. Multiple linear regression calculations with dose, body surface area, sex, age, and MTX pretreatment as independent variable and clearance as dependent variable confirmed the dependency of clearance on dose and body surface area but also showed that, with equal FU dose per m2, clearance was higher in males than in females, on the average, by 0.22 l/min. There was also suggestive (although not significant) evidence of a (reducing) influence of age on FU clearance.