Prediction of gentamicin serum levels using a one-compartment open linear pharmacokinetic model

The accuracy of predicting serum gentamicin levels based on a one-compartment open linear pharmacokinetic model was studied. Twenty-two patients accounted for 59 serum gentamicin levels which were measured by microbiologic assay and compared with predicted serum levels determined by pharmacokinetic calculation. Seventeen serum levels were collected at peak times, 15 at trough time and 27 at times between peak and trough. Forty-nine of the levels were obtained from patients with impaired renal function. Predicated gentamicin levels correlated well with measured serum levels (r = 0.85, p less than 0.001). Of the measured levels, 56% were within +/- 1 microgram/ml of the predicted levels. Of 49 levels collected from patients with impaired renal function, 59% were within +/- 1 microgram/ml of the predicted level. In 13 patients from whom multiple serum gentamicin levels were collected and predictions based on half-life or elimination rate obtained by fitting the first level, 83% of the measured levels were within +/- 1 microgram/ml of the predicted level. The one-compartment open linear pharmacokinetic calculations can be used to adequately predict serum gentamicin levels. In patients with changing or diminished renal function, pharmacokinetic predictions may not be accurate, and actual serum level determinations may be needed to monitor gentamicin therapy.     

Evaluation of gentamicin pharmacokinetics and dosing protocols in 195 neonates

Gentamicin pharmacokinetics and dosing protocols in neonates were studied. Demographic and pharmacokinetic data on 202 neonates treated with gentamicin at a 500-bed medical center were collected over a three-year period. Administered doses, gentamicin concentration measurements, and recorded times were used to calculate each patient's clearance, volume of distribution, elimination rate constant, and half-life. The performance of 15 dosing protocols, including 6 previously published ones and 9 developed on the basis of the study, was evaluated using the pharmacokinetic data. Of the 202 patients, 195 were included in the analysis. The mean +/- S.D. clearance, volume of distribution, elimination rate constant, and half-life were 0.047 +/- 0.015 L/hr/kg, 0.45 +/- 0.11 L/kg, 0.107 +/- 0.032 L/hr, and 7.19 +/- 2.64 hours, respectively. Weight, urine output, gestational age, and postconceptional age (PCA) had the highest correlation with the pharmacokinetic values. Blood urea nitrogen concentration (BUN) and Apgar score were poor predictors of the pharmacokinetic values. There were no significant differences among patient subsets based on race and BUN, but subset analysis based on PCA did indicate significant differences. In simulations, the protocols based on the study patients tended to perform better than the literature protocols, with all but three achieving therapeutic goals in 75% or more of the neonates. Of the published protocols, Murphy and Carter's produced the greatest percentage of neonates with peaks from 5 to 10 mg/L and troughs of <2 mg/L. The devised protocols tended to perform poorly in producing troughs between 1 and 2 mg/L, yet performed comparatively well in providing therapeutic peaks from 5 to 10 mg/L.     

Role of physiologic concentrations of stem cell factor in leukemic type growth of myelodysplastic CD34+ cells

Extrapolation of animal data to assess pharmacokinetic parameters in humans is an important tool in drug development. Allometric scaling has many proponents, and many different approaches and techniques have been proposed to optimise the prediction of pharmacokinetic parameters from animals to humans. The allometric approach is based on the power function Y = aWb, where the bodyweight of the species is plotted against the pharmacokinetic parameter of interest on a log-log scale. Clearance, volume of distribution and elimination half-life are the 3 most frequently extrapolated pharmacokinetic parameters. Clearance is not predicted very well (error between predicted and observed clearance > 30%) using the basic allometric equation in most cases. Thus, several other approaches have been proposed. An early approach was the concept of neoteny, where the clearance is predicted on the basis of species bodyweight and maximum life-span potential. A second approach uses a 2-term power equation based on brain and body weight to predict the intrinsic clearance of drugs that are primarily eliminated by phase I oxidative metabolism. Most recently, the use of the product of brain weight and clearance has been proposed. A literature review reveals different degrees of success of improved prediction with the different methods for various drugs. In a comparative study, the determining factor in selecting a method for prediction of clearance was found to be the value of the exponent. Integration of in vitro data into in vivo clearance to improve the predictive performance of clearance has also been suggested. Although there are proponents of using body surface area instead of bodyweight, no advantage has been noted in this approach. It has also been noted that the unbound clearance of a drug cannot be predicted any better than the total body clearance (CL). In general, there is a good correlation between bodyweight and volume of the central compartment (Vc); hence, Vc does not face the same complications as CL. The relationship between elimination half-life (t 1/2 beta) and bodyweight across species results in poor correlation, most probably because of the hybrid nature of this parameter. When a reasonable prediction of CL and Vc is made, t 1/2 beta may be predicted from the equation t 1/2 beta = 0.693 Vc/CL.     

Genotoxic activity detected in soils from a hazardous waste site by the Ames test and an SOS colorimetric test

The pharmacokinetics of vancomycin were evaluated simultaneously using both arterial and venous plasma data in five rabbits after a rapid bolus intravenous (i.v.) dosing. Initial arterial to venous concentration ratios at 5 s after i.v. injection were the highest, with values of 27.1, 36.2, 36.6, 43.7 and 29.7 for rabbits 1-5, respectively. This could be the result of diffusion of vancomycin from the arterial plasma into the extravascular tissues. Both curves decayed in parallel at the terminal phase with the venous levels higher than the arterial levels by 23, 37, 34, 13 and 14% for rabbits 1-5, respectively. This difference could be the result of continuous release of vancomycin from the extravascular tissues to the venous blood. Detailed analysis showed differences in various pharmacokinetic parameters based on arterial and venous data. For example, values for venous Vc were 9.2, 11, 1.9, 7.2 and 8.8 times greater than the arterial values for rabbits 1-5, respectively. The values for both venous Vss and MRT were higher than those of the arterial values in all five rabbits studied. This could be due to more extensive distribution of vancomycin in the extravascular tissues. A plot of 1/Q (urine flow rate) versus 1/ClR of vancomycin yielded a straight line in rabbits 6-10, indicating that the renal clearance of vancomycin in rabbits is dependent upon urine flow.     

Comparative pharmacokinetics and bioavailability of two cotrimoxazole preparations

The objective of this study was to assess both pharmacokinetic properties and bioavailability of a newly developed cotrimoxazole preparation (Bioprim tablets, 80 mg of trimethoprim/400 mg sulfamethoxazole), in comparison with a reference preparation commercially available (Bactrim tablets, 80 mg of trimethoprim/400 mg of sulfamethoxazole). The pharmacokinetics and bioavailability of cotrimoxazole from these preparations were compared in an open randomized crossover study in 12 healthy males. Plasma concentrations of trimethoprim and sulfamethoxazole were measured by HPLC after protein precipitation. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The obtained pharmacokinetic values (Cmax, tmax, beta, t1/2 beta, CL, Vd, AUC36, AUC infinity) of both trimethoprim and sulfamethoxazole determined in our study agreed with values reported in the literature. Westlake's and Nonparametric probability tests with the 90% confidence intervals, for both trimethoprim and sulfamethoxazole gave the differences within 80 and 120%, for all necessary measures (Cmax, tmax and AUC infinity). Statistical analysis of the data has shown that the preparations have similar pharmacokinetic profiles and therefore can be considered equally bioavailable.     

Integration of in vitro data into allometric scaling to predict hepatic metabolic clearance in man: application to 10 extensively metabolized drugs

In this study, we investigated rational and reliable methods of using animal data to predict in humans the clearance of drugs which are mainly eliminated through hepatic metabolism. For 10 extensively metabolized compounds, adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro dramatically improved the predictions of human clearance compared to the approach in which clearance is directly extrapolated using body weight. Using hepatocyte data to normalize the in vivo clearances led to lower median deviations between the observed and predicted clearances in man compared to the approach normalizing data with brain weight (30-40% vs 60-80%, respectively). In addition, the approach integrating in vitro data appeared to be superior with respect to the range of deviations: approximately 2-fold underestimation, in the worst case, was observed by using in vitro data, whereas normalizing data by brain weight led to up to 10-fold underestimation of clearance in man. In addition, the integration of in vitro data provides a more rational basis to predict the metabolic clearance in man and may be applicable to compounds undergoing phase I and phase II metabolism as well.     

Interspecies scaling of renally secreted drugs

The objective of this study is to predict pharmacokinetic parameters (clearance, volume of distribution at steady state, and elimination half-life) in humans from animal data for drugs which are renally secreted in humans. Pharmacokinetic parameters of ten drugs were scaled-up from animal data obtained from the literature. Using simple allometry (pharmacokinetic parameter of interest vs body weight), total, renal and nonrenal clearances, volume of distribution and half-life were predicted in humans. The predicted parameters were compared with the observed parameters. The results of the study indicated that it is likely that the predicted total and renal clearances from animal data will be underestimated in humans for renally secreted drugs. The prediction of renal clearance was improved by normalizing the renal clearance by a 'correction factor' for animals who exhibited renal secretion. The predicted volume and half-life were comparable with the observed values in man. Overall, the results of this study indicate that caution should be employed in interpreting the total and renal clearance of renally secreted drugs predicted by the allometric approach.     

Discrimination between rival dosing histories

PURPOSE: In population pharmacokinetic studies, the dosing history is sometimes recorded in more than one way. The purpose of this study was to develop and evaluate a procedure for discriminating between rival dosing histories, i.e., for each individual in a data set, identify the dosing history that is the most plausible. METHODS: The procedure consists of four steps. In the first step we identify individuals whose dosing histories produce predictions that are consistent. In the second step these individuals are used to build a population pharmacokinetic model which is used, in step three, to select the dosing history for the individuals not identified in step one. In step four the population model is refined using the best available dosing histories for all individuals. The proposed procedure was evaluated using both simulations and a real data set, in which two dosing histories, based on patient diaries and electronic monitoring devices (MEMS) were available. RESULTS: In the real data set, estimated variabilities were almost always lower when the selected dosing histories were used compared to when no selection procedure was used. The diary dosing histories were selected more often than the MEMS dosing histories. In the simulations, the parameter estimates obtained using the selection procedure were closer to the true parameter values compared to when only one of the dosing histories was used. CONCLUSIONS: The proposed procedure appears to be robust and should be beneficial in at least two respects: improved parameter estimation of population pharmacokinetic and PK/PD models and objective information by which dosage recording methodologies can be compared and patient dose recording behavior can be assessed.     

Identifying individuals with high fat levels and low P:S ratios, in their diets, for intensive dietary intervention

OBJECTIVE: Interindividual variability in plasma concentrations of nicotine and its proximate metabolite, cotinine, is considerable during smoking and transdermal nicotine treatment, even among individuals taking in nominally similar doses of nicotine. This report explores the determinants of this variability and the utility of baseline (smoking) plasma concentrations to predict concentrations during transdermal nicotine treatment. METHODS: Data were analysed from a smoking cessation study (n = 466), and from a pharmacokinetic study (n = 12). Multiple regression models examined the relationships of plasma concentrations to individual characteristics such as smoking pattern, absorbed dose of nicotine, and pharmacokinetic parameters. RESULTS: Plasma concentrations of nicotine and cotinine were highly variable in both studies. Indirect estimates of plasma clearance (baseline plasma concentration divided by cigarettes per day) together with other factors could account for 18 to 33% of the variability during transdermal nicotine treatment in the smoking cessation study. In contrast, 75 to 99% was accounted for by direct measurements of plasma clearances and systemic dose of nicotine in the pharmacokinetic study. CONCLUSION: Plasma concentrations of nicotine and cotinine during transdermal nicotine treatment are poorly predicted by clinical history or baseline plasma concentrations. This is a result of inadequate characterisation of highly variable individual pharmacokinetic parameters and absorbed dose of nicotine. Considering the interindividual variability of plasma nicotine and cotinine concentrations together with the lack of clinical end-points for transdermal nicotine dosing, it seems logical to investigate the utility of a therapeutic drug monitoring approach for transdermal nicotine treatment-particularly for high dose regimens (> 22 mg per 24 hours).     

Steady-state pharmacokinetic properties of pramipexole in healthy volunteers

Pramipexole is a dopamine receptor agonist that has proved effective in the treatment of Parkinson's disease. The pharmacokinetic properties of pramipexole at steady-state concentrations were studied in 16 healthy men and women at four dose levels throughout the range recommended for Parkinson's patients. Plasma and urine samples collected within the four dose intervals were assayed for concentrations of pramipexole, using high-performance liquid chromatography. The total oral clearance for all participants was 419 mL/min. The mean volume of distribution and elimination half-life for all participants was 486 +/- 93.2 L and 12.9 +/- 3.27 hours. Concentrations of pramipexole were proportional to dose, although the drug's pharmacokinetic properties differed between men and women. The area under the concentration-time curve for each dose level was 35% to 43% greater in women, mainly because of a 24% to 27% lower oral clearance. The mean creatinine clearance in men and women was 112 +/- 12.8 mL/ min/1.73 m2 and 80.9 +/- 15.6 mL/min/1.73 m2, respectively. The renal clearance of pramipexole accounts for approximately 80% of oral clearance, and there was a significant correlation between renal and creatinine clearances. The influence of gender could not be distinguished from the influence of age and the resulting reduced creatinine clearance, but the measurement of pharmacokinetic properties produced linear results in both men and women.     

Relationship between hemodynamic and vital support measures and pharmacokinetic variability of amikacin in critically ill patients with sepsis

OBJECTIVE: To examine the relationship between aminoglycoside disposition kinetics and hemodynamic response to sepsis, as well as vital support therapy, in critically ill patients with sepsis. DESIGN: Cross-sectional study of critically ill patients with sepsis undergoing physiologic and aminoglycoside pharmacokinetic monitoring. SETTING: Ten-bed general intensive care unit in a tertiary care center. PATIENTS: Thirty consecutive critically ill patients who had Gram-negative sepsis treated with amikacin and who were undergoing hemodynamic monitoring. INTERVENTIONS: Clinical, hemodynamic, oxygenation, and amikacin pharmacokinetic data were obtained simultaneously in each patient during aminoglycoside therapy. MEASUREMENTS AND MAIN RESULTS: Aminoglycoside pharmacokinetic values were estimated from serum amikacin concentration-time data using a nonlinear least squares regression computer program, assuming a one-compartment infusion pharmacokinetic model. Individual pharmacokinetic values were subjected to statistical analysis to explain their variability. Selection of the subset of variables to be used in the final model was performed by combining principal component analysis and multiple stepwise linear regression. The mean prediction error and the root mean square error, as expressions of bias and precision, were estimated. Mean volume of distribution was 0.47 L/kg, with a coefficient of variation of 35%. Mean serum amikacin clearance was 60.2 mL/min, with a coefficient of variation of 34%. Seventy-six percent of the variability in volume of distribution was explained by three covariates: body weight (p < .0001); oxygen extraction (p < .001); and serum albumin (p < .001). For serum amikacin clearance, 70% of the variability was explained by three covariates: creatinine clearance (p < .001); positive end-expiratory pressure (p < .01); and use of catecholamines as vital support therapy (p < .05). CONCLUSIONS: Factors related to hemodynamic response and vital support measures have a significant influence on the disposition kinetics of amikacin in severely ill patients with sepsis. Consideration of hemodynamic response and vital support measures, in addition to other previously described covariates, can be of great value in the design of initial dosing regimens.     

Risk factors for cardiovascular disease in children with type I diabetes: Part 1

This study characterizes the pharmacokinetics of bumetanide after an intravenous dose of 0.05 or 0.10 mg/kg to 14 neonates (weight range 820-4,000 g; gestational age 26-40 weeks) during the first week of life. Blood samples and urine were collected for up to 12 h after dosing. Estimated serum clearance was 0.2-1.0 ml/min.kg (range), volume of distribution was 0.22 l/kg (range 0.11-0.32 l/kg), and the harmonic mean half-life was 6-7 h (range of 4-19 h). Nonrenal clearance accounted for 58-97% of the serum clearance with the presence of certain oxidative metabolites of bumetanide in the urine. These findings suggest higher dosing requirements and prolonged intervals as compared to adults. Utilizing these pharmacokinetic data, pharmacodynamic and ototoxicity studies should be conducted to establish a safe and effective neonatal dose.     

A saturable tissue-angiotensin I converting enzyme (ACE) binding model for the pharmacokinetic analysis of imidapril, a new ACE inhibitor, and its active metabolite in human

In order to obtain a rational explanation and analytical method of the unique pharmacokinetic behaviors of imidapril and imidaprilat in human, a new pharmacokinetic model was designed by introducing a saturable-reversible angiotensin I converting enzyme (ACE)-imidaprilat binding process and a linear imidapril-imidaprilat conversion process. According to the new model, six differential equations were given which considered the mass balance of both compounds in each component. Various pharmacokinetic parameters were estimated by the simultaneous curve fitting method using the plasma concentration data and the urinary excretion data of imidapril and imidaprilat in a multiple dosing study of healthy human volunteers. To validate the value of each parameter, this pharmacokinetic model was also applied to analyze the various plasma concentration data of both compounds in the single dosing studies with four different dosages, 2.5,5, 10, and 20 mg. Excellent curve fitting was obtained in every case, suggesting that the proposed pharmacokinetic model is applicable for predicting the plasma concentrations of imidapril and imidaprilat under various dosage conditions of clinical use.     

Predictability of sacral base levelness based on iliac crest measurements

The pharmacokinetic profile of the melanotropic peptide, melanotan-II (MT-II), was determined in rats following a 0.3 mg kg-1 intravenous dose. Regression analysis of the plasma MT-II concentrations determined using HPLC and bioassay methods indicated the existence of a significant linear correlation (r = 0.90, p < 0.001). The plasma concentration versus time plots determined using the two assay methods yielded biphasic disposition profiles that were essentially superimposable. The following pharmacokinetic parameters were assessed from plasma concentration versus time data using both methods: Cmax, AUC, CLs, t1/2 beta, MRT, Vd beta, and Vss. Statistical comparison showed that the parameters measured by each method were not significantly different (at the 0.05 level) except for t1/2 beta, MRT and Vss. The presence of even one aberrant data point in the beta-phase can significantly influence t1/2 beta when only a few data points are available in the beta-phase. Since MRT and Vss were calculated from t1/2 beta it is not surprising that these two parameters also differed between methods.     

Disposition of the selective alpha1A-adrenoceptor antagonist tamsulosin in humans: comparison with data from interspecies scaling

Tamsulosin-HCl is an alpha1A-adrenoceptor antagonist that is mainly eliminated by metabolism in animals and humans and is highly bound to alpha1-acid glycoprotein in blood plasma. The disposition of the compound (0.4 mg as modified-release granules in a capsule) was determined in male volunteers, using intravenous (iv) infusion of tamsulosin-HCl (0.125 mg over 4 h) as reference treatment for the assessment of absolute oral bioavailability. Disposition parameters of iv tamsulosin in humans was compared with data predicted from animal data by interspecies scaling techniques. Levels after iv dosing in humans showed a biexponential decline, with mean half-lives (+/-SD) of 1.2 +/- 0.6 and 6.8 +/- 3.5 h, respectively. The mean systemic clearance (+/-SD) was low (viz., 48 +/- 24 mL/min). The mean volume of distribution (+/-SD) was rather small (21 +/- 6 L), and was estimated at 16 +/- 4 L in the steady state. The mean absolute oral bioavailability (+/-SD) was approximated at 100 +/- 19%. Systemic clearance in humans was poorly predictable from a logarithmic clearance versus body weight relation of rat, rabbit, and dog data. The prediction improved dramatically (accuracy 213%) when scaling was done with systemic clearance values of unbound drug, and it improved further (accuracy 59%) with the product of unbound clearance and maximum life-span potential. Also, the prediction of volume of distribution improved dramatically (accuracy 81%) after correction for differences in extent of protein binding between species. The terminal disposition half-life of 7.0 h, as predicted after integrating maximum life-span potential and protein binding in scaling of clearance, was very close to the value of 6.8 h established experimentally in humans. The present results with tamsulosin underline the importance of correction for extent of protein binding in allometric scaling of clearance and distribution volume.     

Depth-Averaged Velocity Distribution in Straight Trapezoidal Channels

In trapezoidal channels that are not “wide,” the banks exert form drag on the fluid and thereby control the depth-averaged velocity distribution. As such, commonly used equations for predicting depth-averaged velocities in wide channels are not well suited for predicting depth-averaged velocities in trapezoidal channels. Using data from three previous studies, we developed two models for predicting depth-averaged velocity distributions in straight trapezoidal channels. The data used to develop the models had a range of discharges (8.05–4,248?L/s), velocities (0.16–1.03?m/s), bottom widths (0.305–3.62?m), flow depths (0.0518–0.805?m), and bank slopes (1.0–3.0, horizontal/vertical). The first model requires measured velocity data for calibrating the model coefficients, whereas the second model uses prescribed coefficients. The first model yielded velocity distributions with coefficients of determination (r2) from 0.84 to 0.90 and we recommend its use when possible because it yields predictions that are more accurate. The second model also yielded good results (r2 = 0.86 and 94% of the predicted velocities were within 20% of the observed values).     

The CAG repeat within the androgen receptor gene and benign prostatic hyperplasia

Thalidomide, a glutamic acid derivative, has recently been shown to inhibit in vitro angiogenesis, the process of formation of new blood vessels. This Phase II study examined the pharmacokinetics of thalidomide in patients with clinically progressive hormone-refractory prostate cancer. Patients (aged 55 to 80 years) were randomized to two different arms, low dose versus high dose. Patients in the low-dose group were given 200 mg of thalidomide and patients in the high-dose group received 200 mg of thalidomide, with subsequent dose escalations to 1200 mg. Serial serum or blood samples were obtained for pharmacokinetic assessment after administration of a single oral dose or multiple daily dosing of thalidomide and were assayed by reversed-phase HPLC. Pharmacokinetic parameters for both the single and multiple dosing were calculated with ADAPT II. A one-compartment model best fit the data. After single dosing, the oral clearance and apparent volume of distribution for the low-dose regimen (n = 13) were 7.41 +/- 2.05 L/h and 66.93 +/- 34.27 L, respectively, whereas for the high-dose regimen (n = 11), these values were 7.21 +/- 2.89 L/h and 165.81 +/- 84.18 L, respectively. The elimination half-lives for the low and high dose were 6.52 +/- 3.81 and 18.25 +/- 14.08 h, respectively. After the multiple dosing of thalidomide, the oral clearance and apparent volume of distribution for the low-dose group (n = 10) were 6.35 +/- 1.64 L/h and 64.63 +/- 23.20 L, respectively, whereas for the high-dose group (n = 11), these values were 7.73 +/- 2.27 L/h and 167.85 +/- 82.08 L, respectively. The elimination half-lives for the low and high dose were 7.08 +/- 1.87 and 16.19 +/- 9.57 h, respectively. For both the single and multiple dosing of thalidomide, the apparent volume of distribution and half-life were significantly higher for the high-dose group than those for the low-dose group. The higher apparent volume of distribution may be attributable to several factors, such as change in absorption, protein binding, etc. A dose-proportional increase in thalidomide steady-state concentrations was seen after multiple daily dosing of thalidomide.     

Pyrimethamine pharmacokinetics in human immunodeficiency virus-positive patients seropositive for Toxoplasma gondii

Pyrimethamine pharmacokinetics were studied in 11 human immunodeficiency virus (HIV)-positive patients who were seropositive for exposure to Toxoplasma gondii and were taking zidovudine (AIDS Clinical Trials Group Protocol 102). Pyrimethamine was administered at 50 mg daily for 3 weeks to achieve steady state, and pharmacokinetic profiles were determined after administration of the last dose. Noncompartmental and compartmental analyses were performed. Population pharmacokinetic analysis assuming a one-compartment model yielded the following estimates: area under the 24-h concentration-time curve, 42.7 +/- 12.3 micrograms.h/ml; halflife, 139 +/- 34 h; clearance, 1.28 +/- 0.41 liters/h; volume of distribution, 246 +/- 641; and absorption rate constant, 1.5 +/- 1.3 liters/h. These values are similar to those seen in subjects without HIV infection. Pyrimethamine pharmacokinetics did not differ significantly in those subjects who were intravenous drug users. Adverse effects were noted in 73% of those initially enrolled in this study, leading to discontinuation for 38%. No association was noted between pyrimethamine levels and the incidence of adverse events. No significant differences were seen in zidovudine pharmacokinetic parameters obtained from studies performed before and during treatment with pyrimethamine. In summary, pyrimethamine exhibited pharmacokinetics in HIV-infected patients that were similar to those in non-HIV-infected subjects and it did not alter the pharmacokinetics of zidovudine in these patients.     

Pharmacokinetic considerations in the design of optimal chemotherapeutic regimens for the treatment of breast carcinoma: a comceptual approach

Pharmacological data are currently available for a number of antineoplastic agents which have shown clinical activity in advanced breast carcincoma. Preclinical data reveal a relationship between therapeutic response and certain pharmacokinetic parameters such as time of effective cytotoxic exposure (Teff) and the product of concentration with time (Cxt). We have attempted to apply human pharmacologic data to get estimates of these parameters for 6 active agents in breast cancer, to relate them to response rates, and to suggest a method for estimating the role of individual drugs in a multidrug combination. The response rates for 6 single agents were obtained from literature review and related to estimates of Teff and Cxt. The Cxt-response relations for single drugs were linear for cyclophosphamide, 5-fluorouracil, and thiotepa; exponential for vincristine; and relatively flat for methotrexate and cytoxine arabinoside. Most Teff values for the active single agents clustered about 15 hr/dose. From the graphs of response rate vs Cxt, the individual contribution of each agent in a combination study was estimated to arrive at a predicted response rate. The predicted response rates for the combination studies correlated with the actual response rates determined in the clinical study, for 6 of 6 nonrandomized studies and for 12 of 14 randomized studies analyzed. In 2 studies, deviations from the predicted response rate were attributed to differences in study design or analysis. There was no correlation between Teff and predicted response rate. Analyses of pharmacokinetic data may be useful to simulate combination chemotherapy studies to predict the effectiveness of clinical trials in breast cancer. Since the pharmacologic data were not obtained for any of the agents in the actual clinical trials done, we can only speculate on the usefulness of this method. We would encourage the prospective collection of this data in future clinical trails.