Predicted Plasma Concentrations Research Articles

This Month in Anesthesiology

This Month in Anesthesiology

In vitro/in vivo correlation studies for transdermal Δ8-THC development

The present study was carried out in order to develop a transdermal therapeutic system (TTS) for Δ8-THC. The in vitro permeability studies of Δ8-THC in human skin and hairless guinea pig skin with and without a rate-controlling membrane were conducted in flow-through diffusion cells. Δ8-THC pharmacokinetic parameters were determined after topical application of transdermal patches and intravenous administration in guinea pigs. The in vitro results indicated that there was no significant difference in the mean flux or in the permeability coefficient of Δ8-THC in human skin versus hairless guinea pig skin. The flux of Δ8-THC through the human skin/membrane composite was not significantly lower than that through the hairless guinea pig skin/membrane composite; and the skin controlled the Δ8-THC delivery rate. Intravenous doses of Δ8-THC followed a two-compartment model with a significant distribution phase. On application of the TTS patch, the plasma concentration of Δ8-THC reached a mean steady-state level of 4.4 ng/mL within 1.4 h and was maintained for at least 48 h. Significant amounts of metabolites were observed in the plasma after topical application. The in vitro-study predicted plasma concentration following application of the transdermal patch was in agreement with the observed guinea pig plasma concentrations of Δ8-THC. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93: 1154–1164, 2004

Absorption model based on transport physics theory applied to paracetamol

Absorption of orally administered drugs from the GI tract is an important determinant of the onset of the drug effect. Models of drug absorption are frequently based on a direct or a delayed first-order rate process. In practice, the use of the first-order approach to predict plasma concentrations frequently yields a considerable mismatch between predicted and measured concentration profiles, particularly for the upswing of the plasma concentration after oral administration. In this investigation an alternative model, based on the advection-dispersion equation describing the transport of chemicals through a one-dimensional transport medium is evaluated for describing the absorption rate. It is shown that for a specific set of initial and boundary conditions the solution of the advection-dispersion equation is similar to the Inverse Gaussian Density (IGD) input function. The latter is occasionally used to describe the absorption rate as a function of time based on two parameters, the transport velocity and the dispersion coefficient. The IGD input function was combined with a one-compartment PK model with first-order elimination to describe normal, accelerated, and delayed absorption of paracetamol in a 22yr old man after oral administration. A comparison of the model fit with results obtained on the basis of a first-order absorption model demonstrate that the IGD function is more accurate in describing the PK curve after oral administration. Clinical Pharmacology & Therapeutics (2004) 75, P80–P80; doi: 10.1016/j.clpt.2003.11.307

A mathematical model to predict plasma concentrations of morphine and its active metabolite morphine-6-glucuronide in healthy young persons

A mathematical model to predict plasma concentrations of morphine and its active metabolite morphine-6-glucuronide in healthy young persons

Pharmacokinetic modeling to predict morphine and morphine-6-glucuronide plasma concentrations in healthy young volunteers.

This investigation focused on the development of a predictive model of morphine, including morphine-6-glucuronide (M6G) for healthy young volunteers after morphine administration. Population compartmental pharmacokinetic modeling with NONMEM was applied to the plasma concentration-time data of morphine and M6G obtained from 8 healthy volunteers (4 men and 4 women; age range, 23 to 30 years) after intravenous bolus injection of 5.64 mg morphine base (7.5 mg morphine sulfate) and of 1 mg deuterium-labeled M6G. Two models were identified that described the plasma concentration versus time courses of morphine and M6G after administration of morphine. The model consisted of a standard 3-compartment model for morphine and a standard 2-compartment model for M6G, with input into and output from the central compartments. The formation of M6G from morphine was modeled as a fraction of morphine clearance of about 14%, which accounted for the formation of M6G, and a delay of the appearance of M6G in plasma modeled as a first-order process, with a mean metabolic transit time of 17.2 minutes. An alternative model assigned the formation of M6G among the first peripheral compartment of morphine and the central compartment of M6G. Therefore the alternative 3-compartment model of morphine had the input into the central compartment and renal excretory elimination from the central compartment, but the metabolic clearance of morphine started from the first peripheral compartment. M6G was again modeled with a standard 2-compartment model. Both models predicted morphine and M6G plasma concentrations available from an independent study with acceptable accuracy and without bias. Two models are provided that can predict plasma concentrations of morphine and M6G with acceptable accuracy in healthy young volunteers.

Heart-rate variability (HRV) in the ECG trace of routine EEGs: fast monitoring for the anticholinergic effects of clozapine and olanzapine?

Drug monitoring in psychiatry usually serves psychoactive drug plasma concentration measurement. Anticholinergic properties offer a faster approach to monitoring pharmacodynamic intraindividual effects of the drug by measuring their effects on heart rate variability (HRV), which is sympathetically and parasympathetically controlled via cholinergic synapses. The plasma concentrations of the atypical antipsychotics clozapine and olanzapine correlated with parameters of HRV in 59 patients suffering from schizophrenia or schizoaffective disorder. HRV during 4 minutes at rest was extracted from the ECG trace of a routine digital EEG registration in addition to blood sampling for plasma concentration measurement (HPLC method). We calculated sympathetically and parasympathetically controlled heart frequency bands (low, medium and high frequency) and other HRV parameters, coefficient of variation (CV), and root mean square of successive differences (RMSSD). All HRV parameters were significantly more impaired in clozapine patients (n = 33, mean clozapine plasma concentration 331 +/- 294 ng/ml) than in olanzapine patients (n = 26, mean olanzapine plasma concentration 42 +/- 32 ng/ml) and demonstrated 1.7 - 4.8 times the cardiac anticholinergic properties of clozapine in vivo. 14 out of 14 patients with a CV beyond 3.2 % had clozapine plasma concentrations below the proposed optimal therapeutic concentration of 350 ng/ml. All HRV parameters were inversely and significantly correlated with the clozapine plasma concentrations (such as lgCV: r = - 0.73, p < 0.001) and, to a lesser extent, with the olanzapine plasma concentrations (lgCV r = - 0.44, p < 0.05). These results underline the potential clinical value of HRV parameter extraction from routine ECGs in predicting plasma concentrations and objective individual neurocardiac effects of drugs with anticholinergic properties.

Drug interactions between HIV protease inhibitors based on physiologically-based pharmacokinetic model

A Physiologically-based pharmacokinetic (PB-PK) model was developed to describe the aspects of pharmacokinetic interactions between five HIV protease inhibitors (ritonavir, amprenavir, nelfinavir, saquinavir, indinavir) in rats. To increase usefulness of this BP-PK model, liver, intestinal tissue and other organ were assumed as compartments in this model. Each compartment was linked with the blood flow and the blood-to-plasma concentration ratios of those drugs, and the absorption process in the intestinal tract was presumed as a first-order kinetics. In addition, this PB-PK model incorporates two elimination processes due to hepatic and intestinal metabolism constructed by in vitro metabolic clearance rates and inhibition constants between HIV protease inhibitors. Excellent agreements were obtained between the predicted and observed concentrations of HIV protease inhibitors in rat plasma after a 20 mg/kg oral dose or co-administration of two kinds of HIV protease inhibitors (amprenavir/indinavir, nelfinavir/amprenavir, saquinavir/amprenavir, amprenavir/ritonavir, indinavir/ritonavir, nelfinavir/ritonavir, and saquinavir/ritonavir) with each 20 mg/kg oral dose. However, underestimates in the predicted plasma concentrations of saquinavir, indinavir and amprenavir were observed during the terminal phase after co-administration with ritonavir or amprenavir, suggesting that a term of other inhibitory process, such as a mechanism-based inhibition, might be incorporated into this PB-PK model. This BP-PK model enables us to know useful information about pharmacokinetic interaction when HIV infected patients would receive double protease therapy. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:680–689, 2002

The Optimal Target Propofol and Alfentanil Concentrations during Plastic Surgery

Background: Propofol and alfentanil are frequently combined to provide total intravenous anesthesia (TIVA). The goals of this study were to determine the target plasma concentration (predicted plasma concentration) of propofol required to provide satisfactory anesthesia in the presence of nitrous oxide over a range of alfentanil infusions for analgesia and to determine the dosing rates required to achieve adequate anesthesia. Methods: Sixty patients undergoing plastic surgery were anesthetized with 50% nitrous oxide, alfentanil (0 [A0 group] or 5g/kg loading followed by 0.12g/kg/min [A5 group] or 10g/kg loading followed by 0.25g/kg/min [A10 group] or 20g/kg loading followed by 0.5g/kg/min [A20 group]) and propofol using a target-controlled infusion (TCI). The mean target concentration and infusion rate of propofol, and induction and recovery time according to changes of the alfentanil regimen were checked. Results: Induction and recovery time were prolonged in the A0 group more than other groups, and recovery time was shortened in the A10 group more than the other three groups (P 0.05). The infusion rate and mean target concentration of propofol had significant impact among the groups (P 0.05). Side effects did not differ among the groups. Conclusions: The optimal target plasma propofol concentrations and infusion rates of alfentanil, both with satisfactory intraoperative anesthetic conditions and speed of recovery, are 3.51, 3.02, 2.35g/ml and 0.12, 0.25, 0.5g/kg/min with 5, 10, 20g/kg loading in plastic surgery patients. We recommand 0.25g/kg infusion with 10g/kg loading of alfentanil combined with 3.02g/ml of target plasma concentration of propofol as the best combination dosage to shorten recovery time.

Monitored Anesthetic Care (MAC) Using Ketamine, Midazolam and a Target-Controlled Propofol Infusion for Minor Surgery

Background: There are many kinds of anesthetic methods. One of them, monitored anesthetic care (MAC) is a useful tool for minor surgery. Whether MAC can be substituted for conventional anesthesia in minor surgery was investigated. Methods: Sixty-five patients were studied. Midazolam was given intravenously as a premedication, and then, target-controlled infusion (TCI) using propofol was started and ketamine 25 mg was given intravenously before a painful stimuli. The initial target concentration of propofol was 2.5g/ml. During the procedure, we adjusted the target concentration of propofol according to clinical signs and sometimes added 25 mg of ketamine intravenously. For 10 minutes after starting the propofol infusion, blood pressure, heart rate, SpO2 and respiratory rate were recorded. During recovery, we monitored the predicted concentrations of propofol at eye opening and orientation recovery, the time from stopping the propofol infusion and intraoperative complications. In addition, we checked the patient's satisfaction with the anesthesia. Results: The average consumption of ketamine and propofol were 0.68 I 0.43 mg/kg and 9.0 2.1 mg/kg/hr, respectively. The time to eye opening and recovery of orientation were 9.5 5.5 min and 10.2 I 5.3 min, respectively. The predicted plasma concentrations at eye opening and orientation recovery were 0.98 0.34g/ml and 0.93 B 0.28g/ml, respectively. Most patients (87.7%) were satisfied with the anesthetic method. However during the procedure, airway obstruction was the most frequent (21.5%) comlication. Conclusions: MAC is a useful and excellent anesthetic method, but corresponding anesthesiologists must attend closely and monitor respiratory complications.

Saliva as an alternative body fluid for therapeutic drug monitoring of the nonnucleoside reverse transcription inhibitor nevirapine.

The objective of this study was to evaluate the applicability of saliva as an alternative body fluid for therapeutic drug monitoring of nevirapine. The pharmacokinetics of nevirapine in plasma and saliva during a dosing interval was assessed in HIV-1-infected patients taking nevirapine (200 mg twice daily) to explore the relation between the concentration of nevirapine in plasma and saliva. To validate the anticipated relationship prospectively, single, paired plasma and saliva samples were obtained from nevirapine-treated HIV-1-infected outpatients. The plasma nevirapine concentration was strongly correlated with the salivary concentration. The mean saliva/plasma concentration ratio was 0.51 and was independent of the time after ingestion. Salivary nevirapine concentrations were used to estimate the corresponding plasma concentrations for 31 outpatients. Compared with the true plasma concentrations, the estimated concentrations were biased by -4.2%, with a precision of 13.3%. These data show a strong correlation between the salivary and plasma concentrations of nevirapine at a dosage of 200 mg twice daily. This relation has been validated prospectively, and the prediction of plasma concentrations was accurate and precise. Therefore, the authors conclude that saliva can be a useful body fluid for therapeutic drug monitoring of nevirapine.

Ocular microtremor: a tool for measuring depth of anaesthesia?

Ocular microtremor (OMT) is a fine high frequency tremor of the eyes caused by extra-ocular muscle activity stimulated by impulses emanating in the brain stem. Several studies have shown that the frequency of this tremor is reduced in patients whose consciousness is reduced by anaesthesia or head injury. Therefore, OMT may possibly be used to determine depth of anaesthesia. Twenty-two unpre-medicated subjects undergoing surgery with general anaesthesia were studied. OMT activity was measured at admission using the open eye piezoelectric strain gauge technique. Anaesthesia was induced with propofol using a target controlled infusion delivery system (Diprifusor). OMT activity was then recorded at predicted plasma propofol concentrations of 1, 2, 3 and 5 microg ml(-1). The patient's level of consciousness (response to command or stimulation) was assessed after each OMT measurement. OMT activity was reduced progressively at predicted plasma concentrations of propofol of I and 2 microg ml(-1) and then plateaued between 3 and 5 microg ml(-1). There was a significant difference between the last awake OMT recording and the first recording at loss of consciousness (P < 0.001). OMT recording holds promise as a practical indicator of the depth of anaesthesia.

Therapeutic drug monitoring as a tool in treating HIV infection.

Despite its success antiretroviral therapy (ART) is still associated with a significant risk of toxicity and subsequent virological failure. Pending the introduction of drugs with greater potency and durability one of the most pressing priorities in HIV treatment is to identify ways in which to maximize the efficacy of existing therapeutic options while minimizing its toxicity. Resistance testing has been shown to be one such strategy. Therapeutic drug monitoring (TDM) for HIV drugs has been widely proposed as another tool by which treatment may be optimized. There are some parallels with resistance testing not least the potential difficulties or pitfalls in interpreting test results and the understandable pressure for provision of this service in the face of increasingly limited treatment options notwithstanding the current lack of data from controlled clinical studies. In this reviews we shall discuss the value of TDM in the context of a ‘monitoring service (in other words drug concentrations are provided in conjunction with interpretation and advice) rather than a facility for ‘measuring drug concentrations. This distinction is important since the interpretation of drug concentrations is fraught with complexity. (excerpt)

Time-dependent oral absorption models.

The plasma concentration-time profiles following oral administration of drugs are often irregular and cannot be interpreted easily with conventional models based on first- or zero-order absorption kinetics and lag time. Six new models were developed using a time-dependent absorption rate coefficient, ka(t), wherein the time dependency was varied to account for the dynamic processes such as changes in fluid absorption or secretion, in absorption surface area, and in motility with time, in the gastrointestinal tract. In the present study, the plasma concentration profiles of propranolol obtained in human subjects following oral dosing were analyzed using the newly derived models based on mass balance and compared with the conventional models. Nonlinear regression analysis indicated that the conventional compartment model including lag time (CLAG model) could not predict the rapid initial increase in plasma concentration after dosing and the predicted Cmax values were much lower than that observed. On the other hand, all models with the time-dependent absorption rate coefficient, ka(t), were superior to the CLAG model in predicting plasma concentration profiles. Based on Akaike's Information Criterion (AIC), the fluid absorption model without lag time (FA model) exhibited the best overall fit to the data. The two-phase model including lag time, TPLAG model was also found to be a good model judging from the values of sum of squares. This model also described the irregular profiles of plasma concentration with time and frequently predicted Cmax values satisfactorily. A comparison of the absorption rate profiles also suggested that the TPLAG model is better at prediction of irregular absorption kinetics than the FA model. In conclusion, the incorporation of a time-dependent absorption rate coefficient ka(t) allows the prediction of nonlinear absorption characteristics in a more reliable manner.

General pharmacokinetic model for drugs exhibiting target-mediated drug disposition.

Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents. Simulations show that model predicted plasma concentration vs. time profiles are expected to be polyexponential with steeper distribution phases for lower doses and similar terminal disposition phases. Noncompartmental parameters always show apparent Vss and CL(D) decreasing with dose, but apparent clearance decreases only when the binding process produces drug elimination. The proposed model well captured the time-course of drug concentrations for the aldose reductase inhibitor imirestat, the endothelin receptor antagonist bosentan, and recombinant human interferon-beta 1a. This type of model has a mechanistic basis and considerable utility for fully describing the kinetics for various doses of relevant drugs.

Pharmacokinetic model-driven infusion of sufentanil and midazolam during cardiac surgery: Assessment of the prospective predictive accuracy and the quality of anesthesia

Objective: To evaluate the prospective predictive accuracy and the quality of anesthesia of pharmacokinetic model-driven infusion of sufentanil and midazolam designed to establish and maintain a plasma level of drug during cardiac surgery. Design: Prospective analysis. Setting: Operating room at a university hospital. Participants: Twenty adult patients younger than 75 years old scheduled for valvular or coronary artery bypass graft surgery. Interventions: Patients were anesthetized using a variable predicted concentration of sufentanil (1 to 10 ng/mL) combined with a stable predicted concentration of midazolam (100 ng/mL). Measurements and Main Results: For each patient, arterial samples were taken before (6 samples), during (2 samples), and after (2 samples) cardiopulmonary bypass (CPB). Plasma sufentanil and midazolam concentrations were measured by specific radioimmunoassay and high-performance liquid chromatography techniques. Predicted sufentanil and midazolam concentrations were derived using the data sets of Gepts et al and Maitre et al. The predictive performance, the percentage prediction error (PE), and the absolute percentage error were calculated for each sample. The bias, inaccuracy, and dispersion were assessed by determining the median of the individual medians of the prediction errors (MDPE), the median of the individual median of the absolute prediction errors (MDAPE), and the 10th and 90th percentiles of PE. For midazolam, the inaccuracy was low (MDAPE < 21%), but CPB was associated with a dilution of the measured concentration associated with a negative bias. For sufentanil, the inaccuracy was also low before CPB (MDAPE = 18%) but increased during and after CPB (MDAPE > 40%). During the whole procedure, the hemodynamic control necessitated only a few interventions. Conclusions: Pharmacokinetic model–driven infusion of sufentanil and midazolam using the pharmacokinetic sets of Gepts et al and Maitre et al is a safe and accurate anesthetic technique before CPB in adult patients undergoing cardiac surgery when high sufentanil (1 to 10 ng/mL) and low midazolam (100 ng/mL) predicted plasma concentrations are targeted. Copyright © 2000 by W.B. Saunders Company

Saliva as a Specimen for Monitoring Compliance But Not for Predicting Plasma Concentrations in Patients With HIV Treated With Indinavir

The presence of the HIV-protease inhibitor indinavir in saliva was analyzed to investigate whether salivary indinavir concentrations are applicable to monitor compliance and/or predict plasma indinavir levels. Fourteen HIV-infected outpatients treated with indinavir and 24 healthy volunteers who ingested a single dose of indinavir were included. Paired plasma and citric-acid-stimulated saliva samples were analyzed by high-performance liquid chromatography (HPLC). Stimulated salivary indinavir concentrations showed a high correlation (r = 0.85, p < 0.01) with corresponding plasma levels. The median saliva/plasma ratio was 65% (P25 50%; P75 94%). The ratios were independent of the plasma concentration; however, a relation with time after ingestion was seen. The unbound fraction of indinavir in plasma was not significantly correlated with the saliva/plasma ratio after stimulated saliva collection, in contrast with a subset of nonstimulated saliva from healthy volunteers, where we did find a significant correlation. Although stimulated salivary indinavir concentrations are highly correlated with plasma concentrations, it is not possible to predict plasma indinavir levels by the salivary concentrations for purposes of therapeutic drug monitoring, due to large interindividual and intraindividual variation. Nevertheless, monitoring compliance by measuring the presence of indinavir in saliva is possible: ingestion of indinavir can be assessed with a sensitivity of 84.8% in the whole dosing interval or with 98.8% between 1 and 6 hours after the last dose, which is comparable with plasma.

Streptococcus pneumoniae in the USA: in vitro susceptibility and pharmacodynamic analysis

Ninety-two laboratories in the USA submitted isolates of Streptococcus pneumoniae to a single laboratory for susceptibility testing. Overall, 64% of 4489 isolates were susceptible to penicillin, 24% were intermediate and 13% were resistant to penicillin, although susceptibilities varied depending on geographical region. Macrolide/azalide resistance varied from 4 to 30%, with some regions having macrolide/azalide resistance higher than penicillin resistance. Children 12 years of age were significantly more likely to be infected with a penicillin-resistant pneumococcus than were adolescents or adults. Isolates from the respiratory tract were more likely to be penicillin resistant and >50% of pneumococci from the ear were resistant to penicillin. Almost 25% of penicillin-susceptible isolates had cefaclor MICs 2.0 mg/L and 15% of penicillin-susceptible isolates had loracarbef MICs 2.0 mg/L. These isolates would be erroneously reported as susceptible using NCCLS guidelines, and this finding may explain the lack of clinical response in patients treated with these antibiotics. The predicted plasma concentrations of all cephalosporins tested exceeded the geometric mean MIC for at least 40% of the dosing interval for penicillin-susceptible S. pneumoniae; for penicillin-intermediate S. pneumoniae, only cefprozil (56%), cefuroxime (64%) and cefpodoxime (63%) reached >40% of time above the geometric mean MIC in the dosing interval. None of the cephalosporins evaluated achieved a substantial time above the geometric mean MIC during its dosing interval for fully penicillin-resistant S. pneumoniae.

Diet and Waist-to-Hip Ratio: Important Predictors of Lipoprotein Levels in Sedentary and Active Young Men with no Evidence of Cardiovascular Disease

Objective Healthy, young men were studied to determine the relationship of energy and nutrient intake and physical activity to concentrations of plasma lipoprotein and cholesteryl ester transfer protein. Design A cross-sectional study compared active and sedentary male subjects (17 to 35 years old) with no personal or family history of coronary heart disease. Participants kept 20-day food and activity journals. Individual intakes of energy, protein, carbohydrate, fat, saturated fat, monounsaturated fatty acids, polyunsaturated fatty acids, dietary fiber, and alcohol were evaluated. Measurements of blood lipids (total cholesterol and triglycerides, high- and low-density lipoprotein cholesterol); apolipoproteins; cholesteryl ester transfer protein; anthropometric variables (body mass index, waist-to-hip ratio, percentage of body fat); and aerobic capacity were taken during fall and spring data collection periods. Subject selection Subjects were selected on the basis of normal blood lipid levels, absence of underlying disease, and willingness to comply with their current level of physical activity for the duration of the study. Minimal sample size for statistical power was 12 men per group: 12 of 15 subjects who exercised and 13 of 15 subjects who were sedentary completed all phases of the study. Statistical analyses Statistical analyses consisted of 2-way analysis of variance (activity level and season). Pearson product moment correlations and multiple regression analyses were conducted to assess whether energy and nutrient intakes, physical activity status, and/or anthropometric variables predicted plasma concentrations of lipids and apolipoproteins. Results Lower waist-to-hip ratio, and not specifically activity level, was associated with higher levels of high-density lipoprotein cholesterol (HDL-C) and lower levels of low-density lipoprotein cholesterol (LDL-C). Dietary intake of saturated and monounsaturated fats and alcohol predicted changes in some apolipoprotein and lipoprotein levels. Applications Use of waist-to-hip ratio in the primary prevention of coronary heart disease is a simple and cost-effective measure to predict development of abnormal lipoprotein profiles in young men. Specific dietary recommendations include adoption of a heart-healthy diet with emphasis on monounsaturated fatty acids (10% to 12% of energy or one third of total fat intake) and the suggestion that small amounts of alcohol (<3 drinks per week) may, indeed, be beneficial. Because alcohol and waist-to-hip ratio were both important predictors of LDL-C level, even in active young men, the consumption of low levels of alcohol may be beneficial only if waist-to-hip ratio is maintained within the healthful range by achieving an appropriate balance of physical activity and macronutrient intake. J Am Diet Assoc. 1999;99:1373–1379.

Can pharmacokinetic monitoring improve clinical use of fluorouracil?

Fluorouracil is used clinically against a variety of solid tumors. It is a prodrug that undergoes a series of intracellular conversions to active cytotoxic species. There is wide interindividual variability in fluorouracil metabolism; furthermore, it has nonlinear kinetics that make it relatively more difficult to predict plasma concentrations after brief infusions compared with prolonged infusions. There is an increasing body of evidence that relates plasma fluorouracil concentrations to toxicity and effectiveness, and consequently there may be a definable mathematical relationship that describes a 'therapeutic window'. Dose nomograms and pharmacokinetic models based on limited sampling strategies have been developed, as have empirical dose escalation schedules based on multivariate analysis of the determinants of toxicity, The utility of these approaches should be tested in properly powered, prospective, randomised trials.

PHARMACOKINETICS OF DOPAMINE IN HEALTHY MALE VOLUNTEERS

Introduction: Dopamine is an endogenous catecholamine with dose dependent pharmacologic effects. No one to date has been able to correlate these effects with plasma concentrations. The purpose of this study is to define the pharmacokinetics of dopamine in healthy male volunteers and to develop a pharmacokinetic model to help predict plasma concentrations for given dosages of the drug. Methods: Nine healthy male volunteers were recruited for the study. An intravenous and intraarterial catheter were used for drug delivery and blood sampling, respectively. An infusion of dopamine was used in the following manner: 10 [micro sign]g/kg/min for 10 min followed by a 30 min washout; 3 [micro sign]g/kg/min for 90 min followed by another 30 min washout, with arterial blood samples collected. BP and HR were recorded before, during and after the infusions. Assay data from each subject was fit to both one and two compartment disposition models using nonlinear mixed effects regression (NONMEM software, UCSF). The Schwartz-Bayesian criterion was used to determine whether the one or two compartment model best fit the data. To date we have completed the dopamine assays in four of the nine volunteers. Results: Baseline plasma dopamine concentrations ranged from 22 to 367 pg/mL; peak plasma concentrations reached as high as 201.5 ng/mL. The one compartment model best fits the data, with a median volume of distribution (Vd) of 5.2L and median clearance of 1.90 L/min (Table 1).Table 1Discussion: Institution of a dopamine infusion results in huge increases in plasma concentrations, reaching as much as a 10,000-fold increase over basal dopamine concentrations. Dopamine appears to fit a one-compartment model best, with a volume of distribution approximately equal to circulating blood volume, and a clearance of 1.9 L/min. Infusion of "renal dose" dopamine (3 [micro sign]g/kg/min) resulted in sustained plasma levels nearly equivalent to those obtained with a 10 min infusion of 10 [micro sign]g/kg/min. (Figure 1)Figure 1Support: Southern Medical Association Research Project Grant; General Clinical Research Center of Wake Forest University Medical Center #M01-RR07122