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Biomedical subjects

T M Ludden

Publications and source records attributed to T M Ludden.

At least 37 records · Page 2Linked to original sources
PubMed1994

Comparison of single and multiple dose pharmacokinetics using clinical bioequivalence data and Monte Carlo simulations.

The purpose of this study was to evaluate the relative performance and usefulness of single dose (SD) and multiple dose (MD) regimens for bioequivalence (BE) determination. Drugs such as indomethacin, procainamide, erythromycin, quinidine, nifedipine were tested for BE under SD and MD dose regimens. Drugs characterized by low accumulation indices (AI) showed virtually no change in the 90% confidence interval (CI) of AUC and CMAX upon multiple dosing. On the other hand, drugs with higher AI appeared to have smaller CI at steady-state. For example, the CI range of AUC and CMAX of quinidine (AI of 1.54) decreased from 26 to 12 and from 22 to 12, respectively, upon multiple dosing. A Monte Carlo simulation study of SD and MD bioequivalence trials was performed. The probability of failing the bioequivalence test was evaluated for several situations defined by different levels of variability and correlation in ka constants, presence or absence of inter- and/or intra-individual variability in clearance (CL) and volume of distribution (V), and different degrees of accumulation. All the possible combinations of these factors were tested with SD and MD study designs. All simulations used 1000 data sets with 30 subjects in each data set for a total of 144 unique designs (total of 144,000 simulations of bioequivalence trials). Upon multiple dosing, narrowing of CI ranges was observed for drugs simulated to have high AI high variability and a large difference in absorption constants (ka) between test and reference formulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Bioavailability of controlled release carbamazepine estimated by mixed effect modelling.

The absorption properties of a conventional tablet of carbamazepine (T) and a controlled release form of carbamazepine (TCR) have been compared using a nonlinear mixed effect model (NONMEM). Plasma carbamazepine concentration data were obtained from an open, steady-state, crossover bioavailability study in which 494 measurements were obtained from 13 patients, with an equal number of samples per patient for each dosage form. The pharmacokinetic model used as a one-compartment open model with first-order absorption and elimination. The objective function was used as a measure of the goodness of fit of the model to the data. Body weight was an important determinant of carbamazepine clearance (CL) but not volume of distribution (V). Accounting for the interindividual variability in volume of distribution did not significantly influence the objective function. Including different rates of absorption (ka) for the two dosage forms resulted in a significant improvement in the objective function, as well as reducing the interindividual variability in the rate of absorption. Adding a parameter for relative bioavailability (f) of TCR improved the objective function statistically, but an unrealistic value for V was obtained, and the absorption and elimination rates appeared to be transposed in the classical "flip-flop" manner. Fixing V to the value obtained before introducing f did not change the objective function and permitted estimation of f without the confounding influence of excessive parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1993

Distribution and metabolism of pentoxifylline in non-tumor-bearing mice.

Pentoxifylline increases tissue oxygen delivery in patients with atherosclerotic arterial disease by several mechanisms, including lowering blood viscosity and increasing erythrocyte flexibility. Since tumor neo-vessels are also abnormal and associated with intra-tumoral hypoxia and, thus, with radiation failure, pentoxifylline might also be useful as a radiation sensitizer. The mouse is frequently used to study such drugs, but the pharmacokinetics of pentoxifylline in the mouse have not been determined. We investigated this in three separate experiments by administering pentoxifylline intraperitoneally, subcutaneously, or orally. Plasma was assayed for the parent drug and its metabolites by capillary gas chromatography. High plasma levels of pentoxifylline and both major derivatives occurred within several minutes after intraperitoneal or subcutaneous injection, but plasma levels were low after oral administration.

Administration, Oral↗
PubMed1993

Serum levels of pentoxifylline and its metabolites in non-tumor-bearing mice after chronic oral pentoxifylline administration.

Pentoxifylline lowers blood viscosity and increases erythrocyte flexibility in patients with atherosclerosis, thus increasing tissue oxygen delivery. Since tumor neo-vessels are associated with tissue hypoxia, which contributes to failure of radiation therapy, pentoxifylline might also be useful as a radiation sensitizer. Such drugs are often evaluated in the murine model, but serum levels of pentoxifylline and its metabolites have not been determined in the mouse after chronic oral dosing. We investigated this by administering pentoxifylline via liquid diet or solid diet to young adult male CF1 mice for one to six weeks and assaying plasma for the parent drug and its metabolites. At one, three, and six weeks, plasma levels of pentoxifylline and major derivatives were consistently detectable. Mice remained healthy during this period, indicating that ingestion of large amounts of this drug is well tolerated.

Administration, Oral↗
PubMed1992

Comparative bioavailability of a sustained-release ion-exchange hydralazine product with a potassium (cation) challenge.

A sustained-release formulation of hydralazine was manufactured by binding hydralazine to an ion-exchange resin and coating the drug-resin complex with a semipermeable membrane. Because the sustained-release characteristics are due in part to displacement of drug from the drug-resin complex by gastrointestinal ions, the stability of the sustained-release formulation could be compromised if challenged by a high concentration of ions. In this study, 12 healthy male volunteers participated in a two-way crossover trial that was designed to test the bioavailability and release of drug from the sustained-release formulation both with and without concomitant ingestion of a solution of KCl. Blood samples were collected over a 14-h period after administration of either treatment. Analysis of whole blood for hydralazine and comparison of the values of the area under the curve of the concentration of hydralazine versus time, the maximum concentration of hydralazine, and the time to reach the maximum concentration between the two experimental groups showed that KCl had no influence on the bioavailability or release characteristics of hydralazine from the sustained-release formulation.

Adult↗
PubMed1992

Pharmacokinetics of quinidine in male patients. A population analysis.

Quinidine pharmacokinetic behaviour was evaluated in 139 adult hospitalised men receiving oral quinidine therapy. A total of 391 serum quinidine concentrations were measured by enzyme immunoassay for routine clinical purposes. The NONMEM programme was used to examine the relationship between quinidine pharmacokinetics and several potential covariates. A 1-compartment open model with first-order absorption and elimination was assumed. The mean apparent volume of distribution (Vd) was about 230L. When measured, alpha 1-acid glycoprotein (AAG) levels were not included in the analysis. Oral quinidine clearance (CL) decreased with age, severe congestive heart failure and renal disease, and increased in patients with a history of alcohol abuse. The interpatient variability in CL and the intrapatient residual variability expressed as coefficients of variation (CV) were 28 and 31%, respectively. When AAG values were incorporated into the analysis, the only important covariates of CL were the AAG measurements and the presence of renal dysfunction as indicated by a calculated creatinine clearance of less than 50 ml/min (3 L/h). The interpatient variability in CL and the residual intrapatient CVs decreased to approximately 24 and 26%, respectively. Improvement of the CL model by inclusion of measured AAG strongly suggests that quinidine elimination is dependent on the free concentration of drug in plasma and supports the use of free serum quinidine concentrations when evaluating and monitoring quinidine therapy.

Aged↗
PubMed1991

Human pharmacokinetics of betaxolol enantiomers.

Betaxolol is a cardioselective beta-adrenergic antagonist effective in the treatment of hypertension. The pharmacokinetic behavior of betaxolol enantiomers in healthy male subjects is reported. Betaxolol enantiomer concentrations were determined in samples collected up to 48 h after iv administration of a 10-mg dose over a 30-min period by constant-rate infusion in 12 subjects and after oral administration of 40-mg capsules to eight of the same subjects. Betaxolol extracted from whole blood was reacted with (+) or (-)-1-naphthylethyl isocyanate. The resulting diastereoisomeric derivatives were analyzed by reversed-phase HPLC with fluorimetric detection. Following the iv dose, there were no differences in clearance or volume of distribution for the two enantiomers (15.6 +/- 4.4 versus 16.4 +/- 4.1 L/h and 342 +/- 62 versus 340 +/- 65 L, respectively). Likewise, after the oral dose, there were no differences in the maximum concentration, time of maximum concentration, bioavailability, or apparent absorption rate constant (41.0 +/- 8.6 versus 42.0 +/- 7.0 ng/mL, 214 +/- 59 versus 215 +/- 56 min, 0.89 +/- 0.26 versus 0.94 +/- 0.23, and 1.0 +/- 0.6 versus 1.2 +/- 0.6 h-1, respectively). Thus, the pharmacokinetic behavior of racemic betaxolol accurately reflects the behavior of betaxolol enantiomers in this subject group.

Administration, Oral↗
PubMed1991

Sensitivity analysis of the effect of bioavailability or dosage form content on mean steady state phenytoin concentration.

Stochastic simulations were used to examine the sensitivity of mean phenytoin steady state concentrations (Css) to changes in the effective dosing rate produced by differences in average product content or bioavailability. Changes of +/- 4%, +/- 6%, +/- 8% and +/- 10% in the effective dosing rate (based on a starting dose yielding a Css of 15 mg/L) were examined. Monte Carlo simulations were performed for each change in dosing rate assuming a one-compartment open model with parallel Michaelis-Menten and first-order elimination. Parameter sets were comprised of a combination of values for maximal rate of saturable elimination (410 or 510 mg/day), the concentration at which the rate of saturable elimination is half maximum (Km, 4.4 or 5.7 mg/L), and linear clearance (CL, 0.15 or 1.5 L/day). These parameters were assumed to be log-normally distributed with coefficients of variation of 30%, 50%, and 15%. The percentages of "individuals" who would be predicted to have Css of less than 10 mg/L following a reduction in the effective dosing rate increased with decreasing Km and CL values. For a Km of 5.7 mg/L and CL of 1.5 L/day, 5% of the "individuals" had Css values of less than 10 mg/L with an 8% decrease in the dosing rate. If the dosing rate was reduced by 10%, then 14-16% of the "individuals" were predicted to have concentrations of less than 10 mg/L. All other combinations of Km and CL values yielded higher percentages of "individuals" with Css of less than 10 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Availability↗
PubMed1991

Nonlinear pharmacokinetics: clinical Implications.

Nonlinear pharmacokinetics (in other words, time or dose dependences in pharmacokinetic parameters) can arise from factors associated with absorption, first-pass metabolism, binding, excretion and biotransformation. Nonlinearities in absorption and bioavailability can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. One of the more important sources of nonlinearity is the partial saturation of presystemic metabolism exhibited by such drugs as verapamil, propranolol and hydralazine. In such cases, circulating drug concentrations are sensitive not only to dose size but also to rate of absorption: slower absorption may decrease the overall systemic availability. The binding of drugs to plasma constituents, blood cells and extravascular tissue may exhibit concentration dependence. This can cause pharmacokinetic parameters based on total blood or serum drug concentrations to be concentration-dependent. Often, in these cases, parameters based on free drug concentration appear linear. An important consideration in regard to concentration-dependent serum binding is the difficulty in relating total concentration to a usual therapeutic range if free concentration is a better indicator of drug effect. Measurement of free concentration is needed in these cases, particularly if the intersubject variability in binding is high. An example of this behaviour is valproic acid. Partial saturation of elimination pathways can result in the well known behaviour typical of Michaelis-Menten pharmacokinetics. Small changes in dosing rate can make much larger differences in steady-state concentration. The time to achieve a given fraction of steady-state becomes longer as the dosing rate approaches the maximum elimination rate. Alcohol and phenytoin are examples of drugs that exhibit such behaviour. The sensitivity of steady-state concentration and cumulation rate to changes in dosing rate are both influenced by the magnitude of parallel first-order elimination pathways: even a first-order pathway that is only 1 to 2% of maximum clearance (which occurs at very low concentration) can be an important determinant of steady-state concentration and cumulation rate when concentrations are high. Theophylline and salicylate have significant parallel first-order elimination pathways as well as saturable pathways. Autoinduction causes an increase in clearance with long term administration. In some cases, dosage adjustment must be made to compensate for the increase, and the possibility that the degree of induction may be dose- or concentration-dependent must be kept in mind. Carbamazepine is a major example of autoinduction. It is fortunate that only a few of the many hundreds of drugs in use exhibit nonlinear behaviour that leads to clinical implications.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗
PubMed1990

Determination of betaxolol and its metabolites in blood and urine by high-performance liquid chromatography with fluorimetric detection.

Analytical methods for the determination of betaxolol and two of its metabolites in blood and urine are described. Betaxolol, alpha-hydroxybetaxolol, and the acid metabolite were extracted, with over 65% efficiency, from biological samples by liquid-liquid extraction methods. Analysis was performed using reversed-phase high-performance liquid chromatography with fluorimetric detection. N,N-Dimethyloctylamine (0.005 M) was used to improve the chromatography of betaxolol and alpha-hydroxybetaxolol, while acetic acid (1%) was used for the acid metabolite. An excitation wavelength of 200 nm was found to produce the best detector response. Linear standard curves were obtained for all three compounds with detection limits (signal-to-noise ratio = 3) varying between 1 and 10 ng/ml. The coefficients of variation of the determination for all three compounds in blood and urine varied between 3.0 and 8.7%. The metabolism of betaxolol was studied in twelve healthy male subjects. The amounts (mean +/- S.D.) of betaxolol, alpha-hydroxybetaxolol and the acid metabolite renally excreted in the first 48 h after intravenous administration of 10 mg of betaxolol hydrochloride are 17.1 +/- 6.2, 0.4 +/- 0.1 and 14.5 +/- 3.7%, respectively, of the administered dose.

Adult↗
PubMed1990

Effect of food on oral availability of apresoline and controlled release hydralazine in hypertensive patients.

Hydralazine is a vasodilator antihypertensive drug that has been in use for many years. Efficacy after oral administration correlates well with the levels of the drug in blood. Factors such as food ingestion that affect blood levels of hydralazine may therefore be of importance. There is dispute regarding the effect of food intake on blood levels of hydralazine and on the antihypertensive response. This randomized cross-over study examined the effect of food (642 K calories, 25 g protein, 43 g fat, 40 g carbohydrates, 32 mEq sodium, 17 mEq potassium) ingested immediately before hydralazine (taken as Apresoline, Ciba Geigy, or as slow-release hydralazine, SRH, Pennwalt Corporation) on the blood levels of hydralazine in 16 essential hypertensive patients who were slow acetylators currently taking at least 100 mg Apresoline daily. Peak blood hydralazine levels were reduced by food after both Apresoline and SRH, by 69 and 66%, respectively. Time to peak blood hydralazine concentration was delayed significantly with SRH. We could detect a statistically significant food-related reduction of area under blood hydralazine concentration versus time curves (AUC) only with Apresoline (by 44%). The AUC for SRH was decreased only 29% by food. Hydralazine should be taken at a consistent time with respect to meals.

Administration, Oral↗
PubMed1989

Pharmacokinetics of felbamate, a novel antiepileptic drug: application of mixed-effect modeling to clinical trials.

Felbamate is a novel antiepileptic drug currently undergoing clinical trials in the United States. Serum felbamate concentration data from a phase II safety and efficacy trial were analyzed using NONMEM. A one-compartment, open model with first-order absorption and elimination was used. Body weight, sex, concurrent folic acid therapy, and phenytoin dose and dose:concentration ratio did not affect the estimates for felbamate clearance (Cl). Carbamazepine dose and dose:concentration ratio (CDCR) led to significant improvements in the objective function. The final models for felbamate clearance and volume of distribution (Vd) were as follows: Cl(L/hr) = 2.43 + 0.429*CDCR/240, Vd (L) = 51. The coefficient of variation of clearance was only about 12%, which may be indicative of the highly selective patient population. The clearance estimates are similar to those obtained in healthy volunteers and in patients receiving lower dosages of felbamate. The volume of distribution estimate, however, is slightly smaller than that reported previously. Valuable pharmacokinetic information can be obtained from the routine monitoring of serum concentrations during safety and efficacy trials.

Adolescent↗
PubMed1989

Evaluation of theophylline pharmacokinetics in a pediatric population using mixed effects models.

Routine clinical pharmacokinetic data collected prospectively from pediatric patients receiving theophylline were analyzed using the NONMEM (nonlinear mixed effects model) digital computer program. A total of 314 measured serum theophylline concentrations (STCs) were obtained from 84 hospitalized patients ranging in age from 4 months to 15.2 years with the majority of patients between the ages of 1 and 8 years. Fifty-six percent were male. The race/ethnicity distribution was 71.4% Latin, 15.5% black, 11.9% Caucasian, and 1.2% (one subject) Pakistani. Of the total number of observed STCs, 16.2% reflected some degree of outpatient dosing. The pharmacokinetic model used was a one-compartment open model with either zero-order or first-order absorption and first-order elimination. Age was the most important determinant of theophylline clearance (Cl); weight was inferior to age and did not statistically improve the model (p greater than 0.005) when combined with age. Total Cl increased by 10%/year over the age range of 1 to 15 years of age. Black race and male gender were associated with higher Cl values: for a given age, Cl was 34% higher for blacks than the reference population composed of the remaining patients, and Cl for males was 25% higher than that for females. The volume of distribution (Vd) for the population was estimated to be 0.62 L/kg. The interindividual variability in Cl and Vd expressed as coefficients of variation were 19 and 28%, respectively. The residual intraindividual error variance corresponded to a standard deviation of 2.8 micrograms/ml. The STCs that represented some degree of outpatient dosing were 21% lower than those reflecting only inpatient dosing. Alternate models that include weight as a determinant of theophylline clearance are also provided. The NONMEM method of determining population pharmacokinetics is well suited to the pediatric population since it does not require a large number of STCs per patient. In this study a mean of only 3.7 STCs per patient were utilized to provide information which should prove useful in the design and adjustment of theophylline dosage regimens in children.

Adolescent↗
PubMed1989

Evaluation of a Bayesian regression program for predicting warfarin response.

The ability of a Bayesian regression program (Warfcalc) to predict warfarin response was evaluated retrospectively in 48 inpatients and prospectively in 10 inpatients. The prothrombin ratio (PR) on the last day of inpatient therapy was predicted using zero (naive) to five sequential, daily PR feedbacks. Bias and precision were measured using mean error (ME) and mean absolute error (MAE), respectively. Root mean squared error (RMSE) was used as a combined measure of bias and precision. In the retrospective group, the use of five PR feedbacks yielded the lowest ME, MAE, and RMSE (0.22, 0.30, and 0.45, respectively). The use of two and three daily PR feedbacks resulted in larger prediction errors compared with the use of naive parameters. Further evaluation of the retrospective patient data indicated that deletion of PR feedbacks associated with an activated partial thromboplastin time greater than 100 s and exclusion of metabolic inhibitors in the estimation of warfarin clearance resulted in more reliable predictions (ME = 0.07, MAE = 0.20, RMSE = 0.28). Similarly, deletion of such PR feedbacks and metabolic inhibitors from the prospective data and use of PRs for the first 5 days of therapy yielded ME, MAE, and RMSE values of 0.07, 0.21, and 0.27, respectively. The variance for prothrombin complex activity (PCA) as a function of the variance in the prothrombin time (PT) was investigated using Monte Carlo simulation assuming four different random error models for the PT measurements. These error models yielded functions that exhibit a maximum coefficient of variation at PCA values of 40-70%.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

Clinical utility of a Bayesian dosing program for phenytoin.

We performed two studies to assess the clinical utility of a Bayesian regression analysis computer program for phenytoin (PHT). In a randomized prospective study of 40 epileptic patients, the dosing program was significantly more accurate (p = 0.002) and less biased (p = 0.02) than a group of physicians at hitting a target PHT serum-concentration. Initial serum PHT concentrations that were not steady state were associated with the largest dosing errors by physicians but did not affect the accuracy of the dosing program. In a second study, we used the dosing program to predict 91 serum concentrations in 31 patients with PHT toxicity after the drug was stopped (initial concentration 26-69 micrograms/ml). The program predicted serum concentrations with a mean error of 3.49 +/- 0.29 micrograms/ml without significant tendency to over- or underpredict. We conclude that this dosing program may aid clinicians by improving dosing accuracy and predicting serum concentrations in patients with PHT toxicity.

Adolescent↗