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T M Ludden

Publications and source records attributed to T M Ludden.

At least 55 records · Page 3Linked to original sources
PubMed1988

Population pharmacokinetics.

The major strength of the population analysis approach is that useful information can be extracted from sparse data using blood samples and pharmacologic monitoring during routine safety and efficacy studies conducted during the development of a drug product. The results of these analyses may lead to integrated pharmacokinetic-pharmacodynamic models that can aid the clinician during the initiation and adjustment of therapeutic regimens. In some cases it may be possible to develop closed-loop control systems that monitor a drug concentration or a response and automatically adjust the drug administration rate. Overall, an increase in the safety and efficiency of drug use can be anticipated.

Humans↗
PubMed1988

Absolute bioavailability and dose proportionality of betaxolol in normal healthy subjects.

The absolute bioavailability and dose proportionality of betaxolol [(+/-)-1-(p-[2-cyclopropylmethoxy)ethyl]phenoxy]-3- (isopropylamino)-2-propanol hydrochloride], a cardioselective beta-adrenergic antagonist effective in the treatment of angina and hypertension, was studied in 12 healthy male subjects using a four-way crossover Latin Square design. Each subject received a 10-mg iv dose administered by constant-rate infusion over a period of 30 min and three oral doses (10, 20, and 40 mg). Blood and urine were collected over a 48-h period and analyzed for betaxolol using gas-liquid chromatography with electron capture detection. Maximum concentrations occurred 3-4 h after the dose. The maximum mean (+/- SD) blood concentrations normalized to the 10-mg oral dose were 21.6 +/- 3.7, 21.1 +/- 3.7, and 22.5 +/- 4.0 micrograms/L following the 10-, 20-, and 40-mg doses, respectively. A significant lag time of 10-80 min was observed after oral doses but was not related to dose size. The terminal slope (ts), absolute bioavailability (F), and renal clearance (CLr) were likewise not affected to an important degree by dose (ts: 0.043 +/- 0.006, 0.044 +/- 0.005, 0.046 +/- 0.006 h-1; F: 0.88 +/- 0.08, 0.82 +/- 0.06, 0.84 +/- 0.07; CLr: 0.68 +/- 0.22, 0.69 +/- 0.19, 0.65 +/- 0.22 mL/min kg). Unlike many beta-adrenergic antagonists, betaxolol has a long half-life (13-20 h) and high and consistent bioavailability (70-90%), and its disposition is independent of the size of the administered dose.

Adrenergic beta-Antagonists↗
PubMed1988

Relative bioavailability of immediate- and sustained-release hydralazine formulations.

The in vivo performance of hydralazine sustained-release dosage forms prepared using an ethylcellulose-coated drug:resin complex was studied in healthy males who were determined to be slow acetylators. Two studies were performed. The first study (I) compared four different coating levels (6.8, 8.7, 10, and 12%) with an immediate-release tablet and a solution. The second study (II) compared three additional coating levels (4, 5, and 7.8%) to the 6.8% formulation from the first study. Both hydralazine peak blood concentration (Cmax) and area under the blood concentration-time curves (AUC) decreased as the coating level increased [coating level (Cmax, ng/mL; AUC, ng.h/mL): 4% (37; 58), 5% (31; 55), 6.8% (13; 42 and 14; 39); 7.8% (16; 38), 8.7% (11; 34), 10% (7.8; 21), 12% (8.9; 17)]. In Study I both the solution and the immediate-release tablet were administered in two divided doses at 8 a.m. (fasting) and 2 p.m. (post-prandial). There was evidence for decreased bioavailability of unchanged hydralazine after the 2 p.m. doses as compared with the 8 a.m. doses. On the other hand, an assay that measures primarily the pyruvic acid conjugate of hydralazine yielded much higher concentrations after the afternoon dose. The results of these studies indicate that a sustained-release dosage form of hydralazine can be prepared using an ethyl-cellulose coated drug:resin complex and its in vivo characteristics are related to the coating level. Hydralazine bioavailability is influenced by food or recent prior exposure to hydralazine.

Adult↗
PubMed1988

Immunoassay of alpha 1-acid glycoprotein in the Cobas Bio centrifugal analyzer.

There is an increasing demand for quantification of serum alpha 1-acid glycoprotein (AAG, orosomucoid) in studies evaluating the protein binding of highly bound basic drugs. This paper describes an adaptation of an automated immunoturbidimetric assay for this protein to the Cobas Bio centrifugal analyzer. Replicate analyses of aliquots from six different solutions were used in determining precision. We also analyzed 367 patients' serum samples, in duplicate, to determine the distribution of AAG in hospitalized patients. The intra- and inter-run CVs ranged from 1.3% to 4.4% and from 0.6% to 6.6%, respectively. AAG concentrations in patients' samples ranged from 0.38 to 3.16 g/L. Results by this method correlate well with those by radial immunodiffusion, with no significant amount of bias between the two methods. This immunoturbidimetric procedure is faster and less expensive than currently used radial immunodiffusion techniques, and precision is acceptable.

Centrifugation↗
PubMed1988

Clinical assessment of a two-compartment Bayesian forecasting method for lidocaine.

The predictive performance of a two-compartment Bayesian forecasting method for lidocaine (L) was evaluated concurrently with lidocaine therapy in 46 hospitalized patients; 14 of these patients presented with congestive heart failure (CHF). Using an HP-85 microcomputer, demographic and dose-concentration information obtained during continuous lidocaine therapy was used to forecast subsequent lidocaine concentrations. One lidocaine concentration was obtained within each of the three intervals following initiation of lidocaine infusions: I1 (1-6 h), I2 (6-12 h), and I3 (greater than 12 h). Patients were categorized into 4 groups: (a) short-term infusions (less than 24 h) without CHF, (b) short-term infusions with CHF, (c) long-term infusions (greater than 24 h) without CHF, and (d) long-term infusions with CHF. The mean prediction errors (range -0.60-0.27) included zero (95% confidence limits) in all groups and suggested no bias. Forecasts of the I3 lidocaine concentrations were consistently more precise [lower mean absolute errors (MAE) and root mean squared errors] using the lidocaine concentration obtained during the 6-12-h interval (I2) than when the lidocaine concentration obtained at the earlier interval (I1) was used. The MAE was reduced by 20-40% when a single lidocaine concentration obtained during I2 was used as compared to I1. Precision was only slightly improved with the use of two lidocaine concentrations. We conclude that this Bayesian algorithm is unbiased and delivers acceptable precision in forecasting lidocaine concentrations.

Adult↗
PubMed1987

Pharmacokinetics of ametantrone acetate (NSC-287513).

Ametantrone is the second anthracene derivative to enter clinical trials. The pharmacokinetic parameters for ametantrone acetate (CI-881) were characterized in six patients concurrently with the phase I clinical trial. Biological samples were assayed by a specific and sensitive high-performance liquid chromatography procedure. Plasma levels of ametantrone declined in a triexponential fashion, with a mean terminal half-life (t 1/2 gamma) of 25 h. The estimated mean total-body plasma clearance was 25.9 +/- 14.7 1 h-1 m-2. The steady-state volume of distribution (Vdss) was large, averaging 568 +/- 630 l/m2. Excretion of unchanged ametantrone in the urine over 48 h averaged 5.7% of the total dose, indicating that there is another major route of elimination.

Aged↗
PubMed1987

Evaluation of a proposed method for phenytoin maintenance dose prediction following an intravenous loading dose.

A large clinical study, designed to investigate the induction of theophylline metabolism by phenytoin, provided the opportunity to test a previously proposed method for estimating dose requirements of phenytoin. This method involves prediction of the oral maintenance dosage from data obtained following the administration of an intravenous loading dose. In 30 subjects, trough plasma concentration at steady-state were 12.0 +/- 4.9 micrograms X ml-1 (mean +/- SD) and differed by -2.7 +/- 39.3% from a mean target plasma concentration of 12.5 +/- 1.5 micrograms X ml-1. A Bayesian regression programme was used to forecast an estimate of each subject's individual pharmacokinetics. These were then used to predict the steady-state plasma concentrations which would be expected from a standard dosing regimen (4 mg per kg per day). When compared to the results expected from the use of this standard dosage, the proposed method gave acceptable steady-state plasma phenytoin concentrations with significant reductions in deviations from target concentrations. This method for the rapid individualization of phenytoin dosage requirements provides an improvement over more traditional methods of choosing an arbitrary dose adjusted for body weight followed by dosage adjustments based on achieved plasma concentration.

Adult↗
PubMed1987

Disposition of phenytoin in critically ill trauma patients.

Estimates of phenytoin pharmacokinetic variables and protein binding were determined in 10 adult critically ill trauma patients. Each study subject received phenytoin sodium as an intravenous loading dose of 15 mg/kg, followed by an initial intravenous maintenance dose of 6 mg/kg/day. Serial blood samples were obtained throughout the seven-day study period and analyzed for total and unbound serum phenytoin concentrations. The concentration data for each patients were fitted to a one-compartment model with elimination defined by the Michaelis-Menten constant Km and the maximum rate of metabolism (Vmax) and to a one-compartment model with first-order elimination. The Michaelis-Menten model used Bayesian parameter estimation while the linear model used weighted non-linear least-squares regression analysis. Unbound phenytoin fraction ranged from 0.073 to 0.25. Free fraction increased 7% to 108% in 9 of 10 patients (median increase 29%) from day 1 to day 7 of therapy. Variable estimates using the Michaelis-Menten model were as follows: volume of distribution, 0.76 +/- 0.15 L/kg (0.58-1.01 L/kg); Vmax, 568 +/- 197 mg/day (350-937 mg/day); and Km, 4.5 +/- 1.8 mg/L (1.8-6.2 mg/L). These estimates fell within the wide range of values obtained in studies using stable patients or healthy volunteers. The Michaelis-Menten model was significantly less biased and more precise than the linear model. Three of four patients who continued to receive their study maintenance dose had substantially lower measured total serum concentrations of phenytoin than predicted using the study variable estimates.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Evaluation of a Bayesian regression-analysis computer program using non-steady-state phenytoin concentrations.

The predictive performance of a Bayesian regression-analysis computer program that uses non-steady-state phenytoin data was evaluated. Forty patients receiving phenytoin or phenytoin sodium who had two or more non-steady-state serum concentrations were selected for study. Additional serum concentrations and dosing data were collected as they became available, but no effort was made to control the number or timing of serum concentration determinations. Patients were categorized into four groups for evaluation of the effect of potential bioavailability problems and length of dosing history (time over which serum concentration-time data were collected) on the ability to predict subsequent phenytoin concentrations. Population parameters for phenytoin maximum rate of elimination (Vmax), apparent Michaelis-Menten constant (Km), volume of distribution (V), and bioavailability (F) were obtained from the literature. Predictions based on serum phenytoin concentrations and dosing histories (information intervals) of 5 or 10 days were compared with predictions based on naive (population-based) estimates using prediction-error analysis. In each patient group, the use of either 5-day or 10-day information intervals resulted in a significant increase in precision and a significant reduction in bias compared with naive estimates. For the group of patients who initially had two or more serum concentrations within the first five days of monitoring, predictions showed a marked increase in bias and a decrease in precision as the time interval from the last measured concentration to the time of prediction increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Bayes Theorem↗
PubMed1986

High-performance liquid chromatographic assay for etoposide in human plasma.

A sensitive, selective reversed phase-high performance liquid chromatographic (HPLC) assay that uses UV detection has been developed for etoposide (4'-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-beta-D-glucopyranoside) 1. Parent drug is separated from its known metabolites, the cis-picrolactone 2, the hydroxy derivative 3, and the aglycone 4. After the addition of the internal standard (teniposide, 5) to 0.5 mL of plasma, 3 mL of chloroform is added and the sample is centrifuged. The lower organic layer is removed, evaporated in a stream of nitrogen, and reconstituted with 500 microL of mobile phase prior to injection. A phenyl mu Bondapak column (30 cm X 4 mm) and a mobile phase, consisting of 10 microM ammonium acetate (pH 5.5) in methanol:water:acetonitrile (50:45:5), were used to separate the compounds. The flow rate was 2 mL/min. Detection was achieved with a UV monitor set at 230 nm. The aglycone 4, etoposide (1), cis-picrolactone 2, and teniposide (5) had retention times of 3, 4, 4.8, and 9 min, respectively. The extraction efficiency of etoposide ranged from 88 to 94% with a coefficient of variation of 12% at 0.8 micrograms/mL and 4% at 28 micrograms/mL. This assay has an intraday and interday coefficient of variation of 6%, quantitates etoposide at concentrations as low as 0.4 micrograms/mL, and separates etoposide from its known metabolites. The procedure described represents an alternative to a previously published assay that also separated etoposide from its metabolites, but used electrochemical detection.

Aged↗
PubMed1986

Pharmacokinetic study of fludarabine phosphate (NSC 312887).

Characterization of the pharmacokinetics of 2-FLAA has been completed in seven patients receiving 18 or 25 mg/m2 daily X 5 of 2-FLAMP over 30 min. Assuming 2-FLAMP was instantaneously converted to 2-FLAA, the plasma levels of 2-FLAA declined in a biexponential fashion. Computer fitting of the plasma concentration-time curves yielded an average distribution half-life (t1/2 alpha) of 0.60 h and a terminal half-life (t1/2 beta) of 9.3 h. The estimated plasma clearance was 9.07 +/- 3.77 l/h per m2 and the steady state volume of distribution, 96.2 +/- 26.0 l/m2. There was a significant inverse correlation between the area under the curve (AUC) and absolute granulocyte count (r = -0.94, P less than 0.02). A relationship between creatinine clearance and total body clearance was noted, but was not statistically significant (r = 0.828; P less than 0.1). Approximately 24% +/- 3% of 2-FLAA was excreted renally over the 5-day course of drug administration.

Agranulocytosis↗
PubMed1986

A method for the combined measurement of ethiofos and WR-1065 in plasma: application to pharmacokinetic experiments with ethiofos and its metabolites.

An analytical method for the combined measurement of ethiofos (WR-2721) and a major metabolite (WR-1065) in plasma is described. Plasma samples were subjected to conditions which quantitatively converted both ethiofos and bound WR-1065 to free WR-1065 which was subsequently separated by HPLC and detected electrochemically using established procedures. Although bound WR-1065 in plasma is thought to exist mainly in the form of mixed disulfides, the symmetrical disulfide, WR-33278, also was quantitatively converted to the free thiol form. Standard curves were linear over the range 0.10 to 25 micrograms/mL (0.75 to 186 mumol/L). Mean precision over the range was 5.4% (coefficient of variation, CV) and recoveries of various mixtures of ethiofos, WR-1065 and WR-33278 averaged 102% (CV = 6.6%). This analytical procedure and others specific for ethiofos, free WR-1065 and WR-33278 were applied to dosing experiments in which the parent drug and its major metabolites were variously administered to beagle dogs and rhesus monkeys. Following i.v. administration of ethiofos (120-150 mg per kg body weight) to monkeys, plasma concentrations of unchanged drug ranged from 477 micrograms/mL (2.23 mM) down to the minimum detectable limit of the analytical procedure (0.05 micrograms/mL, 0.23 microM) 2-3 hours postinfusion. Clearances averaged 43.5 +/- 13.4 (SD) mL min-1 kg-1 and half-lives observed in the 20-60 minute postinfusion period were 8-15 min.

Amifostine↗
PubMed1986

Measurement of lidocaine free concentration.

Since lidocaine exhibits significant variation in serum protein binding, the availability of a practical method for measuring free lidocaine concentration could contribute to the optimization of individual lidocaine dosage regimens. Fifty serum samples from patients receiving lidocaine were partitioned by ultrafiltration and equilibrium dialysis. The lidocaine concentration in the ultrafiltrate was measured using an enzyme multiplied immunoassay (EMIT) and a gas-liquid chromatographic assay (GLC). The lidocaine concentrations in dialysates and filtered retentates were measured by EMIT. Ultrafiltrate concentrations measured by EMIT correlated well with those measured by GLC (r2 = 0.77), but the EMIT results were approximately 10-20% higher than the GLC measurements (GLC = 0.09 + 0.79 EMIT). At least a portion of this difference could be attributed to minor calibrator differences. The concentrations in dialysate and filtered retentate agreed well (r2 = 0.93; filtered retentate = -0.05 + 1.12 X dialysate). The fraction free values obtained by ultrafiltration were slightly lower than those obtained by equilibrium dialysis (0.301 +/- 0.086 vs. 0.345 +/- 0.137; p less than 0.05). It can be concluded that sample partitioning with ultrafiltration and measurement of free lidocaine concentration by EMIT yields results similar to those obtained by equilibrium dialysis or a GLC assay procedure.

Chromatography, Gas↗
PubMed1986

Evaluation of a Bayesian regression-analysis computer program for predicting phenytoin concentration.

A microcomputer program using Bayesian regression analysis to predict serum phenytoin concentrations was evaluated. Phenytoin concentration-time data from nine healthy male volunteers and one male patient were obtained from published studies. For two different dosage regimens that each subject received, the last available predose concentration on the sixth day of the regimen was predicted using observed predose concentrations on both the morning of the third day and on each of the first three days of phenytoin administration. In nine subjects who received at least 10 days of phenytoin therapy, observed concentrations after more than 10 days of therapy were predicted using both one and three observed serum concentrations. Also, in six subjects, the observed predose concentrations for the first three days of an initial phenytoin regimen were used to predict the last predose concentration observed during each subject's second regimen. Predictive performance of the program was evaluated using mean error (m.e.) as a measure of bias, mean absolute error (m.a.e.) as a measure of precision, and root mean square error (r.m.s.e.) as a composite measure of bias and precision. The majority of the predicted serum concentrations were accurate. Predictions of serum concentrations after six days and after more than 10 days of phenytoin therapy were somewhat more accurate when three serum concentrations were used than when only one concentration was used. In the six subjects for whom concentrations from an initial regimen were used to predict those in a second regimen, the largest prediction error was 5 mg/L (m.e. 0.88, m.a.e. 1.9, and r.m.s.e. 2.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Bayes Theorem↗
PubMed1986

Measurement of WR-1065 in plasma: preliminary pharmacokinetics in the beagle.

Described is a high-performance liquid chromatographic (HPLC) method for the quantification of WR-1065 [2-(3-aminopropylamino)-ethanethiol] in plasma. After a brief sample preparation, the drug and internal standard were separated in less than 15 minutes using a reversed-phase column and ion-pairing reagent. An electrochemical detector provided a minimum quantifiable limit of 0.05 microgram/mL. The analytical method was applied in three experiments to measure drug concentrations in the plasma of beagle dogs following IV administration of WR-1065 (60 mg/kg). The concentration-time data, best described by a three-compartment open kinetic model, were used to estimate pharmacokinetic parameters. Mean values were: steady state volume of distribution--2.27 L X kg-1; clearance--0.064 L X min-1 X kg-1; and terminal elimination half-life--81.4 min. The high clearance is consistent with the formation of mixed disulfides in the circulation.

Animals↗
PubMed1985

A phase I and pharmacokinetic comparison of hepatic arterial and peripheral vein infusions of bisantrene for liver cancer.

Bisantrene (NSC-337766) was administered to five patients with cancer of the liver (one case of hepatocellular carcinoma, two of metastatic carcinoma of unknown primary, two of metastatic colorectal carcinoma). Under fluoroscopic guidance, percutaneous hepatic venous catheters were placed in five patients and percutaneous hepatic arterial catheters in four. A fifth patient's hepatic arterial catheter was implanted at laparotomy. Hepatic plasma flow was estimated by the Fick principle using peripheral vein indocyanine green infusion. On the first day of treatment, patients received a 2- or 4 h hepatic arterial infusion of bisantrene (130 mg/m2); peripheral venous, hepatic arterial, and hepatic venous timed blood samples were drawn during and for 18 h after drug infusion. On the second day of treatment, 2- or 4 h peripheral vein infusion of bisantrene (130 mg/m2) was followed by the same blood sampling schedule. Patients were followed weekly for toxicity. Four patients received only one course of treatment, while a fifth received two courses. All patients experienced leukopenia (median nadir 2400/mm3; range 1400-2700/mm3). Two patients developed fever after drug infusion. No antitumor responses were observed. Plasma bisantrene concentrations were measured by HPLC. Pharmacokinetic analyses are reported for four patients. The hepatic extraction ratio ranged from 15% to 49%, hepatic plasma clearances were 0.029-0.353 1/min/m2; peripheral vein areas under the concentration-time curve during hepatic arterial infusion ranged from 35% to 50% of peripheral vein areas under the curve during peripheral vein infusion. We conclude that hepatic arterial bisantrene infusion offers only modest pharmacokinetic advantage to the target organ or to the systemic circulation over peripheral vein infusion.

Aged↗