Biomedical subjects

J Hempenius

Publications and source records attributed to J Hempenius.

11 recordsLinked to original sources

PubMed1996

Rational experimental design for bioanalytical methods validation. Illustration using an assay method for total captopril in plasma.

Generally, bioanalytical chromographic methods are validated according to a predefined programme and distinguish a pre-validation phase, a main validation phase and a follow-up validation phase. In this paper, a rational, total performance evaluation programme for chromatographic methods is presented. The design was developed in particular for the pre-validation and main validation phases. The entire experimental design can be performed within six analytical runs. The first run (pre-validation phase) is used to assess the validity of the expected concentration-response relationship (lack of fit, goodness of fit), to assess specificity of the method and to assess the stability of processed samples in the autosampler for 30 h (benchtop stability). The latter experiment is performed to justify overnight analyses. Following approval of the method after the pre-validation phase, the next five runs (main validation phase) are performed to evaluate method precision and accuracy, recovery, freezing and thawing stability and over-curve control/dilution. The design is nested, i.e., many experimental results are used for the evaluation of several performance characteristics. Analysis of variance (ANOVA) is used for the evaluation of lack of fit and goodness of fit, precision and accuracy, freezing and thawing stability and over-curve control/dilution. Regression analysis is used to evaluate benchtop stability. For over-curve control/dilution, additional to ANOVA, also a paired comparison is applied. As a consequence, the recommended design combines the performance of as few independent validation experiments as possible with modern statistical methods, resulting in optimum use of information. A demonstration of the entire validation programme is given for an HPLC method for the determination of total captopril in human plasma.

Calibration↗

PubMed1995

Biopharmaceutic characteristics of a new extended-release theophylline formulation (Uni-Dur).

BACKGROUND: There is a close relationship between improvement in airway function and the plasma concentration of theophylline, as well as between rapidly rising plasma theophylline concentrations and increased frequency of undesired effects. Development of pharmaceutical formulations and prescribed dosage intervals for theophylline dosage forms should therefore be directed toward providing the most stable plasma concentrations attainable. OBJECTIVE: To characterize the steady-state biopharmaceutic profile of Uni-Dur following once-daily or twice-daily administration. METHODS: Twenty-four adult male volunteers with average theophylline clearance (3.0 and 5.5 L.h-1) received three treatments on separate occasions: Uni-Dur 800 mg once-daily, Uni-Dur 400 mg twice-daily, and Uniphyl 800 mg once-daily. Treatments were taken after a meal for five days with at least 1 week washout between treatment periods. Trough blood samples were collected prior to the AM dose on days 3, 4, and 5, and at specified intervals up to 48 hours after the AM dose on day 5 for subsequent determination of theophylline concentrations in plasma. RESULTS: The area under the plasma concentration-time curve (AUC; microgram.mL-1.h) for theophylline over 24 hours on day 5 was 187 for Uni-Dur 800 mg once-daily, 187 for Uni-Dur 400 mg twice-daily, and 172 for Uniphyl 800 mg once-daily; the peak plasma concentrations were 10.4, 9.4, and 11.0 micrograms.mL-1 and the trough concentrations were 5.5, 7.2, and 3.5 micrograms.mL-1, respectively; fluctuation index (peak minus trough divided by trough) was 78%, 16%, and 231%, respectively. No further accumulation of theophylline occurred after day 3. No serious nor severe adverse events were reported during any treatment. CONCLUSIONS: Uni-Dur is an extended-release formulation that provides stable plasma concentrations of theophylline over a 24-hour period with less fluctuation than observed with a once-daily reference formulation. In subjects with normal theophylline clearance, Uni-Dur administered twice-daily provided remarkably stable theophylline plasma concentrations over a 24-hour period. Absorption of theophylline from Uni-Dur was not affected by food, and no evidence of dose-dumping was observed. Uni-Dur should provide efficacious theophylline therapy with minimal adverse events in patients with symptoms of asthma and reversible bronchospasm associated with chronic bronchitis and emphysema.

Adult↗

PubMed1994

An automated analytical method for the determination of felbamate in human plasma by robotic sample preparation and reversed-phase high performance liquid chromatography.

An automated analytical method for the determination of felbamate in human plasma is described. Sample cleanup and preparation was performed by means of a Zymate II laboratory robot and consisted of a liquid-liquid extraction of felbamate and the internal standard, primidone, from human plasma to dichloromethane. The dichloromethane was evaporated and reconstituted in a phosphate buffer. Separation was performed by reversed-phase high performance liquid chromatography using a 5 microns Hypersil ODS column (150 x 4.6 mm) and a mobile phase consisting of a mixture of phosphate buffer (pH = 6.5, 0.015 M) and acetonitrile (79:21, v/v). Quantitation was performed by measurement of the UV absorbance at a wavelength of 210 nm. The lower limit of quantitation was 0.100 micrograms ml-1 using 200 microliters of plasma. The mean absolute analytical recovery of felbamate was 75.2% (n = 28). The recovery of the internal standard, primidone was 74.7% (n = 10). The within-day precision was below 3.8% at all concentration levels, except at the lower limit of quantitation (18.3%). The within-day accuracy varied between -3.7 and +7.4%. The between-day precision was below 5.0% at all concentration levels. The between-day accuracy of the method varied between -5.7 and +1.6%. The selectivity of the method towards several other anti-epileptic drugs has been demonstrated.

Anticonvulsants↗

PubMed1990

Development of a laboratory robotic system for automated bioanalytical methods--I. The determination of theophylline in human plasma: a comparison between the robotized and manual method.

The quality of bioanalytical methods is often determined by the quality of sample preparation. Using a robot for sample treatment may give better results than manual sample preparation, since the robot lacks human behaviour and incidental errors that are part of it. The use of a laboratory robot has the additional advantage of giving each sample the same analytical history, resulting in better reproducibility. An automated method has been developed for the analysis of drugs in plasma using a laboratory robot. Theophylline was used as a probe drug. Sample preparation was automated with a Zymate II robot, followed by separation and quantitation on an HPLC-system. The robotic method showed a good correlation with the manual method, while sample throughput was doubled.

Chemistry, Clinical↗

PubMed1990

Development of a laboratory robotic system for automated bioanalytical methods--II. A robot computer program for guarding totally automated bioanalytical methods.

The application of fully automated, unattended sample preparation performed by a laboratory robot for the analysis of drugs in biological samples requires the prevention of system failures which may arise in the on-line coupled chromatographic system or in other components of the robotic system. A computer program has been developed which can help to detect such problems. The control program for the robotic sample preparation contains a number of safety measures to intercept robotic or human errors. A routine is implemented, guarding for chromatographic malfunctions and errors in dispensing liquids by the robot. After detection of trouble, sample preparation is interrupted.

Algorithms↗

PubMed1986

Clinical pharmacokinetics of theophylline during co-treatment with cefaclor.

The effect of cefaclor on the steady state pharmacokinetics of theophylline was investigated in healthy young adults by comparing the pharmacokinetic parameters as found during a nine days course of theophylline alone and as obtained during co-medication with the antibiotic cefaclor. The pharmacokinetic parameters obtained on Day 9 during the two periods of drug treatment accounted for the following figures respectively: minimum plasma concentration 5.0 +/- 1.7 mg X 1(-1) (mean +/- SD) and 6.0 +/- 2.0 mg X 1(-1); maximum plasma concentration 9.7 +/- 2.6 mg X 1(-1) and 9.0 +/- 2.6 mg X 1(-1); time to peak 3.2 +/- 0.4 h and 3.9 +/- 0.8 h; AUC 132.54 +/- 41.73 mg X 1(-1) X h and 126.90 +/- 40.45 mg X 1(-1) X h; half-life of elimination 6.6 +/- 1.6 h and 7.1 +/- 1.2 h; clearance 0.059 +/- 0.011 1 X h-1 X kg-1 and 0.063 +/- 0.014 1 X h-1 X kg-1; volume of distribution 0.54 +/- 0.09 1 X kg-1 and 0.64 +/- 0.17 1 X kg-1. Only the values for cmax and tmax after cefaclor co-treatment were slightly, but significantly (p less than 0.05) different from the values found after administration of theophylline alone. As the volume of distribution and the clearance were not affected by cefaclor, it is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.

Adult↗

PubMed1985

Lack of influence of co-trimoxazole on theophylline pharmacokinetics.

In an open cross-over experiment, the influence of the antimicrobial agent co-trimoxazole on the single-dose pharmacokinetics of theophylline was studied in six healthy adults by comparing the pharmacokinetic parameters found after intravenous administration of theophylline without and with co-medication of co-trimoxazole for the previous 8 d. Theophylline concentrations in plasma were measured by high-performance liquid chromatography (HPLC) analysis. During each treatment, a concentration-time curve was evaluated. No influence of co-trimoxazole on the rate of elimination and volume of distribution of theophylline could be found, as a result of which theophylline concentrations in plasma were not significantly different in both periods of drug administration. A similar lack of influence of co-trimoxazole may apply to the steady-state pharmacokinetics of theophylline. The present study suggests that both drugs can be given concomitantly without the need for dosage adjustment of theophylline.

Adult↗

PubMed1985

No influence of doxycycline on theophylline pharmacokinetics.

The influence of the antibiotic drug doxycycline on steady-state pharmacokinetics of theophylline was studied in nine healthy adults by comparing the pharmacokinetic parameters measured during a 9-day course of theophylline alone and during comedication with doxycycline. Theophylline plasma concentrations were measured by means of high performance liquid chromatography analysis. Trough theophylline plasma concentrations were measured on days 1-8. On day 9 of each of the two periods of drug administration, a plasma concentration-time curve was evaluated. No influence of doxycycline on absorption, elimination, and volume of distribution of theophylline was found. Mean steady-state plasma concentrations were not significantly different during the two treatments. It is concluded that the drugs can be given concomitantly without any dosage adjustment of theophylline.

Adult↗

PubMed1985

Lack of effect of amoxicillin on theophylline pharmacokinetics.

The effect of the antibiotic drug amoxicillin on steady state pharmacokinetics of theophylline was studied in healthy adults by comparing the pharmacokinetic parameters as found during a 9 day course of theophylline alone and as obtained during comedication with amoxicillin. Theophylline plasma concentrations were measured by means of h.p.l.c. analysis. On the ninth day of each of the two periods of drug administration a concentration-time curve was evaluated. It showed no influence of amoxicillin on absorption, elimination and volume of distribution of theophylline, as a result of which mean steady state plasma concentrations were not significantly different during both treatments. It is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.

Adult↗

PubMed1985

Clinical pharmacokinetics of amoxycillin and theophylline during cotreatment with both medicaments.

The influence of amoxycillin and theophylline on their mutual steady-state pharmacokinetics was studied in healthy adults by comparing the pharmacokinetic parameters as obtained during a 10-day course of each drug alone and after giving the drugs in combination. Amoxycillin and theophylline plasma concentrations were measured by means of HPLC methods. On the 9th day of each of the two periods of drug administration, a concentration-time curve was evaluated. These showed no influence of theophylline on absorption, elimination or volume of distribution of amoxycillin, demonstrating that the mean steady-state plasma concentrations were not significantly different during the two treatments. Amoxycillin also has no significant effect on theophylline steady-state pharmacokinetics. It is concluded that both drugs can be given concomitantly without any dosage adjustment.

Adult↗

PubMed1985

No effect of cefaclor on theophylline pharmacokinetics.

The effect of the antibiotic drug cefaclor on steady state pharmacokinetics of theophylline was studied in healthy adults by comparing the pharmacokinetic parameters as found during a 9 days course of theophylline alone and as obtained during comedication with cefaclor. Theophylline plasma concentrations were measured by means of HPLC analysis. On the ninth day of each of the 2 periods of drug administration, a concentration-time curve was evaluated. It showed no influence of cefaclor on volume of distribution and clearance of theophylline and only a slight, but significant (p less than 0.05) influence on the values for Cmax and tmax after cefaclor co-treatment. It is concluded that both drugs can be given concomitantly without any dosage adjustment of theophylline.

Adult↗