Marilee A. Andrew

Ketorolac tromethamine: Stereo-specific Pharmacokinetics and Single dose Use in Postoperative Infants aged 2– 6 months

Objective:  We determined the postoperative pharmacokinetics (PK), safety, and analgesic effects of ketorolac in 14 infants (aged <6 months) receiving a single intravenous (IV) administration of racemic ketorolac or placebo.

The status of pharmacometrics in pregnancy: highlights from the 3rd American conference on pharmacometrics

Physiological changes during pregnancy may alter drug pharmacokinetics. Therefore, mechanistic understanding of these changes and, ultimately, clinical studies in pregnant women are necessary to determine if and how dosing regimens should be adjusted. Because of the typically limited number of patients who can be recruited in this patient group, efficient design and analysis of these studies is of special relevance. This paper is a summary of a conference session organized at the American Conference of Pharmacometrics in April 2011, around the topic of applying pharmacometric methodology to this important problem. The discussion included both design and analysis of clinical studies during pregnancy and in silico predictions. An overview of different pharmacometric methods relevant to this subject was given. The impact of pharmacometrics was illustrated using a range of case examples of studies around pregnancy.

Physiologically based pharmacokinetic model of midazolam disposition during pregnancy

Disposition of drugs in pregnant women is poorly understood in spite of widespread prescription of drugs to women during gestation. We have developed a whole body physiologically based pharmacokinetic (PBPK) model to explore the effects of pregnancy on pharmacokinetics. The model accounts for maternofetal changes over the course of gestation; physiological and drug-specific parameters are taken from literature. Here we preliminarily demonstrate the models utility to predict midazolam pharmacokinetics following intravenous bolus dosing in women undergoing Caesarian section. Simulations of maternal venous plasma concentrations compare favorably with data extracted from historical studies.

Effects of Cranberry Juice on Pharmacokinetics of β-Lactam Antibiotics following Oral Administration

ABSTRACT Cranberry juice consumption is often recommended along with low-dose oral antibiotics for prophylaxis for recurrent urinary tract infection (UTI). Because multiple membrane transporters are involved in the intestinal absorption and renal excretion of β-lactam antibiotics, we evaluated the potential risk of pharmacokinetic interactions between cranberry juice and the β-lactams amoxicillin (amoxicilline) and cefaclor. The amoxicillin-cranberry juice interaction was investigated in 18 healthy women who received on four separate occasions a single oral test dose of amoxicillin at 500 mg and 2 g with or without cranberry juice cocktail (8 oz) according to a crossover design. A parallel cefaclor-cranberry juice interaction study was also conducted in which 500 mg cefaclor was administered with or without cranberry juice cocktail (12 oz). Data were analyzed by noncompartmental methods and nonlinear mixed-effects compartmental modeling. We conclude that the concurrent use of cranberry juice has no significant effect on the extent of oral absorption or the renal clearance of amoxicillin and cefaclor. However, delays in the absorption of amoxicillin and cefaclor were observed. These results suggest that the use of cranberry juice at usual quantities as prophylaxis for UTI is not likely to alter the pharmacokinetics of these two oral antibiotics.

The status of pharmacometrics in pregnancy

Physiological changes during pregnancy may alter drug pharmacokinetics. Therefore, mechanistic understanding of these changes and, ultimately, clinical studies in pregnant women are necessary to determine if and how dosing regimens should be adjusted. Because of the typically limited number of patients who can be recruited in this patient group, efficient design and analysis of these studies is of special relevance. This paper is a summary of a conference session organized at the American Conference of Pharmacometrics in April 2011, around the topic of applying pharmacometric methodology to this important problem. The discussion included both design and analysis of clinical studies during pregnancy and in silico predictions. An overview of different pharmacometric methods relevant to this subject was given. The impact of pharmacometrics was illustrated using a range of case examples of studies around pregnancy.

Quantitative assessment of thermal dose using photographic measurements of tissue discoloration

High Intensity Focused Ultrasound (HIFU) is rapidly gaining widespread clinical use in China, and is undergoing regulatory evaluation in Europe and the US for many target diseases. Nevertheless, tools for therapy planning, monitoring, and assessment remain at a rudimentary level. In particular, measurement of thermal dose in tissues exposed with HIFU has not been sufficiently quantitative to make detailed comparisons with numerical simulations, required for validation of therapy planning models. Indeed, model validation is complicated by high sensitivity of the results to small changes in parameter values and by the general difficulty of performing geometrical registration with sufficient precision to meaningfully compare millimeter scale features typical of HIFU lesions. Our work uses photographic measurement of visible tissue discoloration so that it can be used to accurately and rapidly quantify HIFU‐induced bioeffects at scales of several centimeters for comparison with the prior therapy plan. Precise...

The status of pharmacometrics in pregnancy: highlights from the 3rdAmerican conference on pharmacometrics: Pharmacometrics in pregnancy

Physiological changes during pregnancy may alter drug pharmacokinetics. Therefore, mechanistic understanding of these changes and, ultimately, clinical studies in pregnant women are necessary to determine if and how dosing regimens should be adjusted. Because of the typically limited number of patients who can be recruited in this patient group, efficient design and analysis of these studies is of special relevance. This paper is a summary of a conference session organized at the American Conference of Pharmacometrics in April 2011, around the topic of applying pharmacometric methodology to this important problem. The discussion included both design and analysis of clinical studies during pregnancy and in silico predictions. An overview of different pharmacometric methods relevant to this subject was given. The impact of pharmacometrics was illustrated using a range of case examples of studies around pregnancy.

Bounds on Thermal Dose Estimates using Ultrasonic Backscatter Monitoring of Heating

Diagnostic ultrasound provides a means for estimating the spatial distribution of temperature in tissue in response to HIFU therapy. One approach to estimating the temperature is to distort backscattered ultrasound between two frames, one preceding and one following the treatment, in a manner consistent with the heat equation, the exposure protocol, the beam pattern, and the specific material properties of the tissue. Ascribing a probability distribution to the measurements taken after treatment, the Cramer Rao bound may be determined for coefficient estimates in a functional expansion for the applied heating during therapy. This formulation also identifies the function with coefficient estimates having least variance, providing the lower bound. We study the implications of this characterization for heat deposition from a linear scan, examining how estimation accuracy is influenced by the lesion length and the delay following treatment and preceding acquisition. It is shown that for these studies, tempera...

Design and Evaluation of Complex Moving HIFU Treatment Protocols

The use of moving high‐intensity focused ultrasound (HIFU) treatment protocols is of interest in achieving efficient formation of large‐volume thermal lesions in tissue. Judicious protocol design is critical in order to avoid collateral damage to healthy tissues outside the treatment zone. A KZK‐BHTE model, extended to simulate multiple, moving scans in tissue, is used to investigate protocol design considerations. Prediction and experimental observations are presented which 1) validate the model, 2) illustrate how to assess the effects of acoustic nonlinearity, and 3) demonstrate how to assess and control collateral damage such as prefocal lesion formation and lesion formation resulting from thermal conduction without direct HIFU exposure. Experimental data consist of linear and circular scan protocols delivered over a range of exposure regimes in ex vivo bovine liver.

Comparison between coupled KZK‐BHTE numerical simulations and scanned HIFU exposures in excised bovine liver

The use of moving high intensity focused ultrasound (HIFU) treatment protocols is of interest in achieving efficient formation of large‐volume lesions in tissue. However, potentially unwanted thermal effects, such as prefocal heating, should be considered. A KZK acoustic model coupled with the BioHeat Transfer Equation has been extended to simulate multiple, moving scans in tissue. Simulation results are compared with experimental data collected over a range of exposure regimes for linear and concentric circular scans with a 3.5‐MHz single‐element transducer in ex vivo bovine liver. Of particular interest are investigating prefocal thermal buildup and ablating the central core of a circular pattern through conductive heating, that is without direct HIFU exposure. Qualitative agreement is observed between experimental and simulated data; limits of the predictive capability of the model in cavitation regimes will be discussed. [Support provided by the U.S. Army Medical Research Acquisition Activity through ...