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Utilization of optimal study design for maternal and fetal sheep propofol pharmacokinetics study: a preliminary study.

ABSTRACT: Multiple blood samples are generally required for measurement of pharmacokinetic (PK) parameters. D-optimal design is a popular and frequently used approach for determination of sampling time points in order to minimize the number of samples, while optimizing the estimation of PK parameters. Optimal design utilizing ADAPT (v5, BSR, University of Southern California, Los Angeles) developed a sparse sampling strategy to determine measurement of propofol in pregnant sheep. Propofal was administered as supplemental anesthetic agent to inhalation anesthesia to mimic anesthesia for open fetal surgery. In our preliminary study, propofol 3 mg/kg was given as a bolus to the ewe, followed by propofol infusion at rate 450 mcg/kg/min for 60 minutes, then decreased to 75 mcg/kg/min for 90 more minutes and then ceased. A three compartment model described the PK parameters with the fetus assumed as the third compartment. Initially, sampling times were chosen from thirteen time points as previously stated in the literature. Using priori propofol PK estimates, the final 9 sample time points were proposed in an optimal design with a change in infusion rate occurring between 65 and 75 minutes and sampling proposed at 5, 15, 25, 65, 75, 100, 110, 150, and 180 minutes. D-optimal design optimized the number and timing of samplings, which led to a reduction of cost and man power in the study protocol while preserving the ability to estimate propofol PK parameters in the maternal and fetal sheep model. Initial evaluation of samples collected from three sheep using the optimal design strategy confirmed the performance of the design in obtaining effective PK parameter estimates.

SUBMITTER: Sherwin CM

PROVIDER: S-EPMC5564389 | biostudies-other | 2014 Feb

REPOSITORIES: biostudies-other

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Project description:Key pointsFetal growth restriction induces a haemodynamic response that aims to maintain blood flow to vital organs such as the brain, in the face of chronic hypoxaemia Maternal sildenafil treatment impairs the hypoxaemia-driven haemodynamic response and potentially compromises fetal development.AbstractInadequate substrate delivery to a fetus results in hypoxaemia and fetal growth restriction (FGR). In response, fetal cardiovascular adaptations redirect cardiac output to essential organs to maintain oxygen delivery and sustain development. However, FGR infants remain at risk for cardiovascular and neurological sequelae. Sildenafil citrate (SC) has been examined as a clinical therapy for FGR, but also crosses the placenta and may exert direct effects on the fetus. We investigated the effects of maternal SC administration on maternal and fetal cardiovascular physiology in growth-restricted fetal sheep. Fetal sheep (0.7 gestation) underwent sterile surgery to induce growth restriction by single umbilical artery ligation (SUAL) or sham surgery (control, AG). Fetal catheters and flow probes were implanted to measure carotid and femoral arterial blood flows. Ewes containing SUAL fetuses were randomized to receive either maternal administration of saline or SC (36 mg i.v. per day) beginning 4 days after surgery, and continuing for 20 days. Physiological recordings were obtained throughout the study. Antenatal SC treatment reduced body weight by 32% and oxygenation by 18% in SUAL compared to AG. SC did not alter maternal or fetal heart rate or blood pressure. Femoral blood flow and peripheral oxygen delivery were increased by 49% and 30% respectively in SUALSC compared to SUAL, indicating impaired cardiovascular adaptation to chronic hypoxaemia. Antenatal SC directly impairs the fetal haemodynamic response to chronic hypoxaemia. Consideration of the consequences upon the fetus should be paramount when administering interventions to the mother during pregnancy.

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Utilization of optimal study design for maternal and fetal sheep propofol pharmacokinetics study: a preliminary study.

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