Development of PK/PD Model for Individualized Propofol Dosing
The U.S. National Health and Nutrition Examination Survey of 1994 indicated that 59% of American men and 49% of women have body mass indexes (BMIs) over 25. Extreme obesity, defined as a BMI of 40 or more, was found in 2% of the men and 4% of the women [http://www.cdc.gov/nchs/nhanes.htm]. The newest survey in 2007 indicates an alarming increase in BMI; 63% of Americans are overweight, with 26% now in the obese category. With extreme obesity as high as 26-30% in adults, obesity percentages in children are also sharply on the rise. These alarming numbers pose a major clinical problem in terms of the safe and effective use of drugs in children.
Obesity may alter the disposition and/or clearance of drugs in the body as well as the response, which should be considered when using anesthetics in these patients. Total intravenous anesthesia (TIVA) with propofol is widely used in children, adolescents and adults undergoing surgery, because of rapid onset of action, ease of titration and rapid offset of action. While extensive research on optimal propofol dosing has been performed in non-obese adults, including in critically ill mechanically ventilated adult patients by the investigators' collaborators, there is no evidence on required dosages in morbidly obese adult or pediatric patients of this highly lipophilic agent. As a consequence, serious problems do arise due to under- and overdosing, increasing the risk of inadequate effects and adverse events, respectively. Crucial additional information is needed on the pharmacokinetics of drugs used in morbidly obese children to improve safety and efficacy.
This proposal will test a novel approach by identifying pharmacokinetic/pharmacodynamic (PK/PD) factors that are associated with response to therapy and adverse events. If successful, this study will provide proof of concept data for PK/PD model-based dosing strategy that can be implemented into daily clinical care to allow tailoring of dose to individual needs. Propofol is a versatile anesthetic agent which if dosed to individual needs based on a patient's characteristics and specific PK/PD parameters, will allow individualized dosing, thereby greatly reducing related toxicities. The prospective identification of predictive factors in these morbidly obese high-risk patients represents a new approach to an increasingly common clinical problem. The investigators expect that this study will generate the PK/PD data necessary to continue with a well powered prospective clinical trial.
|Study Design:||Observational Model: Case-Only
Time Perspective: Prospective
|Official Title:||A Non-Interventional Study to Develop a Pharmacokinetic - Pharmacodynamic Model for Individualized Propofol Dosing|
- Change in propofol clearance and volume of distribution (for determination of effective concentration); Depth of anesthesia. [ Time Frame: Samples will be analyzed within one month of collection ] [ Designated as safety issue: Yes ]
- Population PK/PD model (NON-MEM) using patient demographic and clinical data. [ Time Frame: one year ] [ Designated as safety issue: Yes ]
Biospecimen Retention: Samples With DNA
Participation involves the collection of one blood sample (3.0 ml) in an EDTA (lavender top) tube for pharmacogenetic testing. Genomic DNA will be extracted using standard procedures. Participation in pharmacogenetic testing is optional and requires additional consent; subjects who refuse pharmacogenetifc testing may still be enrolled in this study.
|Study Start Date:||July 2009|
|Study Completion Date:||December 2013|
|Primary Completion Date:||July 2012 (Final data collection date for primary outcome measure)|
Please refer to this study by its ClinicalTrials.gov identifier: NCT00948597
|United States, Ohio|
|Cincinnati Children's Hospital Medical Center|
|Cincinnati, Ohio, United States, 45229|
|Principal Investigator:||Alexander A Vinks, PharmD, PhD||Children's Hospital Medical Center, Cincinnati|