RESUMO
PURPOSE: An influential covariate for pharmacokinetics is (body) size. Recently, the method of estimation of normal fat mass (NFM) has been advocated. Here, the relative contribution of fat mass, estimated as a fraction fat (Ffat), is used to explain differences in pharmacokinetic parameters. This concept is more and more applied. However, it remains unclear whether NFM can be reliably estimated in these typical studies. METHODS: We performed an evaluation of the reliability of NFM estimation in a typical study size (n = 30), otherwise best-case scenario, by means of a pharmacokinetic simulation study. Several values of Ffat were investigated. RESULTS: In a typical pharmacokinetic study, high imprecision was observed for NFM parameter estimates over a range of scenarios. For example, in a scenario where the true value of Ffat on clearance was 0.5, we found a 95% confidence interval of - 0.1 to 2.1, demonstrating a low precision. The implications for practice are that one could conclude that fat-free mass best describes the relationship of the pharmacokinetics with body size, while the true relationship was between fat-free mass and total body weight. Consequently, this could lead to incorrect extrapolation of pharmacokinetics to extreme body sizes. CONCLUSION: In typical pharmacokinetic studies, NFM should be used with caution because the Ffat estimates have low precision. The estimation of Ffat should always be preceded by careful study design evaluation before planning a study, to ensure that the design and sample size is sufficient to apply this potentially useful methodology.
Assuntos
Composição Corporal/fisiologia , Peso Corporal/fisiologia , Farmacocinética , Índice de Massa Corporal , Simulação por Computador , Meia-Vida , Humanos , Taxa de Depuração Metabólica , Modelos Biológicos , Reprodutibilidade dos Testes , Fatores SexuaisRESUMO
Dosing gentamicin in pediatric patients can be difficult due to its narrow therapeutic index. A significantly higher percentage of fat mass has been observed in children receiving oncology treatment than in those who are not. Differences in the pharmacokinetics of gentamicin between oncology and nononcology pediatric patients and individual dosage requirements were evaluated in this study, using normal fat mass (NFM) as a body size descriptor. Data from 423 oncology and 115 nononcology patients were analyzed. Differences in drug disposition were observed between the oncology and nononcology patients, with oncology patients having a 15% lower central volume of distribution and 32% lower intercompartmental clearance. Simulations based on the population pharmacokinetic model demonstrated low exposure target attainment in all individuals at the current clinical recommended starting dose of 7.5 mg/kg of body weight once daily, with 57.4% of oncology and 35.7% of nononcology subjects achieving a peak concentration (Cmax) of ≥25 mg/liter and 64.3% of oncology and 65.6% of nononcology subjects achieving an area under the concentration-time curve at 24 h postdose (AUC24) of ≥70 mg · h/liter after the first dose. Based on simulations, the extent of the impact of differences in drug disposition between the two cohorts appeared to be dependent on the exposure target under examination. Greater differences in achieving a Cmax target of >25 mg/liter than an AUC24 target of ≥70 mg · h/liter between the cohorts was observed. Further investigation into whether differences in the pharmacokinetics of gentamicin between oncology and nononcology patients are a consequence of changes in body composition is required.
Assuntos
Antibacterianos/farmacocinética , Gentamicinas/farmacocinética , Infecções/tratamento farmacológico , Neoplasias/tratamento farmacológico , Composição Corporal , Peso Corporal , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , PediatriaRESUMO
BACKGROUND: Intravenous acetaminophen is commonly administered as an adjunctive to opioids during major surgical procedures, but neither the correct pharmacokinetic size descriptor nor the dose is certain in severely obese adolescents undergoing bariatric surgery. METHODS: Adolescents, 14-20 years of age, with a body mass index (BMI) ≥95th percentile for age and sex or BMI ≥40 kg·m-2 , presenting for laparoscopic or robotic assisted or vertical sleeve gastrectomy were administered intravenous acetaminophen (1000 mg) following completion of the surgical procedure. Venous blood was drawn for acetaminophen assay at eight time points, starting 15 minutes after completion of the infusion and up to 12 hours afterward. Time-concentration data profiles were analyzed using nonlinear mixed effects models. Parameter estimates were scaled to a 70-kg person using allometry. Normal fat mass was used to assess the impact of obesity on pharmacokinetic parameters. RESULTS: The study cohort comprised 11 female patients, age 17 SD 2 years with a weight of 125 SD 19 kg and a mean BMI of 46 SD 5 kg·m-2 . The plasma acetaminophen serum concentration was 17 (SD 4) µg·mL-1 at 10-20 minutes after completion of the infusion and 5 (SD 6) µg·mL-1 at 80-100 minutes. A two-compartment model, used to investigate pharmacokinetics, estimated clearance 10.6 (CV 72%) L·h·70 kg-1 , intercompartment clearance 37.3 (CV 63%) L·h·70 kg-1 , central volume of distribution 20.4 (CV 46%) L·70 kg-1 , and peripheral volume of distribution 16.8 (CV 42%) L·70 kg-1 . Clearance was best described using total body weight. Normal fat mass with a parameter that accounts for fat mass contribution (Ffat) of 0.88 best described volumes. CONCLUSION: Current recommendations of acetaminophen to a maximum dose of 1000 mg resulted in serum concentrations below detection limits in all patients within 2 hours after administration. Dose is better predicted using total body mass with allometric scaling.
Assuntos
Acetaminofen/farmacocinética , Obesidade/metabolismo , Acetaminofen/sangue , Acetaminofen/uso terapêutico , Administração Intravenosa , Adolescente , Analgésicos não Narcóticos/sangue , Analgésicos não Narcóticos/farmacologia , Analgésicos não Narcóticos/uso terapêutico , Cirurgia Bariátrica/métodos , Índice de Massa Corporal , Feminino , Humanos , Modelos Biológicos , Dinâmica não Linear , Obesidade/sangue , Obesidade/cirurgia , Estudos Prospectivos , Adulto JovemRESUMO
Lean body mass is commonly proposed for anesthesia maintenance drug dosing calculations. However, total body mass used with allometric scaling has been shown to be better for propofol in obese adults and children. Fat-free mass has also been used instead of lean body mass. Fat-free mass is essentially the same as lean body mass but excludes a small percentage of mass of lipids in cell membranes, CNS, and bone marrow. Normal fat mass is a size descriptor that partitions total body mass into fat-free mass and fat mass calculated from total body mass minus fat-free mass. The relative influence of fat mass compared with fat-free mass is described by the fraction of fat mass that makes fat equivalent to fat-free mass in terms of allometric size. This fraction (Ffat) will differ for each drug and each parameter affected by body size (eg, clearance and volume of distribution). This fraction is based on the concept of theory-based allometric size. The normal fat mass based on allometric theory and partition of body mass into fat and fat-free components provides a principle-based approach explaining size and body composition effects on pharmacokinetics of all drugs in children and in adults.