| Summary: | 碩士 === 國立成功大學 === 臨床藥學研究所 === 90 === 英文摘要
Apnea of prematurity is a common problem in premature infants. It is related to immaturity of the infant’s neurologic and respiratory systems. Management of apnea of prematurity involves both pharmacological and nonpharmacological treatment, and aminophyllin (contain 85 % theophylline) is the first-line choice in our hospital. The range of effective theophylline serum concentrations is relatively narrow and generally ranged between 6 and 13 mg/ml. The pharmacokinetics of theophylline in premature infants have been studied using either individual analysis methods or population methods.
The aim of the study was to estimate the pharmacokinetic parameters, clearance rate (CL) using the population pharmacokinetic models proposed by Moore et al. Based on the validated population models, serum theophylline level was predicted to reduce the frequency of blood sampling. The relationship between theophylline concentrations and it’s efficacy or adverse effects was also evaluated.
This study consisted of two parts. We first evaluated the population pharmacokinetics models of theophylline using 429 theophylline serum concentration measurements from 92 neonates receiving theophylline and measured theophylline serum concentration at least once. Mean ± SD gestational age and birth weight were 28.6 ± 2.7 wks and 1,244 ± 0.48 g, respectively. The clearance (CL) in the study population was 0.0309 ± 0.012 L/hr (mean ± SD), ranged 0.0095~0.0929 L/hr. Newborns who had experienced birth asphyxia had a mean theophylline clearance 8% lower than nonasphyxiated newborns. Our findings indicate that postconceptional age rather than postnatal age is a better reference during theophylline therapy in premature infants. Theophylline plasma concentrations increased in a nonlinear proportion to the dosage, and most plasma concentrations over 15 mg/ml occurred in the first three weeks of life. Relationship between estimate area under concentration curve (AUC = Dose / CL) and concentration using current weight is better than birth weight (Pearson Correlation Coefficients: 0.54 vs. 0.45, p <0.0001, Linear Regression: r2 = 0.29 vs. 0.21, p < 0.0001). The final new models were: Dose/CL (mg/kg/day)/(L/hr) = 6.6708 Conc. (mg/ml) + 14.971(Conc. = Concentration).
Predictive performance of the new population models was prospectivly evaluated on another group of 22 infants, with Mean ± SD gestational age and birth weight as 27.8 ± 1.9 wks and 1,096 ± 0.31 g, respectively. Clearance was 0.03 ± 0.13 L/hr (mean ± SD). The residue of -3 to -4 mg/ml was obtained and in the majority of in the study. Error percentage (% Error = % measured – expected /measured) was -14.9 % (mean), ranged 1.2 ~ 228 %. Discrepancy greater than 10 mg/ml was observed in three premature infants because of more than 24 % loss of body weight within 1 week of life. Birth weight less than 1,000 g, dosing interval of every eight hour, and change of dose one day before sampling, were three major factors affecting the predicted serum concentrations.
Then, we conducted a prospective, routine monitoring to evaluate the correlation between efficacy or adverse effect and theophylline serum concentrations in 24 premature infants. Data were collected from premature infants treated with aminophylline from December 2001 through May 2002. Apnea was detected from nursing records, and the success rate of aminophylline treatment was 79 %, with serum concentrations of 6 to 13 mg/ml. The most common side effect was tachycardia, and theophylline was discontinued due to persistent tachycardia in three patients.
In brief, there was a nonlinear correlation between dose and plasma concentrations, and plasma theophylline clearance was unpredictable according to the population pharmacokinetic models proposed by Moore et al. Theophylline effectivnely decreases apnea of prematurity at plasma concentration of 6 – 13 mg/ml, and monitoring of serum theophylline levels is mandatory.
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