Population pharmacokinetics of theophylline in very premature Japanese infants with apnoea

Fukuda, Tsuyoshi; Yukawa, Eiji; Kondo, Genzo; Maeda, Takatsugu; Shino, Tamami; Kondo, Yuki; Imamura, Toshihiro; Irikura, Mitsuru; Irie, Tetsumi

doi:10.1111/j.1365-2710.2005.00689.x

Cited by 18 publications

(18 citation statements)

References 14 publications

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“…This study shows that developmental changes in CYP1A2 activity and in TP clearance were affected by PNA, rather than PMA, and that CYP1A2 activity had a greater influence on TP clearance than urinary excretion did during the preterm period. Previous population pharmacokinetics studies of TP in preterm infants reported the importance of body weight and age , which was consistent with our results. However, we also found that CYP1A2 activity was a major determinant of TP clearance in preterm infants.…”

Section: Discussionsupporting

confidence: 93%

“…Previous population BUN, blood urea nitrogen; Cr, creatinine; AST, aspartate aminotransferase; ALT, alanine aminotransferase Simple linear regression was used for data analysis. a CYP1A2 activity = ratio of (1-methyluric acid +3-methylxanthine) / theophylline Table 3 Factors affecting CYP1A2 activity and theophylline clearance pharmacokinetics studies of TP in preterm infants reported the importance of body weight and age [22][23][24], which was consistent with our results. However, we also found that CYP1A2 activity was a major determinant of TP clearance in preterm infants.…”

Section: Discussionsupporting

confidence: 88%

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Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants

Sohn

Kim

et al. 2017

Brit J Clinical Pharma

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AIMSThe purpose of this study was to explore clinical markers reflecting developmental changes in drug clearance by preterm infants. METHODSPreterm infants administered aminophylline or theophylline to treat apnoea of prematurity were enrolled in this study. Trough and one of 2 h, 4 h or 6 h post-dose blood samples and urine samples were collected during steady state, to determine the concentrations of theophylline and its targeted metabolites. CYP1A2*1C and CYP1A2*1F genotypes were analyzed. Total, renal and nonrenal clearances of theophylline were calculated, and cytochrome P450 1A2 (CYP1A2) activity was obtained from the ratio of 1-methyluric acid and 3-methylxanthine to theophylline in urine. Multiple linear regression analysis was performed to evaluate the relationships between theophylline clearance and the clinical characteristics of preterm infants. RESULTSA total of 152 samples from 104 preterm infants were analyzed. A strong association between the serum trough and urine theophylline concentrations was found (P < 0.001). Total, renal and nonrenal clearances of theophylline were 0.50 AE 0.29 ml kg À1 min À1 , 0.16 AE 0.06 ml kg À1 min À1 and 0.34 AE 0.28 ml kg À1 min À1 , respectively. CYP1A2 activity correlated positively with the postnatal age and postmenstrual age. However, CYP1A2 genotype was not associated with CYP1A2 activity, which was significantly associated with nonrenal clearance. CYP1A2 activity, postnatal age , weight and 24-h urine output were significantly associated with total theophylline clearance. CONCLUSIONSCYP1A2 activity can be monitored using noninvasive random urine samples, and it can be used to assess developmental changes in theophylline clearance by preterm infants. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Neonatal theophylline pharmacokinetics are influenced by developmental changes in liver metabolism and urinary elimination.• Previous population pharmacokinetic studies have focused on the effect of weight and age.• Previous studies have not explored the effects of phenotypic cytochrome P450 1A2 (CYP1A2) activity and genetic polymorphism on theophylline pharmacokinetics in preterm infants. WHAT THIS STUDY ADDS• CYP1A2 activity is a major determinant of theophylline clearance in preterm infants.• Genetic polymorphisms do not affect CYP1A2 activity during the preterm and neonatal period.• Noninvasive urinary metabolite analyses in real time can be used to assess developmental changes in theophylline clearance by preterm infants. Tables of Links

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 88%

Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants

Sohn

Kim

et al. 2017

Brit J Clinical Pharma

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“…Receiving oxygen support was reported to significantly increase theophylline CL in neonates with apnoea . In the study by Preez et al ., they showed that neonates who received oxygen support cleared theophylline 47% faster than those who did not.…”

Section: Discussionmentioning

confidence: 96%

“…Body weight and age were the most frequently used covariates to estimate theophylline clearance in paediatric patients. Body weight was used to estimate the clearance in all six studies performed on neonates and infants, and four of those studies used allometric models . For the estimation of clearance, three studies used PNA, and one study used PCA .…”

Section: Discussionmentioning

confidence: 99%

Theophylline: a review of population pharmacokinetic analyses

Jiang

Meng

et al. 2016

J Clin Pharm Ther

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This review concludes that body weight and age were the most important factors associated with the clearance of theophylline in paediatric patients. Body weight, age and smoking were most frequently used to estimate the clearance of theophylline in adults. Future studies are warranted to detect the influence of new factors, such as cytochrome P450 (CYP) 1A2 gene polymorphisms, on the pharmacokinetics of theophylline because some pharmacokinetic variability was not fully explained.

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“…from Fukuda et al [36] in order to account for changes in oral drug absorption after birth. Patient demographics (Table 4), model equations [8,9] and parameter estimates (Table 5) are provided in the Supplementary Material.…”

Section: Bcs Class I Drugs (High Solubility High Permeability)mentioning

confidence: 99%

Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds

Somani

Thelen

Zheng

et al. 2015

Brit J Clinical Pharma

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AIMSEvidence suggests that the rate of oral drug absorption changes during early childhood. Yet, respective clinical implications are currently unclear, particularly for preterm neonates. The objective of this study was to evaluate changes in oral drug absorption after birth for different Biopharmaceutics Classification System (BCS) class I and II compounds to better understand respective implications for paediatric pharmacotherapy. METHODSTwo paradigm compounds were selected for BCS class I (paracetamol (acetaminophen) and theophylline) and II (indomethacin and ibuprofen), respectively, based on the availability of clinical literature data following intravenous and oral dosing. A comparative population pharmacokinetic analysis was performed in a step-wise manner in NONMEM® 7.2 to characterize and predict changes in oral drug absorption after birth for paracetamol, theophylline and indomethacin. RESULTSA one compartment model with an age-dependent maturation function for oral drug absorption was found appropriate to characterize the pharmacokinetics of paracetamol. Our findings indicate that the rate at which a drug is absorbed from the GI tract reaches adult levels within about 1 week after birth. The maturation function for paracetamol was found applicable to theophylline and indomethacin once solubility limitations were overcome via drug formulation. The influence of excipients on solubility and, hence, oral bioavailability was confirmed for ibuprofen, a second BCS class II compound. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Preterm birth is associated with high morbidity and mortality resulting in a high demand for drug therapy.• Clinical evidence suggests that the oral absorption process of a drug undergoes substantial changes after birth. The impact of these physiological changes on oral drug therapy is currently unclear. WHAT THIS STUDY ADDS• This study improves our understanding of changes in oral drug absorption in preterm neonates for two drugs from both BCS class I and BCS class II.• Our findings indicate that these changes in oral absorption within the first few days after birth are a system-specific property, which can be used to guide oral dosing of BCS class I and BCS class II compounds in preterm neonates.

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Population pharmacokinetics of theophylline in very premature Japanese infants with apnoea

Abstract: Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target theophylline concentrations, thus enabling the clinician to achieve the desired therapeutic effect in very premature Japanese infants.

Cited by 18 publications

References 14 publications

Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants

Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants

Theophylline: a review of population pharmacokinetic analyses

Evaluation of changes in oral drug absorption in preterm and term neonates for Biopharmaceutics Classification System (BCS) class I and II compounds

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