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Population pharmacokinetics of theophylline in adult Chinese patients with asthma and chronic obstructive pulmonary disease

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Abstract

Background Theophylline has a narrow therapeutic range and large interindividual variability in blood levels, so a thorough understanding of its pharmacokinetic characteristics is essential. Population pharmacokinetic (PPK) approaches could achieve it and many PPK studies of theophylline have been reported in infants. However, none was conducted in Chinese adults and none has explored the effect of CYP1A2 genotypes on the PPK characteristics of theophylline in adults. Objective To evaluate the PPK characteristics of theophylline and to assess the possible influence of covariates, including CYP1A2 genotypes, on theophylline clearance in Chinese adult patients. Setting The study is conducted at the department of respiration in Zhujiang Hospital, Guangzhou, China. Methods Theophylline concentrations were obtained from eligible patients and were measured by high performance liquid chromatography. The polymorphisms of − 3860G > A, − 163C > A, C5347T (CYP1A2*1B) and G-3113A were genotyped using a direct sequencing method. Then, CYP1A2 genotypes, age, fat-free mass (FFM) and other covariates were used to develop a PPK model by NONMEM software. Bootstrap analysis was used to asses the accuracy and prediction of the PPK model. Main outcome measure The concentration and clearance of theophylline. Results A total of 134 theophylline concentrations from 95 patients were obtained. The final model was as follows: CL/F(L/h) = 4.530 × (FFM/56.1)0.75 × 0.713CYP1A2*1B, the inter-individual variability in clearance/bioavailability (CL/F) was 44.0%, and the residual variability was 9.8%. The final model was proved to be reliable by bootstrap analysis. Conclusion Theophylline clearance was significantly associated with FFM and CYP1A2*1B genotypes in Chinese adult patients.

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Acknowledgements

The authors thank the physicians for their work and the patients for their participation.

Funding

This research was supported by the National Natural Science Foundation for Young Scientists of China (No. 81302846).

Conflicts of interest

The authors declare no conflicts of interest.

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    Authors and Affiliations

    1. Department of Pharmacy, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China

      Yanjiao Ma, Yong Wang & Liqing Wang

    2. Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, China

      Ling Xue

    3. Department of Respiration, Zhujiang Hospital of Southern Medical University, Guangzhou, 510282, Guangdong, China

      Xin Chen

    4. Department of Pharmacy, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong, China

      Yingbo Kang

    5. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China

      Yong Wang & Liqing Wang

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    1. Yanjiao Ma
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    3. Xin Chen
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    Correspondence to Yong Wang or Liqing Wang.

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    Yanjiao Ma and Ling Xue are contributed equally to this work.

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    Ma, Y., Xue, L., Chen, X. et al. Population pharmacokinetics of theophylline in adult Chinese patients with asthma and chronic obstructive pulmonary disease. Int J Clin Pharm 40, 1010–1018 (2018). https://doi.org/10.1007/s11096-018-0636-6

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