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Nonparametric Expectation Maximisation (NPEM) Population Pharmacokinetic Analysis of Caffeine Disposition from Sparse Data in Adult Caucasians

Systemic Caffeine Clearance as a Biomarker for Cytochrome P450 1A2 Activity

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Abstract

Objective: To explore the ability of the nonparametric expectation maximisation (NPEM) method of population pharmacokinetic modelling to deal with sparse data in estimating systemic caffeine clearance for monitoring and evaluation of cytochrome P450 (CYP) 1A2 activity.

Design and participants: Nonblind, single-dose clinical investigation in 34 non-related adult Bulgarian Caucasians (18 women and 16 men, aged between 18 and 62 years) with normal and reduced renal function.

Methods: Each participant received oral caffeine 3 mg/kg. Two blood samples per individual were taken according to the protocol for measuring caffeine plasma concentrations. A total of 67 measured concentrations were used to obtain NPEM estimates of caffeine clearance. Paraxanthine/caffeine plasma ratios were calculated and correlated with clearance estimates. Graphical methods and tests for normality were applied and parametric and nonparametric statistical tests were used for comparison.

Results: NPEM median estimates of caffeine absorption and elimination rate constants, ka = 4.54 h−1 and ke1 = 0.139 h−1, as well as of fractional volume of distribution and plasma clearance, VS1 = 0.58 L/kg and CLs1 = 0.057 L/h/kg, agreed well with reported values from more ‘data rich’ studies. Significant correlations were observed between paraxanthine/caffeine ratios at 3, 8 and 10 hours and clearance (Spearman rank correlation coefficients, rs, >0.74, p ≤ 0.04). Sex or renal function caused no significant differences in clearance. Heavy smokers and drinkers showed 2-fold higher CYP1A2 activity. Normality tests and graphical methods of analysing caffeine clearance supported a non-Gaussian and multicomponent distribution of CYP1A2 activity.

Conclusions: Collectively, the results show that the NPEM method is suitable and relevant for large-scale epidemiological studies of population phenotyping for cancer susceptibility and for abnormal liver function by monitoring CYP1A2 activity based on sparse caffeine data.

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Acknowledgements

The authors are deeply indebted to Roger W. Jelliffe, MD, for generously making available to them the USC*PACK collection of PC programs, v.10.6. They also wish to express their sincere gratitude to him for working with them on the revised version of the manuscript. The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this study.

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  1. Clinic for Therapeutics and Clinical Pharmacology, University Hospital ‘St. I. Rilsky’, 15 D. Nestorov Street, Sofia, 1431, Bulgaria

    Dimiter Terziivanov, Kristina Bozhinova & Velislava Dimitrova

  2. Department of Drug Policy, Ministry of Health, Sofia, Bulgaria

    Ivanka Atanasova

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  1. Dimiter Terziivanov
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  2. Kristina Bozhinova
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Correspondence to Dimiter Terziivanov.

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Terziivanov, D., Bozhinova, K., Dimitrova, V. et al. Nonparametric Expectation Maximisation (NPEM) Population Pharmacokinetic Analysis of Caffeine Disposition from Sparse Data in Adult Caucasians. Clin Pharmacokinet 42, 1393–1409 (2003). https://doi.org/10.2165/00003088-200342150-00006

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