title: 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.
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.
  
  
  METHODS
  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, k(a) = 4.54 h(-1) and k(el) = 0.139 h(-1), as well as of fractional volume of distribution and plasma clearance, V(S1) = 0.58 L/kg and CL(S1) = 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, r(s), >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.
authors.affiliation: Clinic for Therapeutics and Clinical Pharmacology, University Hospital St. I. Rilsky, Sofia, Bulgaria. terziiv@yahoo.com
authors.forename: Dimiter
authors.initials: D
authors.lastname: Terziivanov
authors.forename: Kristina
authors.initials: K
authors.lastname: Bozhinova
authors.forename: Velislava
authors.initials: V
authors.lastname: Dimitrova
authors.forename: Ivanka
authors.initials: I
authors.lastname: Atanasova
mesh_terms: D000328:Adult; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics*; D000697:Central Nervous System Stimulants / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007408:Intestinal Absorption; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D044465:White People
chemical_list: D000697:Central Nervous System Stimulants; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2