PHARMACOKINETIC ANALYSIS OF SPARSE IN-VIVO NMR-SPECTROSCOPY DATA USING RELATIVE PARAMETERS AND THE POPULATION APPROACH

NMR spectroscopy in vivo when applied to studying drugs and their meta bolites usually measures relative concentration in a tissue over time. Only ratios of clearance and volume parameters can be estimated from these data. Low drug dosages (relative to the sensitivity of in vivo N MR) or rapid drug elimination create the additional problem of data sp arsity where a pharmacokinetic model cannot be fitted individually. We have investigated whether relative and absolute pharmacokinetic param eters can be estimated from such data by applying a population model. The data analysed were relative concentrations of 5-fluorouracil (FU) and of the sum of its catabolites alpha-fluoro-beta-ureido-propanoic a cid (FUPA) and alpha-fluoro-beta-alanine (FBAL) in the liver, as monit ored in 16 cancer patients by [F-19]-NMR spectroscopy during and after a 10-min intravenous infusion of 650 mg FU.m(-2). The ''structural'' part of the population model was a non-linear, two-compartment model f eaturing one FU compartment with volume V-FU, a saturable clearance of FU by conversion into the catabolites where CL = V-max/(k(M)+ C-FU), a catabolite compartment with volume V-cat, and a concentration-indepe ndent clearance of the catabolites, CL(cat). The parameters actually f itted were: gamma, v(max), k(M).V-FU, V-cat/V-FU and CL(cat)/V-cat whe re gamma is a proportionality factor relating the NMR signal intensity of FU to the amount of FU in the body and, therefore, has no purely p harmacokinetic interpretation. All parameters were checked for random interindividual variation; gamma and v(max) were also tested for inter -occasion variation. The program system NONMEM was used for model fitt ing. The estimated mean population parameters were: v(max) = 121 mu mo l.min(-1), k(M).V-FU = 2590 mu mol, V-cat/V-FU = 0.0648, CL(cat)/V-cat = 0.0555.min(-1). The proportionality factor gamma was found to depen d on body weight and, in addition, to have an inter-occasion random va riation (within patients, between examinations). No other random varia tion of a kinetic parameter could be identified. The estimated v(max) is similar to a reported estimate of 2.02 mu mol.min(-1).kg(-1) derive d from FU plasma kinetics. This study shows that sparse relative conce ntration data can be analysed by using relative parameters in a popula tion model. Only one parameter has no unequivocal pharmacokinetic mean ing due to the lack of absolute concentration information. Any contrib ution of the measuring procedure to the inter-occasion variation of in vivo NMR spectroscopy measurements should be minimized in order to al low the detection of possible inter-individual variances of the pharma cokinetic parameters.