Pharmacokinetic Studies with a Long-Acting sulfnamide in Subjects of Different Ages: A Modern Approach to Drug Dosage Problems in Developmental Pharmacology

摘要

Extract: The principle aims of this paper are to discus the stiking differences in sulfonamides pharmacokinetics which can be observed when compaing groups of subjects at very different stages of development and to demonstrate the practical value of investigations to establish the correct dosage of a drug in infants and children. The sulfonamide compound used for this study was 2-sulfa-3-methoxy-pyrazine.The first series of investigations concerned the determination of all the biological constants needed to establish the optimal dosage of the drug for five groups: newborns, infants, children, adults and elderly subjects. The vlues measured included protein-binding and pharmacokinetic constants. The second series of studies investigated the application of the Krüger-Thiemer pharmacokinetic theory in the five age groups.When compared with adult values, the drug concentration in plasma water at half saturation binding is higher in newborn and elderly subjects, while it is rathere low in children (table II). The maximum binding capacity of the plasma did not differ in a signifiacant way among all groups studied, with the exception of the elderly subjects in whom high vlaues were found. As a result of the relatively marked changes with age of these two constants, the minimum concentration of free sulfonamide in plasma was found to be much higher in newborns than in all other groups.In table III, pharmacokinetic constants are reported. The rate constant of absorption was found to decrease from high values in newborns and in infants to low values in children; the lowest values were found in adults, whereas in elderly subjects the constant was again high. The rate constant of elimination was very low in newborns, higher in infants and children, slightly lowere in adults and was very low again in elderly subjects. As was expected, an inverse trend was observed when the time of half elimination (biological half-life) was calculated, being highest in newborns, lower and approximately equal in infants, children and adults and very significantly eleveted in elderly subjects. The coefficient of distribution fo 2-sulfa-3-methoxy-pyrazine was found to be very high in newborns, high in infants, low and about equal in children and adults and again high in elderly subjects.When the theoretical maintenance dose and the ratio between initial and maintenance dose were calculated from the pharmacokinetic constants and from the protein-binding constants, values characteristic of each state of development were obtained (tables III and IV). Relative maintenance dose was found to be very low in newborns, high in infants and children and lower in adults and elderly subjects. The initial to maintenance dose ratio was found, on the contrary, to be very high in newborns and elderly subjects and about equal in infants, children and adults, the children showing the lowest values.The practical value of the Krüger-Thiemer method for calculating an optimal dosage regimen was tested by measuring plasma concerntrations of sulfonamide in subjects of different ages treated for prolonged periods of time. A remarkably constant minimum blood concernation was found in each instance, thus indicating that the theoretic treatment of the variables had permitteed prediction of optimal drug dosage (figs. 4 and 5).Specultion: The Krüger-Thiemer method was found very useful to calculate the optimal drug dosage regimen in subjects of different ages, from birth through senescence. This same type of experimental approach could be used in the future, with profit, to calculate optimal dosages of other drugs for which the therapeutic effect depents chiefly upon the maintenance of a relatively constant plasma concentration.