Monitoring theophylline therapy using citric acid-stimulated saliva in infants and children with asthma

Saliva stimulation is required for measurement of drugs in saliva. Chewing on a piece of paraffin, which is the method usually used for saliva stimulation, requires cooperation of the patient and, thus, is inapplicable in infants and young children. To assess the value of determining theophylline concentrations from noninvasively obtained saliva in this age group, we studied the theophylline plasma to saliva concentration ratio in citric acid-stimulated saliva. Theophylline concentration was measured in 137 simultaneously obtained paired specimens of plasma and saliva from 68 patients 2 1/2 months to 14 years of age treated with theophylline for asthma (dosage 20.8 ± 5.2 mg/kg/d, mean ± SD). Saliva secretion was stimulated by placing citric acid crystals on the tongue. A strong and highly significant correlation was observed beteen both determinations (r = .96; P < .01). The plasma to saliva ratio was 1.78 ± 0.22 (mean ± SD), with theophylline concentrations between 3.1 and 32.1 μg/mL of plasma. The ratio of estimated to actual plasma theophylline concentrations was 1.02 ± 0.12 (mean ± SD). Interindividual coefficient of variation of plasma to saliva theophylline concentrations ratios was 12.4%; mean intraindividual coefficient of variation was 5.3%. The use of citric acid for saliva stimulation is easily applicable to infants and young children. Compared with blood drawing, stimulation of saliva secretion by citric acid is painless and noninvasive, is more readily accepted to patients, is at least as clinically relevant for theophylline determination, and allows frequent measurements of drug levels for individualization of the dosage with samples taken at home. The therapeutic concentrations range of theophylline in saliva is estimated to be between 5.6 and 11.2 μg/mL (equivalent to plasma concentrations of 10 to 20 μg/mL) in our laboratory.