Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant.

The pharmacokinetics of amikacin administered intravenously at currently recommended doses (7.5 mg/kg every 12 h for infants with less than 7 days of life; 7.5 mg/kg every 8 h for infants with greater than 7 days of life) were studied in 28 preterm infants weighing less than 2,500 g (mean +/- standard deviation, 1.38 +/- 0.47 kg; postconceptional age, 30.50 +/- 2.86 weeks). The medication was infused over 45 min. Trough and peak serum samples as well as two additional samples were taken at steady state. The results showed a statistically significant inverse relationship between half-life (8.42 +/- 2.55 h) and postconceptional age (P = 0.002) and a direct correlation between total body clearance (0.84 +/- 0.28 ml/min per kg) and postconceptional age (P = 0.02). These pharmacokinetic data were used to calculate a new dosage schedule for preterm infants. The derived intravenous dosage of amikacin for infants of less than 30 weeks of postconceptional age was 9 mg/kg every 18 h. For infants of greater than 30 weeks of postconceptional age, the dosage was 9 mg/kg every 12 h. Peak and trough levels of amikacin in serum that fell within the therapeutic range were compared by using the currently recommended dosage schedule and the dosage schedule derived from our pharmacokinetic data. There was a reduction in the number of peak and trough levels that fell outside the accepted therapeutic range which was not statistically significant. Extension of the dosing interval and a further increase in the dosage may result in further improvement. Based on these data, the current recommendations are inadequate for the preterm infant. Our derived dosage schedule improved but did not eliminate high trough and low peak levels of amikacin in all infants. The current recommendations should be adjusted for the preterm infant. Ongoing therapeutic drug monitoring is essential to tailor the amikacin dosage to the individual patient.

Ranitidine kinetics and dynamics. I. Oral dose studies.

Ranitidine, an H2-receptor antagonist, has been shown to reduce pentagastrin-stimulated gastric secretion. We examined the relationship between inhibition of gastric secretion and ranitidine serum concentration. Twelve normal male subjects received 20, 40, or 80 mg of ranitidine orally 90 min before starting a 3-hr continuous infusion of pentagastrin, 2 micrograms/kg/hr. Ranitidine, 20, 40, and 80 mg, reduced hydrogen ion output by 29%, 50%, and 70% and secretion volume by 21%, 37%, and 47%. Pepsin activity was reduced by 8%, 50%, and 49% by the same doses. Peak serum concentration was correlated positively with percent reduction in hydrogen ion output (r = 0.81, P less than 0.001) and volume (r = 0.71, P less than 0.01) over a 2-hr period. A 50% inhibition of hydrogen ion output was associated with a peak ranitidine serum concentration of 165 micrograms/l and subjects reached peak serum concentration 60 to 120 min after oral dosing. An appropriate therapeutic effect should be achieved with 8 hourly doses of 80 mg ranitidine. No clinically significant subjective or toxic biochemical effect of ranitidine was seen after single doses. White blood cell count was reduced in 11 of 12 subjects 7 days after ranitidine, an observation which calls for further investigation.

Ranitidine kinetics and dynamics. II. Intravenous dose studies and comparison with cimetidine.

Intravenous ranitidine has been shown to reduce pentagastrin-stimulated gastric secretion. Eight normal men received, in randomized order, 60 mg ranitidine or 300 mg cimetidine intravenously over 2 min. Both ranitidine and cimetidine induced decreases in volume hydrogen ion content and pepsin activity of stimulated gastric juice. Ranitidine half-life (t1/2) was 2.1 +/- 0.1 hr and cimetidine (t1/2) was 1.5 +/- 0.1 hr. Ranitidine volume of distribution was 1.6 +/- 0.1 l/kg and that of cimetidine was 1.12 +/- 0.12 l/kg. The clearance of ranitidine was 0.54 +/- 0.04 l/kg hr-1 and that of cimetidine was 0.5 +/- 0.05 l/kg hr-1. It is suggested that the intravenous loading dose of ranitidine necessary to attain a serum concentration of 200 micrograms/l (which would achieve a 50% inhibition of gastric acid) is 0.3 mg/kg, followed by an infusion rate of 0.11 mg/kg hr-1.

Analysis of ranitidine in serum by high performance liquid chromatography.

We describe a simple and rapid micro method for the high pressure liquid chromatographic analysis of ranitidine, N-[2[[[5-[(dimethylamino)-methyl]-2-furanyl]methyl]thio]-ethyl-N'-methyl-2-nitro-1,1-ethenediamine in serum or plasma. The percentage analytical recovery of ranitidine and internal standard (metiamide) was 99% and 81%, respectively. The between-day precision of the procedure (n = 20) at ranitidine plasma concentrations of 500, 250, and 125 microgram/liter generated coefficients of variation of 6.2, 8.7, and 8.9%, respectively. The method was applied in preliminary studies to correlate serum concentrations of ranitidine with gastric acid secretion after continuous pentagastrin stimulation (2 microgram/kg/hr) in patients receiving an oral dose of 20, 40, or 80 mg of the drug.