Influence of age on the disposition kinetics of chloramphenicol in equine neonates

Abstract

SUMMARY The effect of age on the pharmacokinetics of chloramphenicol was determined after iv administration of chloramphenicol sodium succinate (25 mg/kg of body weight) to 6 foals at 1 day and 3, 7, 14, and 42 days of age. The disposition of chloramphenicol was best described, using a two-compartment open model in all foals at all ages evaluated. Significant age-related changes were observed in values for the major kinetic terms describing the disposition of chloramphenicol in foals; the greatest changes were observed between 1 day and 3 days of age. The mean ± sd value for elimination rate constant (β) for chloramphenicol in 1-day-old foals (0.131 ± 0.06 h-1) was significantly (P < 0.005) lower than the value in 3-day-old foals (0.514 ± 0.156 h-1), and both values were significantly (P < 0.05) lower than values for β in 7-, 14-, and 42-day-old foals. With increasing age, the increase in the mean value for β resulted in decrease in the harmonic mean elimination half-time (t1/2β) for chloramphenicol, from 5.29 hours in 1-day-old foals to: 1.35 hours in 3-day-old foals; 0.61 hour in 7-day-old foals; 0.51 hour in 14-day-old foals; and 0.34 hour in 42-day-old foals. At 1, 3, and 7 days of age, values for t1/2β of chloramphenicol in a premature foal born after parturition was induced with oxytocin, were considerably longer than comparable t1/2β values for term foals born naturally. The mean body clearance (ClB) of chloramphenicol in 1-day-old foals (2.25 ± 0.67 ml/min·kg of body weight) was significantly lower than values in: 3-day-old (6.23 ± 2.22 ml/min·kg; P < 0.05); 7-day-old (8.86 ± 1.90 ml/min·kg; P < 0.0005); 14-day-old (9.63 · 1.63 ml/min·kg; P < 0.0005); and 42-day-old (9.68 · 2.76 ml/min·kg; P < 0.0001) foals. In foals of all ages, ClB of chloramphenicol in the parturition-induced premature foal was lower than the mean value for term foals born naturally. The volume of distribution (V′d[area]) of chloramphenicol decreased progressively with increasing age between day 1 and day 42, so that the mean value for 42-day-old foals (362 ± 163 ml/kg) was less than a third the mean value for 1-day-old foals (1,101 ± 284 ml/kg). The mean value for V′d(area) in 1-day-old foals was significantly greater than values for: 7-day-old (491 ± 158 ml/kg; P < 0.01); 14-day-old (426 ± 65 ml/kg; P < 0.005); and 42-day-old (362 ± 162; P < 0.0005) foals, and the mean value for V′d(area)on day 3 was significantly (P < 0.05) greater than the mean value for V′d(area) on days 7, 14, and 42. Using dosage calculations based on mean values for the pharmacokinetic terms derived for each age group, it was predicted that to maintain plasma chloramphenicol concentration > 8 μg/ml, chloramphenicol sodium succinate (25 mg/kg) would have to be administered at dose intervals of 10, 3, 1.5, 1.5, and 1 hours in clinically normal foals 1 day and 3, 7, 14, and 42 days, of age, respectively. It was concluded that the marked changes in the disposition of chloramphenicol detectable during the first few days of life, the variation between individuals, the potentially major effect of prematurity, and the potential for compromised liver function in septicemic foals indicate that use of drugs, such as chloramphenicol, which rely heavily on hepatic metabolic processes for elimination, should be avoided whenever possible during the early neonatal period, unless plasma concentration is monitored.