Boucher F D, Modlin J F, Weller S, Ruff A, Mirochnick M, Pelton S, Wilfert C, McKinney R, Crain M J, Elkins M M
Department of Pediatrics, Stanford University School of Medicine, California.
J Pediatr. 1993 Jan;122(1):137-44. doi: 10.1016/s0022-3476(05)83507-3.
This study evaluated the safety, tolerability, and pharmacokinetics of zidovudine administered intravenously and orally to infants born to women infected with the human immunodeficiency virus. Thirty-two symptom-free infants were enrolled before 3 months of age. The pharmacokinetics of zidovudine were evaluated in each infant after single intravenously and orally administered doses of zidovudine on consecutive days, and during long-term oral administration of the drug for 4 to 6 weeks. As new patients were enrolled, doses of zidovudine were progressively increased from 2 to 4 mg/kg. Therapy was continued for up to 12 months in 7 of the infants proved to be infected with human immunodeficiency virus. Zidovudine was generally well tolerated; 20 children (62.5%) had anemia (hemoglobin level < 10.0 gm/dl) during therapy and 9 (28.1%) had neutropenia (neutrophil count < or = 750 cells/mm3); these hematologic abnormalities usually resolved spontaneously. The total body clearance of zidovudine increased significantly with age, from an average of 10.9 ml/min per kilogram in infants < or = 14 days of age to 19.0 ml/min per kilogram in older infants (p < 0.0001). Concurrently, there was a significant decrease in serum half-life from 3.12 hours in infants < or = 14 days to 1.87 hours in older infants (p = 0.0002). Oral absorption was satisfactory and bioavailability decreased significantly with age, from 89% in infants < or = 14 days to 61% in those > 14 days of age (p = 0.0002). Plasma concentrations of zidovudine were calculated to be in excess of 1 mumol/L (0.267 micrograms/ml) for 4.12 +/- 1.86 hours and 2.25 +/- 0.78 hours after oral doses of 2 mg/kg in infants younger than 2 weeks and 3 mg/kg in older infants, respectively. We conclude that zidovudine administered at oral doses of 2 mg/kg every 6 hours to infants aged less than 2 weeks and 3 mg/kg every 6 hours to infants older than 2 weeks resulted in plasma concentrations that are considered virustatic against human immunodeficiency virus. Zidovudine was well tolerated by infants at these doses.
本研究评估了对感染人类免疫缺陷病毒的女性所生婴儿静脉注射和口服齐多夫定的安全性、耐受性及药代动力学。32名无症状婴儿在3个月龄前入组。在连续数天对每名婴儿单次静脉注射和口服齐多夫定后，以及在长期口服该药4至6周期间，评估了齐多夫定的药代动力学。随着新患者入组，齐多夫定的剂量从2毫克/千克逐渐增加至4毫克/千克。7名被证实感染人类免疫缺陷病毒的婴儿接受治疗长达12个月。齐多夫定总体耐受性良好；20名儿童（62.5%）在治疗期间出现贫血（血红蛋白水平<10.0克/分升），9名（28.1%）出现中性粒细胞减少（中性粒细胞计数<或=750个/立方毫米）；这些血液学异常通常可自发缓解。齐多夫定的全身清除率随年龄显著增加，从14日龄及以下婴儿的平均每千克10.9毫升/分钟增至较大婴儿的每千克19.0毫升/分钟（p<0.0001）。同时，血清半衰期显著缩短，从14日龄及以下婴儿的3.12小时降至较大婴儿的1.87小时（p = 0.0002）。口服吸收良好，生物利用度随年龄显著降低，从14日龄及以下婴儿的89%降至14日龄以上婴儿的61%（p = 0.0002）。在2周龄以下婴儿口服2毫克/千克剂量、3周龄以上婴儿口服3毫克/千克剂量后，齐多夫定的血浆浓度分别在4.12±1.86小时和2.25±0.78小时内超过1微摩尔/升（0.267微克/毫升）。我们得出结论，对2周龄以下婴儿每6小时口服2毫克/千克剂量、对2周龄以上婴儿每6小时口服3毫克/千克剂量的齐多夫定，可使血浆浓度达到对人类免疫缺陷病毒具有抑制病毒活性的水平。婴儿对这些剂量的齐多夫定耐受性良好。
