Sugar A M, Alsip S G, Galgiani J N, Graybill J R, Dismukes W E, Cloud G A, Craven P C, Stevens D A
Santa Clara Valley Medical Center, Stanford University Medical School, California.
Antimicrob Agents Chemother. 1987 Dec;31(12):1874-8. doi: 10.1128/AAC.31.12.1874.
One hundred sixty patients were entered in two multicenter protocols to receive 400 to 2,000 mg of ketoconazole once daily for nonmeningeal or meningeal coccidiodomycosis. For 24 h after administration of all doses, mean concentrations in serum exceeded MICs for Coccidioides immitis (trough concentrations, greater than 1 microgram/ml). Mean peak concentrations occurred 4 to 6 h after administration, ranging from 7 to 17 micrograms/ml for doses of 400 to 2,000 mg. Incremental increases in peak concentrations in serum were greatest at doses of less than or equal to 1,200 mg. To investigate whether long-term therapy altered concentrations in serum, serial data were studied by several methods. The results suggested a trend to increased levels in serum with prolonged therapy, but were not statistically significant. All 168 cerebrospinal fluid (CSF) samples from meningitis patients contained less than or equal to 2.9 micrograms/ml, and only 6 contained greater than 1 microgram/ml. There was no apparent relation between dose, time after dose, site of CSF sampling, or concurrent inflammation and CSF ketoconazole concentration. Neither concentration in serum, toxicity, nor outcome correlated with dose, calculated in milligrams per kilogram at the fixed doses (400-mg increments) under study. Likewise, at the various doses, concentration in serum did not correlate with outcome or toxicity, suggesting that individual drug disposition was not an important factor in outcome or toxicity. Toxicity was reversible, and principal side effects were nausea and vomiting (50%), gynecomastia (21%), decreased libido (13%), alopecia (8%), elevated liver function tests (5%), pruritus (5%), and rash (4%). Gastrointestinal and endocrinologic toxicity were dose related and increased at doses greater than 800 mg. The cumulative percent toxicity requiring discontinuation of drug was 6, 17, 23, and 56% at 400-, 800-, 1,200-, and 1,600-mg doses. Doses of >400 mg are thus markedly more toxic, and efficacy data for nonmeningeal disease have not demonstrated that they are more efficacious.
160名患者被纳入两项多中心试验方案，接受每日一次400至2000毫克酮康唑治疗非脑膜型或脑膜型球孢子菌病。在所有剂量给药后24小时内，血清中的平均浓度超过了粗球孢子菌的最低抑菌浓度（谷浓度，大于1微克/毫升）。给药后4至6小时出现平均峰值浓度，400至2000毫克剂量的峰值浓度范围为7至17微克/毫升。血清中峰值浓度的增量在剂量小于或等于1200毫克时最大。为了研究长期治疗是否会改变血清浓度，通过几种方法对系列数据进行了研究。结果表明，随着治疗时间延长，血清水平有升高趋势，但无统计学意义。来自脑膜炎患者的所有168份脑脊液（CSF）样本中的浓度均小于或等于2.9微克/毫升，只有6份样本的浓度大于1微克/毫升。剂量、给药后时间、脑脊液采样部位或并发炎症与脑脊液酮康唑浓度之间没有明显关系。血清浓度、毒性或疗效均与所研究的固定剂量（400毫克递增）下以毫克/千克计算的剂量无关。同样，在不同剂量下，血清浓度与疗效或毒性也不相关，这表明个体药物处置不是影响疗效或毒性的重要因素。毒性是可逆的，主要副作用为恶心和呕吐（50%）、男子女性型乳房（21%）、性欲减退（13%）、脱发（8%）、肝功能检查值升高（5%）、瘙痒（5%）和皮疹（4%）。胃肠道和内分泌毒性与剂量相关，在剂量大于800毫克时增加。在400、800、1200和1600毫克剂量下，因毒性需要停药的累积百分比分别为6%、17%、23%和56%。因此，剂量大于400毫克时毒性明显更大，且非脑膜型疾病的疗效数据并未表明更高剂量更有效。
