Dixon R, Pozniak A L, Watt H M, Rolan P, Posner J
Department of Clinical Pharmacology, Wellcome Research Laboratories, Kent, United Kingdom.
Antimicrob Agents Chemother. 1996 Mar;40(3):556-60. doi: 10.1128/AAC.40.3.556.
The single- and multiple-dose pharmacokinetics of and tolerability to a new microfluidized suspension of atovaquone were studied in human immunodeficiency virus-seropositive patients with CD4 counts of < or = 200 cells per mm3 in order to define a dosing regimen for the treatment of Pneumocystis carinii pneumonia. This was an open study with groups of six patients each. In the first part of the study, six subjects received escalating single doses of 500, 1,000, and 1,500 mg after an overnight fast at weekly intervals. In the second part of the study, groups of six subjects were dosed for 14 days according to three regimens: 1,000 mg twice daily fasting, twice daily with a high-fat meal, or once daily with a high-fat meal. Plasma atovaquone levels were assayed by high-performance liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental methods, and statistical comparison of parameters for single doses was performed by analysis of variance. Plasma drug concentrations increased with single doses from 500 to 1,000 mg but were no higher with a dose of 1,500 mg. Thus, 1,000 mg was selected for multiple administration. A regimen of 1,000 mg twice daily with food resulted in a 93% increase in the average trough steady-state concentration compared with 1,000 mg once daily with food. Food increased the bioavailability of atovaquone 1.4-fold over that in the fasting state. All patients who received 1,000 mg twice daily with food achieved target steady-state concentrations in plasma of 15 to 25 micrograms/ml. Multiple-dose regimens were generally well tolerated, but the higher levels in plasma achieved by 1,000 mg twice daily with food were associated with an increased incidence of rash. In conclusion, target plasma atovaquone concentrations for the treatment of P. carinii pneumonia can be achieved in most patients with 1,000 mg twice daily in a fasting state and in all patients with 1,000 mg twice daily administered with food, but at higher concentrations in plasma, there may be an increased risk of rash.
为确定卡氏肺孢子虫肺炎治疗的给药方案，对一种新的阿托伐醌微流化混悬液在人类免疫缺陷病毒血清学阳性、CD4计数≤200个细胞/mm³的患者中的单剂量和多剂量药代动力学及耐受性进行了研究。这是一项开放性研究，每组6名患者。在研究的第一部分，6名受试者在每周一次的过夜禁食后接受500、1000和1500mg递增单剂量。在研究的第二部分，6名受试者分为三组，根据三种给药方案给药14天：每天禁食两次，每次1000mg；每天高脂餐两次，每次1000mg；或每天高脂餐一次，每次1000mg。采用高效液相色谱法测定血浆阿托伐醌水平。通过非房室方法确定药代动力学参数，并通过方差分析对单剂量参数进行统计学比较。单剂量从500mg增至1000mg时血浆药物浓度升高，但1500mg剂量时不更高。因此，选择1000mg进行多次给药。与每天一次1000mg高脂餐给药相比，每天两次1000mg高脂餐给药方案使平均谷浓度稳态浓度增加了93%。食物使阿托伐醌的生物利用度比禁食状态下提高了1.4倍。所有每天两次1000mg高脂餐给药的患者血浆中均达到了15至25μg/ml的目标稳态浓度。多剂量方案一般耐受性良好，但每天两次1000mg高脂餐给药使血浆中药物水平更高，这与皮疹发生率增加有关。总之，大多数患者在禁食状态下每天两次1000mg可达到治疗卡氏肺孢子虫肺炎的目标血浆阿托伐醌浓度，所有患者在每天两次1000mg高脂餐给药时均可达到，但血浆浓度较高时，皮疹风险可能增加。
