Evaluation of drug–drug interactions with fesoterodine

Purpose  To assess drug–drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Methods  Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Results  Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C_max; from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C_max (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Conclusions  Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives. Funding for this study was provided by Schwarz Biosciences GmbH, and Pfizer Inc.     

对氨基水杨酸对利福平血药峰浓度的影响

目的:探讨肺结核患者口服对氨基水杨酸异烟肼片时对氨基水杨酸对利福平血药峰浓度的影响。方法:采取同一患者自身前后对照,同时服用对氨基水杨酸异烟肼片和利福平胶囊为观察组,同时服用异烟肼片和利福平胶囊为对照组,分别检测2组异烟肼和利福平的血药峰浓度,观察对氨基水杨酸对利福平血药峰浓度的影响。结果:口服异烟肼片和利福平胶囊后1.5h异烟肼和利福平平均血药浓度分别为(4.88±2.32)μg·mL-1和(6.49±3.40)μg·mL-1,而口服对氨基水杨酸异烟肼片和利福平胶囊后1.5h两者平均血药浓度分别为(2.62±2.34)μg·mL-1和(5.84±2.74)μg·mL-1。2组利福平血药峰浓度比较,差异无统计学意义(P>0.05);2组异烟肼血药峰浓度比较,差异有统计学意义(P<0.05)。结论:对氨基水杨酸异烟肼片中的对氨基水杨酸未对利福平血药峰浓度产生明显影响。     

抗结核药血药浓度监测及临床疗效与安全性分析

目的:建立测定抗结核药血药浓度的方法,并观察其临床疗效与安全性。方法:选择我院2007年8月-2010年12月164例结核病住院患者,采用高效液相色谱(HPLC)法分别测定患者连续服药1个月后异烟肼、利福平、吡嗪酰胺的血药浓度,分析不同血药浓度的临床疗效及肝损害情况。结果:异烟肼、利福平、吡嗪酰胺的血药浓度高于正常浓度范围者分别占9.1%、12.8%、24.4%,低于正常浓度范围者分别占54.3%、9.8%、6.7%。临床疗效以完全改善和明显改善者居多,占92.1%。药物性肝损害多发生在用药后1个月内,以老年人多见。49例肝损害患者中血药浓度高于正常者占73.5%。结论:HPLC法可用于抗结核药血药浓度监测,其结果是临床调整用药剂量的重要依据,对结核病患者合理用药具有重要意义。     

利福喷丁与利福平治疗肺结核的Meta分析

目的:评价利福喷丁与利福平治疗肺结核的疗效及安全性.方法:搜集公开发表的有关利福喷丁与利福平治疗肺结核的随机对照临床试验,按照Meta分析方法,运用Rev Man4.2.10软件对符合条件的纳入文献进行分析.结果:纳入文献13篇,总样本量2294例,利福喷丁治疗组1171例,其中,痰菌转阴1118例,病灶吸收1147倒,空洞闭合393例;利福平治疗组1123例,其中,痰菌转阴1044例,病灶吸收1024例,空洞闭合335例.痰菌转阴、空洞闭合的疗效指标合并OR值分别为1.67,1.48(P＜0.01),病灶吸收疗效指标合并OR值为1.43(P＞0.05).结论:与利福平治疗肺结核病相比,利福喷丁在促进痰菌转阴、空洞闭合方面疗效更显著,但在促进病灶吸收方面疗效差异无统计学意义.     

Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

Objective  The aim was to develop a model to describe the population pharmacokinetics of nevirapine in South African human immunodeficiency virus (HIV)-infected patients who were taking nevirapine-based antiretroviral therapy concomitantly or in the absence of rifampicin-based tuberculosis therapy. Methods  Patients were divided into two groups: (1) patients receiving nevirapine-containing antiretroviral regimen (200 mg twice daily) and continuation phase rifampicin-containing tuberculosis therapy (n = 27) in whom blood samples were obtained before and not less than 14 days after they completed tuberculosis therapy; (2) patients without tuberculosis who were receiving a nevirapine-containing antiretroviral regimen for at least 3 weeks (n = 26). The population pharmacokinetics of nevirapine was described using nonlinear mixed effects modelling with NONMEM software. Based on the developed model, plasma concentration profiles after 300, 400 and 500 mg of nevirapine twice daily were simulated. Results  Concomitant administration of rifampicin increased nevirapine oral clearance (CL/F) by 37.4% and reduced the absorption rate constant (k_a) by almost sixfold. Rifampicin reduced the nevirapine average minimum concentration by 39%. Simulated doses of 300 mg twice daily elevated nevirapine concentrations above subtherapeutic levels in most patients, with minimum exposure above the recommended maximum concentration. The area under the concentration–time curve of 12-hydroxynevirapine was not different in the presence of rifampicin. 2-, 3- and 8-Hydroxynevirapine were not detectable (LLOQ = 0.025 mg/L). Conclusion  The developed model adequately describes nevirapine population pharmacokinetics in a South African population when taken with/and in the absence of rifampicin treatment. The simulations suggest that an increased dose of 300 mg twice daily would achieve adequate nevirapine concentrations in most patients during rifampicin-containing treatment for tuberculosis.     

氨溴索对利福平肺转运作用的影响

目的 研究氨溴索对大鼠肺组织利福平浓度的影响.方法 大鼠分为A、B两组,每组10只:A组单次静注利福平30 mg/kg;B组先静注氨溴索15 mg/kg,20 min后再静注利福平30 mg/kg.于利福平给药后于30 min、1、2、4 h四个时间点采集肺组织.利福平给药后11个不同时间点采集血样,用反相高效液相色谱(HPLC)法测定利福平浓度.比较两组间的血液及肺组织利福平浓度、主要药动学参数.结果 利福平给药后1、2、4 h,B组肺组织利福平浓度均明显高于A组[(35.51±5.33)μg/ml vs.(31.82±4.77)μg/ml、(25.61±4.10)μg/ml vs.(15.21±2.58)μg/ml、(13.62±2.45)μg/ml vs.(6.24±1.18)μg/ml](P<0.01).两组血药浓度及主要药代动力学参数无明显差异.结论 氨溴索与利福平联合使用能显著增加肺组织利福平浓度;其作用机制不是通过对利幅平血药浓度及其代谢的影响.     

滴眼用利福平微生物限度检查法的验证

目的验证滴眼用利福平的最佳微生物限度检查法。方法采用直接接种法与薄膜过滤法进行验证试验。结果滴眼用利福平微生物限度检查法最佳的方法为薄膜过滤法。结论薄膜过滤法为滴眼用利福平的微生物限度检查法可行。     

利福平滴眼液有效使用期限的实验观察

目的 研究0．1％利福平滴眼液有效使用期限。方法 配制以pH5．4、pH6．4、pH7．4的3种硼酸盐缓冲液为溶剂的利福平滴眼液，贮存温度为4-10℃避光条件，观察其性状、测定pH值、应用紫外分光光度法测定含量。确定最佳的pH值和有效使用期限。结果 3种pH值硼酸盐缓冲液的利福平滴眼液的性状、含量、及pH值稳定性均较好，有效使用期限均可定为6个月。结论 pH7．4的硼酸盐缓冲液配制的0．1％利福平滴眼液有效期长，稳定性好，便于临床应用。