Schmitt C, Kaeser B, Riek M, Bech N, Kreuzer C
F. Hoffmann-La Roche, Ltd., Pharmaceutical Division, Basel, Switzerland.
Int J Clin Pharmacol Ther. 2010 Mar;48(3):192-9. doi: 10.5414/cpp48192.
Saquinavir and ritonavir, both human immunodeficiency virus-1 protease inhibitors, also inhibit the adenosine triphosphate-dependent efflux pump P-glycoprotein (P-gp), which is located at a variety of anatomic sites, including the human intestine. P-gp plays an important role in the absorption, distribution and elimination of numerous drugs. This study investigated the inhibitory potential of multiple administrations of ritonavir-boosted saquinavir at the target therapeutic dose of 1,000 mg saquinavir/100 mg ritonavir twice daily on the pharmacokinetics of oral digoxin, a model P-gp substrate that is predominantly excreted as unchanged drug in the urine.
In an open-label, 1-sequence, 2-period crossover study, a single digoxin dose of 0.5 mg was administered orally on Day 1. From Days 11 through 26, participants received oral administration of saquinavir/ritonavir 1,000/100 mg twice daily. A second dose of digoxin was administered on Day 24. Blood and urine sampling for pharmacokinetic analyses of digoxin was performed at scheduled time points on Days 1 - 4 and Days 24 - 27. Serial blood samples were drawn to determine plasma levels of saquinavir and ritonavir on Days 21 - 24. Adverse event reports were collected.
Of the 17 enrolled participants (9 males and 8 females) who received at least one dose of study medication, 16 completed the study. Two weeks of pretreatment with ritonavir and saquinavir resulted in a 1.27-fold increase in digoxin Cmax (90% confidence interval (1.05 - 1.54)) and a 1.49-fold increase in AUC0-72 (90% CI (1.32 - 1.69)). Renal clearance decreased by a factor 0.88 from 111 to 97.3 ml/min while digoxin half-life increased from 37.0 to 45.3 h. The unbound fraction of digoxin was almost unaffected. The changes in digoxin renal clearance and exposure (AUC0-72) following 2 weeks of treatment with saquinavir/ritonavir were found to be more pronounced among female participants compared with males. Plasma concentrations of saquinavir/ritonavir at trough and at 4 h postdose were within the expected ranges for each gender, with female participants showing higher concentrations than male participants. All three treatments were well tolerated, with no serious adverse events noted. Despite the higher digoxin exposure among females compared to males following saquinavir/ritonavir administration, overall safety profiles were similar. On electrocardiographic readings, a trend of a longer PR interval was noted with triple combination of agents.
Pretreatment with saquinavir/ritonavir 1,000/100 mg twice daily increased digoxin exposure most likely via P-gp-inhibition. Given the relatively narrow therapeutic window of digoxin, caution should be exercised when these three drugs are administered together. It is recommended to reduce digoxin doses and to monitor digoxin serum concentrations.
沙奎那韦和利托那韦均为人类免疫缺陷病毒1型蛋白酶抑制剂，它们还可抑制位于包括人体肠道在内的多种解剖部位的三磷酸腺苷依赖性外排泵P - 糖蛋白（P - gp）。P - gp在众多药物的吸收、分布和消除过程中发挥着重要作用。本研究调查了以每日两次、每次1000 mg沙奎那韦/100 mg利托那韦的目标治疗剂量多次服用利托那韦增强型沙奎那韦对口服地高辛（一种主要以原形经尿液排泄的P - gp模型底物）药代动力学的抑制潜力。
在一项开放标签、单序列、两期交叉研究中，第1天口服单剂量0.5 mg地高辛。从第11天至第26天，参与者每日两次口服1000/100 mg沙奎那韦/利托那韦。第24天给予第二剂地高辛。在第1 - 4天和第24 - 27天的预定时间点采集血液和尿液样本用于地高辛的药代动力学分析。在第21 - 24天采集系列血液样本以测定沙奎那韦和利托那韦的血浆水平。收集不良事件报告。
在17名至少接受一剂研究药物的入组参与者（9名男性和8名女性）中，16名完成了研究。用利托那韦和沙奎那韦预处理两周导致地高辛Cmax增加1.27倍（90%置信区间（1.05 - 1.54）），AUC0 - 72增加1.49倍（90% CI（1.32 - 1.69））。肾脏清除率从111降至97.3 ml/min，降低了0.88倍，而地高辛半衰期从37.0小时增加至45.3小时。地高辛的游离分数几乎未受影响。与男性相比，沙奎那韦/利托那韦治疗两周后地高辛肾脏清除率和暴露量（AUC0 - 72）的变化在女性参与者中更为明显。沙奎那韦/利托那韦谷浓度和给药后4小时的血浆浓度在各性别预期范围内，女性参与者的浓度高于男性参与者。所有三种治疗耐受性良好，未观察到严重不良事件。尽管沙奎那韦/利托那韦给药后女性的地高辛暴露量高于男性，但总体安全性概况相似。在心电图读数中，三种药物联合使用时有PR间期延长的趋势。
每日两次口服1000/100 mg沙奎那韦/利托那韦预处理最有可能通过抑制P - gp增加地高辛暴露量。鉴于地高辛的治疗窗相对较窄，这三种药物联合使用时应谨慎。建议降低地高辛剂量并监测地高辛血清浓度。
