Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland.
Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey.
Clin J Am Soc Nephrol. 2020 May 7;15(5):643-650. doi: 10.2215/CJN.08170719. Epub 2020 Apr 2.
Tolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because studies indicated that the tolvaptan oxobutyric acid metabolite inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, United States prescribing information advises avoiding concurrent use with OATP1B1/1B3 substrates, including hepatic hydroxymethyl glutaryl-CoA reductase inhibitors (statins). This analysis of the pivotal phase 3 tolvaptan trials (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes [TEMPO] 3:4 trial [NCT00428948] and Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD [REPRISE] trial [NCT02160145]) examined the safety of concurrent tolvaptan/statin use.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The trials randomized a combined total of 2815 subjects with early- to late-stage ADPKD to tolvaptan (=1644) or placebo (=1171) for 3 years (TEMPO 3:4) and 1 year (REPRISE). Statin use was unrestricted, and 597 subjects (21.2% overall; 332 [20.2%] tolvaptan, 265 [22.6%] placebo) received statins. Statin use (duration, dose change, statin change, permanent discontinuation), incidences of statin-related adverse events, and hepatic transaminase elevations were determined for subjects who received tolvaptan+statin, placebo+statin, tolvaptan alone, and placebo alone.
No differences in statin use parameters between tolvaptan- and placebo-treated subjects were observed. No statistically significant increases in commonly reported statin-related adverse events (, musculoskeletal disorders, gastrointestinal symptoms) were seen between subjects receiving tolvaptan+statin and placebo+statin. For example, in TEMPO 3:4, frequencies were 5.4% and 7.8%, respectively, for myalgia (difference -2.4%; 95% confidence interval, -11.2% to 6.4%) and 9.3% and 7.8%, respectively, for abdominal pain (difference 1.5%; -7.9% to 10.9%). In an analysis that excluded participants concurrently using allopurinol, the frequency of alanine transaminase or aspartate transaminase >3× upper limit of normal in the pooled study populations was 3.6% for the tolvaptan+statin group and 2.3% for the placebo+statin group (difference 1.4%; -2.0% to 4.7%).
Tolvaptan has been used safely in combination with statins in clinical trials.
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3.
托伐普坦获批用于治疗有快速进展风险的常染色体显性多囊肾病（ADPKD）成人，以减缓肾功能下降。由于研究表明托伐普坦的氧丁酸代谢物抑制有机阴离子转运多肽（OATP）1B1 和 OATP1B3，美国处方信息建议避免与 OATP1B1/1B3 底物同时使用，包括羟甲基戊二酰辅酶 A 还原酶抑制剂（他汀类药物）。本分析对关键的 3 期托伐普坦试验（托伐普坦在管理常染色体显性多囊肾病及其结局中的疗效和安全性[ TEMPO]3:4 试验[NCT00428948]和复制保留肾功能的证据：托伐普坦治疗 ADPKD 的安全性和疗效研究[REPRISE]试验[NCT02160145]）考察了托伐普坦/他汀类药物同时使用的安全性。
设计、设置、参与者和测量：这些试验共将 2815 例早期至晚期 ADPKD 患者随机分为托伐普坦组（n=1644）或安慰剂组（n=1171），分别接受托伐普坦（n=1644）或安慰剂（n=1171）治疗 3 年（ TEMPO 3:4 ）和 1 年（REPRISE）。他汀类药物的使用不受限制，597 例患者（总体 21.2%；托伐普坦 332 例[20.2%]，安慰剂 265 例[22.6%]）接受了他汀类药物治疗。对于接受托伐普坦+他汀类药物、安慰剂+他汀类药物、托伐普坦单药和安慰剂单药治疗的患者，确定了他汀类药物的使用情况（持续时间、剂量变化、他汀类药物变化、永久停药）、他汀类药物相关不良事件的发生率和肝转氨酶升高情况。
托伐普坦组和安慰剂组的他汀类药物使用参数无差异。接受托伐普坦+他汀类药物和安慰剂+他汀类药物的患者，常见的他汀类药物相关不良事件（肌肉骨骼疾病、胃肠道症状）发生率无统计学显著增加。例如，在 TEMPO 3:4 中，肌肉疼痛的发生率分别为 5.4%和 7.8%（差异-2.4%；95%置信区间-11.2%至 6.4%），腹痛发生率分别为 9.3%和 7.8%（差异 1.5%；-7.9%至 10.9%）。在排除同时使用别嘌醇的参与者的分析中，在联合研究人群中，丙氨酸氨基转移酶或天冬氨酸氨基转移酶>3×正常值上限的频率，托伐普坦+他汀类药物组为 3.6%，安慰剂+他汀类药物组为 2.3%（差异 1.4%；-2.0%至 4.7%）。
托伐普坦在临床试验中与他汀类药物联合使用是安全的。
