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Original ArticlesCystic Kidney Disease
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A Post Hoc Analysis of Statin Use in Tolvaptan Autosomal Dominant Polycystic Kidney Disease Pivotal Trials

Susan E. Shoaf, John Ouyang, Olga Sergeyeva, Alvin Estilo, Hui Li and Deborah Leung
CJASN May 2020, 15 (5) 643-650; DOI: https://doi.org/10.2215/CJN.08170719
Susan E. Shoaf
1Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland
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John Ouyang
1Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland
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Olga Sergeyeva
2Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey
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Alvin Estilo
2Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey
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Hui Li
1Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland
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Deborah Leung
1Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, Maryland
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Abstract

Background and objectives Tolvaptan is approved to slow kidney function decline in adults with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression. Because in vitro 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 post hoc 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 (n=1644) or placebo (n=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.

Results 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 (e.g., 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%).

Conclusions Tolvaptan has been used safely in combination with statins in clinical trials.

Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_04_06_CJN.08170719.mp3

  • ADPKD
  • chronic renal disease
  • polycystic kidney disease
  • statins
  • pharmacokinetics
  • Alanine Transaminase
  • Polycystic Kidney, Autosomal Dominant
  • Aspartate Aminotransferases
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Tolvaptan
  • Allopurinol
  • Confidence Intervals
  • Incidence
  • Abdominal Pain
  • Research Design
  • Organic Anion Transporters
  • Antidiuretic Hormone Receptor Antagonists
  • chronic kidney disease
  • Received July 15, 2019.
  • Accepted February 26, 2020.
  • Copyright © 2020 by the American Society of Nephrology
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Clinical Journal of the American Society of Nephrology: 15 (5)
Clinical Journal of the American Society of Nephrology
Vol. 15, Issue 5
May 07, 2020
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A Post Hoc Analysis of Statin Use in Tolvaptan Autosomal Dominant Polycystic Kidney Disease Pivotal Trials
Susan E. Shoaf, John Ouyang, Olga Sergeyeva, Alvin Estilo, Hui Li, Deborah Leung
CJASN May 2020, 15 (5) 643-650; DOI: 10.2215/CJN.08170719

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A Post Hoc Analysis of Statin Use in Tolvaptan Autosomal Dominant Polycystic Kidney Disease Pivotal Trials
Susan E. Shoaf, John Ouyang, Olga Sergeyeva, Alvin Estilo, Hui Li, Deborah Leung
CJASN May 2020, 15 (5) 643-650; DOI: 10.2215/CJN.08170719
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Cited By...

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Keywords

  • ADPKD
  • chronic renal disease
  • polycystic kidney disease
  • statins
  • pharmacokinetics
  • Alanine Transaminase
  • polycystic kidney, autosomal dominant
  • Aspartate Aminotransferases
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Tolvaptan
  • allopurinol
  • Confidence Intervals
  • incidence
  • Abdominal Pain
  • Research Design
  • Organic Anion Transporters
  • Antidiuretic Hormone Receptor Antagonists
  • chronic kidney disease

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