NPT-IIb Inhibition Does Not Improve Hyperphosphatemia in CKD
Serum phosphate levels are insufficiently controlled in many patients with end-stage renal disease (ESRD), and novel therapeutic strategies are needed. Blocking intestinal phosphate absorption mediated by sodium-dependent phosphate co-transporter type 2b (NPT-IIb) holds promise; thus, we evaluated t...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-01-01
|
| Series: | Kidney International Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024917303455 |
| _version_ | 1819236776769748992 |
|---|---|
| author | Tobias E. Larsson Chisato Kameoka Ikumi Nakajo Yuta Taniuchi Satoshi Yoshida Tadao Akizawa Ronald A. Smulders |
| author_facet | Tobias E. Larsson Chisato Kameoka Ikumi Nakajo Yuta Taniuchi Satoshi Yoshida Tadao Akizawa Ronald A. Smulders |
| author_sort | Tobias E. Larsson |
| collection | DOAJ |
| description | Serum phosphate levels are insufficiently controlled in many patients with end-stage renal disease (ESRD), and novel therapeutic strategies are needed. Blocking intestinal phosphate absorption mediated by sodium-dependent phosphate co-transporter type 2b (NPT-IIb) holds promise; thus, we evaluated the efficacy, safety, tolerability, and pharmacokinetics of the novel and specific small molecule NPT-IIb inhibitor ASP3325 for the first time in humans.
Methods: We conducted a randomized, double-blind, placebo-controlled, phase 1a single (n = 88) and multiple (n = 36) ascending dose study in healthy subjects, and a randomized, open-label, uncontrolled, phase 1b study in hyperphosphatemic ESRD patients on hemodialysis (single oral dose, n = 5; multiple oral doses, n = 17). Primary efficacy measures were urinary phosphate and fecal phosphorous excretion (healthy subjects) and serum phosphate level (ESRD patients).
Results: No time- or dose-dependent changes in urinary phosphate or fecal phosphorous excretion were observed following single/multiple ASP3325 doses for 7 days in healthy subjects. In ESRD patients, ASP3325 administered 3 times daily for 2 weeks before or after a meal did not reduce serum phosphate levels. ASP3325 was safe and well tolerated in both populations.
Conclusion: NPT-IIb inhibition with ASP3325 was not effective in reducing serum phosphate levels in ESRD patients. The relevance of NPT-IIb in humans and feasibility of oral NPT-IIb inhibitors for treatment of hyperphosphatemia in ESRD remain uncertain. |
| first_indexed | 2024-12-23T13:09:49Z |
| format | Article |
| id | doaj.art-6e7d7f1195d044288303d13fc368a64f |
| institution | Directory Open Access Journal |
| issn | 2468-0249 |
| language | English |
| last_indexed | 2024-12-23T13:09:49Z |
| publishDate | 2018-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Kidney International Reports |
| spelling | doaj.art-6e7d7f1195d044288303d13fc368a64f2022-12-21T17:45:47ZengElsevierKidney International Reports2468-02492018-01-0131738010.1016/j.ekir.2017.08.003NPT-IIb Inhibition Does Not Improve Hyperphosphatemia in CKDTobias E. Larsson0Chisato Kameoka1Ikumi Nakajo2Yuta Taniuchi3Satoshi Yoshida4Tadao Akizawa5Ronald A. Smulders6Astellas Pharma Europe BV, Leiden, NetherlandsAstellas Pharma Inc., Tokyo, JapanAstellas Pharma Inc., Tokyo, JapanAstellas Pharma Inc., Tokyo, JapanAstellas Pharma Inc., Tokyo, JapanDepartment of Nephrology, Showa University School of Medicine, Tokyo, JapanAstellas Pharma Europe BV, Leiden, NetherlandsSerum phosphate levels are insufficiently controlled in many patients with end-stage renal disease (ESRD), and novel therapeutic strategies are needed. Blocking intestinal phosphate absorption mediated by sodium-dependent phosphate co-transporter type 2b (NPT-IIb) holds promise; thus, we evaluated the efficacy, safety, tolerability, and pharmacokinetics of the novel and specific small molecule NPT-IIb inhibitor ASP3325 for the first time in humans. Methods: We conducted a randomized, double-blind, placebo-controlled, phase 1a single (n = 88) and multiple (n = 36) ascending dose study in healthy subjects, and a randomized, open-label, uncontrolled, phase 1b study in hyperphosphatemic ESRD patients on hemodialysis (single oral dose, n = 5; multiple oral doses, n = 17). Primary efficacy measures were urinary phosphate and fecal phosphorous excretion (healthy subjects) and serum phosphate level (ESRD patients). Results: No time- or dose-dependent changes in urinary phosphate or fecal phosphorous excretion were observed following single/multiple ASP3325 doses for 7 days in healthy subjects. In ESRD patients, ASP3325 administered 3 times daily for 2 weeks before or after a meal did not reduce serum phosphate levels. ASP3325 was safe and well tolerated in both populations. Conclusion: NPT-IIb inhibition with ASP3325 was not effective in reducing serum phosphate levels in ESRD patients. The relevance of NPT-IIb in humans and feasibility of oral NPT-IIb inhibitors for treatment of hyperphosphatemia in ESRD remain uncertain.http://www.sciencedirect.com/science/article/pii/S2468024917303455end-stage renal diseasehemodialysishyperphosphatemiaNPT-IIb inhibitorpharmacokineticsphase 1 trial |
| spellingShingle | Tobias E. Larsson Chisato Kameoka Ikumi Nakajo Yuta Taniuchi Satoshi Yoshida Tadao Akizawa Ronald A. Smulders NPT-IIb Inhibition Does Not Improve Hyperphosphatemia in CKD Kidney International Reports end-stage renal disease hemodialysis hyperphosphatemia NPT-IIb inhibitor pharmacokinetics phase 1 trial |
| title | NPT-IIb Inhibition Does Not Improve Hyperphosphatemia in CKD |
| title_full | NPT-IIb Inhibition Does Not Improve Hyperphosphatemia in CKD |
| title_fullStr | NPT-IIb Inhibition Does Not Improve Hyperphosphatemia in CKD |
| title_full_unstemmed | NPT-IIb Inhibition Does Not Improve Hyperphosphatemia in CKD |
| title_short | NPT-IIb Inhibition Does Not Improve Hyperphosphatemia in CKD |
| title_sort | npt iib inhibition does not improve hyperphosphatemia in ckd |
| topic | end-stage renal disease hemodialysis hyperphosphatemia NPT-IIb inhibitor pharmacokinetics phase 1 trial |
| url | http://www.sciencedirect.com/science/article/pii/S2468024917303455 |
| work_keys_str_mv | AT tobiaselarsson nptiibinhibitiondoesnotimprovehyperphosphatemiainckd AT chisatokameoka nptiibinhibitiondoesnotimprovehyperphosphatemiainckd AT ikuminakajo nptiibinhibitiondoesnotimprovehyperphosphatemiainckd AT yutataniuchi nptiibinhibitiondoesnotimprovehyperphosphatemiainckd AT satoshiyoshida nptiibinhibitiondoesnotimprovehyperphosphatemiainckd AT tadaoakizawa nptiibinhibitiondoesnotimprovehyperphosphatemiainckd AT ronaldasmulders nptiibinhibitiondoesnotimprovehyperphosphatemiainckd |