A novel sustained‐release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers
Abstract The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharm...
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doaj-7edf448348d44fbf8dec9db02864388c2021-10-01T09:16:19ZengWileyPharmacology Research & Perspectives2052-17072021-04-0192n/an/a10.1002/prp2.739A novel sustained‐release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteersCécile L. Berends0Lisa Pagan1Michiel J. vanEsdonk2Naomi B. Klarenbeek3Kirsten R. Bergmann4Matthijs Moerland5Vincent van derWel6Saco J. deVisser7Hans Büller8Frans deLoos9Wouter S. deVries10Hans Waals11Leo G. J. deLeede12Jacobus Burggraaf13Ingrid M. C. Kamerling14Centre for Human Drug Research (CHDR) Leiden The NetherlandsCentre for Human Drug Research (CHDR) Leiden The NetherlandsCentre for Human Drug Research (CHDR) Leiden The NetherlandsCentre for Human Drug Research (CHDR) Leiden The NetherlandsCentre for Human Drug Research (CHDR) Leiden The NetherlandsCentre for Human Drug Research (CHDR) Leiden The NetherlandsPatient One Leiden The NetherlandsZonMW Den Haag The NetherlandsFair Medicine Amsterdam The NetherlandsFair Medicine Amsterdam The NetherlandsTioFarma Oud‐Beijerland The NetherlandsTioFarma Oud‐Beijerland The NetherlandsExelion Bio‐Pharmaceutical Consultancy BV Waddinxveen The NetherlandsCentre for Human Drug Research (CHDR) Leiden The NetherlandsCentre for Human Drug Research (CHDR) Leiden The NetherlandsAbstract The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained‐release cysteamine dosage form, PO‐001, in healthy volunteers. This was a randomized, investigator‐blinded, three‐way cross‐over study to compare single doses (600 mg) of PO‐001 with Cystagon® (immediate‐release) and Procysbi® (delayed‐release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM®. Pharmacokinetics showed clear sustained‐release characteristics of PO‐001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi®. All treatment‐emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO‐001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained‐release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained‐release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18).https://doi.org/10.1002/prp2.739compliancecystagoncysteaminecystinosissustained‐release |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Cécile L. Berends Lisa Pagan Michiel J. vanEsdonk Naomi B. Klarenbeek Kirsten R. Bergmann Matthijs Moerland Vincent van derWel Saco J. deVisser Hans Büller Frans deLoos Wouter S. deVries Hans Waals Leo G. J. deLeede Jacobus Burggraaf Ingrid M. C. Kamerling |
spellingShingle |
Cécile L. Berends Lisa Pagan Michiel J. vanEsdonk Naomi B. Klarenbeek Kirsten R. Bergmann Matthijs Moerland Vincent van derWel Saco J. deVisser Hans Büller Frans deLoos Wouter S. deVries Hans Waals Leo G. J. deLeede Jacobus Burggraaf Ingrid M. C. Kamerling A novel sustained‐release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers Pharmacology Research & Perspectives compliance cystagon cysteamine cystinosis sustained‐release |
author_facet |
Cécile L. Berends Lisa Pagan Michiel J. vanEsdonk Naomi B. Klarenbeek Kirsten R. Bergmann Matthijs Moerland Vincent van derWel Saco J. deVisser Hans Büller Frans deLoos Wouter S. deVries Hans Waals Leo G. J. deLeede Jacobus Burggraaf Ingrid M. C. Kamerling |
author_sort |
Cécile L. Berends |
title |
A novel sustained‐release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers |
title_short |
A novel sustained‐release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers |
title_full |
A novel sustained‐release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers |
title_fullStr |
A novel sustained‐release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers |
title_full_unstemmed |
A novel sustained‐release cysteamine bitartrate formulation for the treatment of cystinosis: Pharmacokinetics and safety in healthy male volunteers |
title_sort |
novel sustained‐release cysteamine bitartrate formulation for the treatment of cystinosis: pharmacokinetics and safety in healthy male volunteers |
publisher |
Wiley |
series |
Pharmacology Research & Perspectives |
issn |
2052-1707 |
publishDate |
2021-04-01 |
description |
Abstract The strict intake regimen of cysteamine bitartrate formulations, associated with side effects, is a concern for the treatment compliance in cystinosis therapy. Therefore, there is a need for a cysteamine formulation with an improved pharmacokinetic profile. This study investigated the pharmacokinetics, safety and tolerability of a new sustained‐release cysteamine dosage form, PO‐001, in healthy volunteers. This was a randomized, investigator‐blinded, three‐way cross‐over study to compare single doses (600 mg) of PO‐001 with Cystagon® (immediate‐release) and Procysbi® (delayed‐release). Collected blood samples were analyzed for plasma cysteamine concentrations and pharmacokinetic parameters were estimated by noncompartmental analysis. In addition, plasma cysteamine concentrations were analyzed using a population pharmacokinetic approach using NONMEM®. Pharmacokinetics showed clear sustained‐release characteristics of PO‐001 over time with a lower Cmax and longer Tmax compared to Cystagon® and Procysbi®. All treatment‐emergent adverse events were of mild severity, with the exception of two subjects who reported moderate severity gastrointestinal problems including vomiting and diarrhea, which were related to Cystagon® intake. Population PK simulations showed a favourable PK profile based on Cmax and Ctrough concentrations at steady state. In conclusion, a single dose of 600 mg PO‐001 was well tolerated with no findings of clinical concern. This new cysteamine bitartrate formulation showed pharmacokinetics of a sustained‐release formulation, which may be beneficial for the treatment of cystinosis patients. This study supports advancing this type of sustained‐release formulation into a subsequent study to confirm reduced dosing frequency with efficient control of white blood cells (WBCs) cystine levels. Netherlands Trial Registry (NTR) (NL67638.056.18). |
topic |
compliance cystagon cysteamine cystinosis sustained‐release |
url |
https://doi.org/10.1002/prp2.739 |
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