A Potential New Method to Estimate Tissue Cystine Content in Nephropathic Cystinosis

Dohil, Ranjan; Carrigg, Alison; Newbury, Robert

doi:10.1016/j.jpeds.2012.03.011

Cited by 11 publications

(9 citation statements)

References 17 publications

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“…If we assume that our animal pK data estimate those seen in humans, then cysteamine may only be detectable above baseline levels for 8–12 h/day. This may help to explain the findings in a recent study in which patients with cystinosis, despite maintaining low WBC cystine levels on regular long‐term cysteamine therapy, continued to show large amounts of cystine in there intestinal mucosal tissue . This might then also explain why these patients continue to have deterioration in renal function despite adequate WBC cystine levels.…”

Section: Discussionmentioning

confidence: 90%

Pharmacokinetics of cysteamine bitartrate following intraduodenal delivery

Dohil

Cabrera

Gangoiti

et al. 2012

Fundamemntal Clinical Pharma

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Cysteamine is approved for the treatment of cystinosis and is being evaluated for Huntington's disease and non-alcoholic fatty liver disease. Little is known about the bioavailability and biodistribution of the drug. The aim was to determine plasma, cerebrospinal fluid (CSF), and tissue (liver, kidney, muscle) cysteamine levels following intraduodenal delivery of the drug in rats pretreated and naïve to cysteamine and to estimate the hepatic first-pass effect on cysteamine. Healthy male rats (n = 66) underwent intraduodenal and portal (PV) or jugular (JVC) venous catheterization. Half were pretreated with cysteamine, and half were naïve. Following intraduodenal cysteamine (20 mg/kg), serial blood samples were collected from the PV or the JVC. Animals were sacrificed at specific time points, and CSF and tissue were collected. Cysteamine levels were determined in plasma, CSF, and tissue. The Cmax was achieved in 5-10 min from PV and 5-22.5 min from JVC. The PV-Cmax (P = 0.08), PV-AUC0-t (P = 0.16), JVC-Cmax (P = 0.02) and JVC-AUC0-t (P = 0.03) were higher in naive than in pretreated animals. Plasma cysteamine levels returned to baseline in ≤120 min. The hepatic first-pass effect was estimated at 40%. Peak tissue and CSF cysteamine levels occurred ≤22.5 min, but returned to baseline levels ≤180 min. There was no difference in CSF and tissue cysteamine levels between naïve and pretreated groups, although cysteamine was more rapidly cleared in the pretreated group. Cysteamine is rapidly absorbed from the small intestine, undergoes significant hepatic first-pass metabolism, crosses the blood brain barrier, and is almost undetectable in plasma, CSF, and body tissues 2 h after ingestion. Sustained-release cysteamine may provide prolonged tissue exposure.

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Section: Discussionmentioning

confidence: 90%

Pharmacokinetics of cysteamine bitartrate following intraduodenal delivery

Dohil

Cabrera

Gangoiti

et al. 2012

Fundamemntal Clinical Pharma

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“…On the other hand, WBC cystine levels may not adequately reflect the whole-body cystine burden and long-term compliance. Alternatively, interstitial macrophages containing cystine crystals have been demonstrated in various organs, including the skin, gastrointestinal mucosa, liver, kidney, and bone marrow, [32][33][34][35][36][37] and macrophage activation has been established as one of the important pathogenic mechanisms of cystinosis. 11,13,38 In addition, substantial evidence indicates a pivotal role for inflammation mediated by macrophages, comprising mainly the macrophage-secreted cytokines IL-6 and TNF-a, the M1/M2 macrophage balance, and macrophage-derived monocytes in the progression of CKD toward ESKD.…”

Section: Discussionmentioning

confidence: 99%

Chitotriosidase as a Novel Biomarker for Therapeutic Monitoring of Nephropathic Cystinosis

Veys

Elmonem

Dyck

et al. 2020

JASN

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BackgroundNephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. White blood cell cystine concentration is the current gold standard for therapeutic monitoring, but the assay is technically demanding and is available only on a limited basis. Because macrophage-mediated inflammation plays an important role in the pathogenesis of cystinosis, biomarkers of macrophage activation could have potential for the therapeutic monitoring of cystinosis.MethodsWe conducted a 2-year prospective, longitudinal study in which 61 patients with cystinosis who were receiving cysteamine therapy were recruited from three European reference centers. Each regular care visit included measuring four biomarkers of macrophage activation: IL-1β, IL-6, IL-18, and chitotriosidase enzyme activity.ResultsA multivariate linear regression analysis of the longitudinal data for 57 analyzable patients found chitotriosidase enzyme activity and IL-6 to be significant independent predictors for white blood cell cystine levels in patients of all ages with cystinosis; a receiver operating characteristic analysis ranked chitotriosidase as superior to IL-6 in distinguishing good from poor therapeutic control (on the basis of white blood cell cystine levels of <2 nmol 1/2 cystine/mg protein or ≥2 nmol 1/2 cystine/mg protein, respectively). Moreover, in patients with at least one extrarenal complication, chitotriosidase significantly correlated with the number of extrarenal complications and was superior to white blood cell cystine levels in predicting the presence of multiple extrarenal complications.ConclusionsChitotriosidase enzyme activity holds promise as a biomarker for use in therapeutic monitoring of nephropathic cystinosis.

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“…[12][13][14] Following on from this, a new delayed-release enteric-coated micro-sphere formulation (RP103, Raptor Pharmaceutical Corp., Novato, CA) was devised which could be ingested within an intact gelatin capsule or as a sprinkle formulation. 16 It is important, therefore, to understand how cysteamine bitartrate delayed-release should be ingested in relation to meals in order to optimize its bioavailability and provide continued tissue cystine depletion. 15 Little is know about the pharmacokinetics of cysteamine, in particular, the effect of food on the bioavailability of the drug.…”

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confidence: 99%

“…Suboptimal drug absorption with Clinical Pharmacology in Drug Development 2 (2) 178-185 reduced tissue cysteamine levels may contribute to inadequate tissue cystine depletion and the progression to renal failure despite good compliance with therapy. 16 It is important, therefore, to understand how cysteamine bitartrate delayed-release should be ingested in relation to meals in order to optimize its bioavailability and provide continued tissue cystine depletion.…”

mentioning

confidence: 99%

“…A recent study showed that the absorption of immediate‐release cysteamine (Cystagon®, Mylan Pharmaceuticals, Inc., Morgantown, WV) was significantly impaired when drug was ingested with high fat or high protein diets. Suboptimal drug absorption with reduced tissue cysteamine levels may contribute to inadequate tissue cystine depletion and the progression to renal failure despite good compliance with therapy . It is important, therefore, to understand how cysteamine bitartrate delayed‐release should be ingested in relation to meals in order to optimize its bioavailability and provide continued tissue cystine depletion.…”

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confidence: 99%

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Pharmacokinetic Studies of Cysteamine Bitartrate Delayed‐Release

Dohil

Rioux

2013

Clinical Pharm in Drug Dev

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A twice-daily microsphere formulation of cysteamine bitartrate has been developed for cystinosis and other potential applications. To date, there are no published pharmacokinetic data for cysteamine bitartrate delayed-release in healthy adults. Three randomized open-label, crossover studies to determine the effects of fasting, high fat, and carbohydrate meals on the bioavailability of cysteamine bitartrate delayed-release (600 mg) administered in capsule or sprinkle form to healthy adults. Adverse events were monitored. Fifty-eight adults were studied. Cysteamine absorption (AUC0-24 hours ) was the same for capsule and sprinkle forms during all meal/fasting states. The AUC0-24 hours for capsules while fasted, 30 and 120 minutes before a carbohydrate meal and during a high fat meal were 6,313 ± 329, 4,616 ± 878, 6,691 ± 669, 2,572 ± 295 minutes × µM, respectively, and the mean Cmax values were 29.4 ± 1.7, 20.7 ± 4.9, 31.6 ± 3.0, and 10.9 ± 1.7 µM, respectively. The mean Tmax following fasting and high fat meal were about 3 and 6 hours, respectively. Minor transient GI adverse events occurred. Cysteamine bitartrate delayed-release capsule and sprinkle forms are bioequivalent and optimal absorption occurs during fasting state. High fat diet reduces drug absorption, increases the Tmax and should be avoided at the time of drug ingestion. Cysteamine bitartrate delayed-release (RP103) is best ingested >30 minutes before a carbohydrate-rich meal.

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A Potential New Method to Estimate Tissue Cystine Content in Nephropathic Cystinosis

Cited by 11 publications

References 17 publications

Pharmacokinetics of cysteamine bitartrate following intraduodenal delivery

Pharmacokinetics of cysteamine bitartrate following intraduodenal delivery

Chitotriosidase as a Novel Biomarker for Therapeutic Monitoring of Nephropathic Cystinosis

Pharmacokinetic Studies of Cysteamine Bitartrate Delayed‐Release

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