Abstract: TH-PO736
Implications of Renal Impairment on Dosing of Delayed-Release Cysteamine Bitartrate
Session Information
- Genetic Diseases of the Kidneys: Non-Cystic - I
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidney
- 1002 Genetic Diseases of the Kidney: Non-Cystic
Authors
- Langman, Craig B., Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
- Sile, Saba, Horizon Pharma Inc, Lake Forest, Illinois, United States
- Fisher, Dennis M., P Less Than, San Francisco, California, United States
Background
Delayed Release Cysteamine Bitartrate(DRCys) is used to treat nephropathic cystinosis (NC) in order to prolong native kidney function and ameliorate other systemic effects of NC. A biomarker, WBC cystine levels (WBCCys) guides optimal cystine reduction. To date, there are no studies on the effects of impaired renal function, including hemodialysis (HD) on DRCys elimination, and Study RP103-16001 was designed to address these missing data.
Methods
Subjects (all without NC) with mild, moderate, or severe renal impairment, or ESRD requiring hemodialysis, (HD) (8 each; NKF classification based on eGFR) and 32 matched healthy controls were studied. HD subjects received a single 200 mg dose of DRCys twice: 3hr before or 2hr after HD on different days. All remaining subjects received one 200 mg DRCys dose. Blood was sampled for 24h after each dose to detemine cysteamine concentrations. Pharmacokinetic analysis was conducted using mixed-effects (population) methods with NONMEM software (ICON Development Solutions, Hanover MD).
Results
Table 1 reports drug clearance relative to healthy controls. For subjects with renal impairment except those on maintenance HD, the effect on DRCys clearance is small, within ±20% of the values in the controls. In HD subjects, clearance fluctuates between successive HD treatments, being maximal post HD and then decreasing.
Conclusion
Although increasing renal impairment is associated with a decrease in the apparent clearance of DRCys, the magnitude is relatively small, and unlikely to necessitate dose reduction However, the decrease in clearance between HD sessions may cause DRCys efficacy to vary over that time frame. Therefore, biomarker WBCCys results should be interpreted in the context of when patients had the WBCCys sampled relative to HD. Mechanisms for HD-associated clearance changes are unknown but may involve HD improving CYP function.
Factors for apparent clearance of DRCys related to residual renal function (eGFR) compared to healthy controls
| Degree of impairment | eGFR (ml/min/1.73m2) | Factor |
| Mild | >90 | 1.192 |
| Moderate | 60-89 | 0.849 |
| Severe | 30-69 | 0.801 |
| ESRD | Maintenance HD | |
| Concurrent HD | 0.602 | |
| Post-HD | 0.803 |
Funding
- Commercial Support –