Abstract: SA-PO637
C-PAM, a Novel Serum Phosphate-Lowering Oral Drug with Dual Mode of Action, Prevents Serum Phosphate Rise After Drug Skip
Session Information
- Pharmacology
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Taupitz, Matthias, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Schnorr, Jörg, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Stolzenburg, Nicola, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Rausch, Franziska, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Ebert, Monika, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Wagner, Susanne E., Wagner MSL Management, Mahlow, Germany
Background
In ESRD patients, medications based on Pi-binders to control serum Pi require regular oral drug intake with each meal. Such a regimen is not conducive to adequate compliance, and occasional drug skipping is one reason why <20% of patients have serum Pi levels within the KDOQI® recommended target range. C-PAM is a novel compound consisting of iron oxide nanoparticles with a maghemite structure, mannitol, inulin, and Arabic gum. C-PAM showed superior Pi-binding in earlier analytical tests and better serum Pi-lowering in experimental in vivo studies, both compared to major approved drugs. The hypothesis for this experimental study was that, for C-PAM, a 1-day drug skip does not significantly increase serum Pi.
Methods
Healthy male Sprague-Dawley rats (CD Charles River) with an initial weight > 320 g were treated with drug co-feeding for 4 weeks (n=8 rats per group). Group A: C-PAM added to Altromin standard 1320 diet (0.47% digestable Pi) at 0.75 wt% total drug substance. Group B: Renvela® at 1.5 wt% total drug substance. Blood was sampled at the end of each week (W1 to W4) for analysis of serum Pi. During one day before W3 blood sampling, rats received the standard diet only. After W4 sampling, rats were sacrificed and the intestine was analyzed for NaPi2b expression using PCR. For statistical analysis student's t-test was used.
Results
Serum Pi was as follows [mmol/l]: C-PAM: BL 2.31±.21; W1 2.13±.21; W2 2.15±.27; W3 (after drug skip) 2.29±.20; W4 1.92±.20. Renvela®: BL 2.60±.25; W1 1.89±.24; W2 1.93±.44; W3 (after drug skip) 2.56±.27; W4 1.87±.13. After drug skip the rise was 7% (n.s.) and 33% (p<.01) resp. After drug skip the values were -10% and +1% resp. compared to age matched controls (n.s.). PCR analysis showed less expression of NaPi2b (ΔΔCt) in the proximal jejunum in the C-PAM group (3.08±.05) compared to the Renvela group (5.30±2.56, p<.05).
Conclusion
C-PAM effectively reduces serum Pi at a low dose and is robust against a 1-d drug skip, which is because of its dual mode of action combining highly effective Pi binding with an effect on NaPi2b transporters. If C-PAM is equally effective in the clinical setting, treatment of ESRD patients may be impoved by a significantly lower pill burden with better maintainance of serum Pi within the KDOQI® recommended target range.
Funding
- Government Support - Non-U.S.