Target Mediated Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis
Open accessAbstract
The amyloid deposits that cause disease in systemic amyloidosis always contain the normal plasma protein, serum amyloid P (SAP) component. SAP is the target of a novel immunotherapy approach now being developed to eliminate amyloid deposits. The treatment is enabled by, and critically depends on, the use of the drug (R)‐1‐[6‐[(R)‐2‐carboxy‐pyrrolidin‐1‐yl]‐6‐oxo‐hexanoyl]pyrrolidine‐2‐carboxylic acid (CPHPC, GSK2315698, Ro 63‐8695), which depletes circulating SAP almost completely but leaves some SAP in amyloid deposits for specific recognition by subsequently administered therapeutic anti‐SAP antibodies. Herein, we report a mechanistic model that predicts, with clinically acceptable precision, the exposure‐response relationship for CPHPC, both in healthy individuals and in patients with systemic amyloidosis. The model covariates are gender, renal function, total amyloid load, and presence of hepatic amyloid, all of which are known at baseline. The model is being used to predict individualized dosing regimens in an ongoing, first‐in‐human study with anti‐SAP antibodies. CPT Pharmacometrics Syst. Pharmacol. (2015) 4, 116–126; doi:10.1002/psp4.15; published online on 4 February 2015.
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CPHPC efficiently reduces SAP concentration in serum (58.5% reduction) and bone marrow (95% reduction) in aged mice.
“Our data demonstrated that CPHPC (miridesap), developed by Pepys’ team at University College London90–92, efficiently reduces SAP concentration in serum (58.5% reduction) and bone marrow (95% reduction) in aged mice.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [92]
The citation is attached to the description of CPHPC as developed by Pepys’ team, not to the aged-mouse reductions, which the citing authors present as their own data. The Abstract identifies CPHPC as a SAP-depleting drug, and Methods > Previous studies to support model development and evaluation links earlier CPHPC studies to M.B. Pepys (page unavailable). Our copy does not establish that his team developed the drug at University College London. (LLM, conf=0.76)
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Cites
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Perl-speaks-NONMEM (PsN) - a Perl module for NONMEM related programming
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“Binding and elimination for SAP-CPHPC complex Although the complex of the pentameric SAP molecule with CPHPC comprises two SAP molecules crosslinked by five drug molecules when sufficient drug is available, very rapid clearance of circulating SAP starts when there is just one mole of drug available per mole of pentame…”
BackgroundMethodResultInfluentialPharmacologic target‐mediated drug disposition
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Antibodies to human serum amyloid P component eliminate visceral amyloid deposits
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“However, after treatment with CPHPC, immunoglobulin G anti-SAP antibodies can be safely administered and can then reach and bind to the amyloid deposits where they trigger very effective, clinically silent, complement dependent, macrophage-mediated clearance of the amyloid.(7) The potent depletion of plasma SAP by CPH…”
BackgroundApproximations of the Target-Mediated Drug Disposition Model and Identifiability of Model Parameters
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“The model-based simulations illustrated in Figure 5 clearly show the impact of the selected covariates on predicted plasma profiles of CPHPC and SAP.”
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“Other commonly used TMDD approximations were investigated(13) and gave similar fits but resulted in SAP synthesis and elimination parameters that were not consistent with the published values measured directly using radiolabeled SAP.(8) To the authors’ knowledge, this is the first instance of this approximation being…”
BackgroundResultInfluentialSerum amyloid P component in chronic renal failure and dialysis.
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“The parameter estimates related to the covariateparameter relationship are available in Table 2 and showed that the estimated gender effect reduction in SAP baseline (30% reduction) was in line with a study by Nelson et al.6 (which reported a 25% reduction).”
ResultInfluentialMolecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component
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Method
Flagged first, then by citations
7 of the 24 references couldn’t be matched to a known paper.
Research works printed but not linked: 4
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- Pepys MB Dyck RF de Beer FC Skinner M Cohen AS Binding of serum amyloid P-component (SAP) by amyloid fibrils Clin. Exp. Immunol 1979 38 284 293 118839 PMC1537850
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Cited by
Sorted by citations
Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component.
Richards, D. B., Cookson, L., Berges, A., Barton, S. V., Lane, T., Ritter, J., Fontana, M., Moon, J., Pinzani, M., Gillmore, J., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504942 · Cited by 342 · see citing works
Self-citationRichards, D. B., Cookson, L. M., Barton, S. V., Liefaard, L., Lane, T., Hutt, D. F., Ritter, J. M., Fontana, M., Moon, J. C., Gillmore, J. D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan3128 · Cited by 136 · see citing works
“The miridesap dose of 60 mg, three times a day, was adjusted for renal impairment, if necessary, to keep predicted exposure below preestablished protocoldefined safety limits (8).”
BackgroundMethodResultSelf-citationWechalekar, A., Antoni, G., Al-Azzam, W. A., Bergström, M., Biswas, S., Chen, C.-G., Cheriyan, J., Cleveland, M., Cookson, L., Galette, P., et al. (2022) · BMC Cardiovascular Disorders · doi:10.1186/s12872-021-02407-6 · Cited by 29 · see citing works
“This was then targetted by the anti-SAP monoclonal antibody (mAb) dezamizumab, which in mice, has been shown to lead to removal of amyloid through a macrophage giant cell response [11, 12].”
MethodSelf-citationSerum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis
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Models of cerebral amyloid angiopathy-related intracerebral hemorrhage
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“Thirteen of the fifteen subjects from Part A and eight newly enrolled subjects were included in Part B [16] to investigate the safety, tolerability and efficacy of up to three cycles of anti-SAP treatment.”
BackgroundInfluentialSelf-citationAmyloid Nephropathy: A Practical Diagnostic Approach and Review on Pathogenesis
Paueksakon, P. (2016) · doi:10.5772/64083 · Cited by 4
“A novel drug, R-1-[6-[R-2carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid is a competitive inhibitor of SAP binding to amyloid fibrils [59, 60].”
BackgroundRichards, D., Bamford, M., Liefaard, L., Haque, N., Lewis, G., Storey, J., Fernando, D., Kumar, S., Thompson, D., & Holmes, D. S. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14956 · Cited by 3
“Given the known pharmacology and favourable safety profile of miridesap (Sahota et al., 2015), the initial (single) doses to be tested in man were selected to give a robust PK assessment.”
BackgroundInfluentialSelf-citationIno, H., Doi, Y., Liefaard, L., Cookson, L., Chen, C., Itoh, H., Igarashi, H., & Nakano, A. (2018) · Clinical pharmacology in drug development · doi:10.1002/cpdd.631 · Cited by 2
Self-citationGaczkowska, A. D., Jagodziński, P. P., & Mostowska, A. (2016) · Journal of Medical Science · doi:10.20883/jms.2016.101 · Cited by 1 · see citing works
- Authors
- Sahota, T., Berges, A., Barton, S., Cookson, L., Zamuner, S., & Richards, D.
- Affiliations
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Sahota, T
- Venue
- CPT: Pharmacometrics & Systems Pharmacology
- Publisher
- Wiley
- Published
- 2015-02
- Volume
- 4
- Issue
- 2
- Pages
- 116-126
- ISSN
- 2163-8306 (ISSN-L)
- PMC
- PMC4360666
- OpenAlex
- W1515410031
- Cited by
- 19
- References
- 24
- Citations by year
- 2025: 1 · 2022: 11 · 2021: 1 · 2019: 1 · 2018: 2 · 2016: 2 · 2015: 1
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- CPT Pharmacometrics & Systems Pharmacology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- GlaxoSmithKline
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- systemic amyloidosis, serum amyloid P component, target-mediated drug disposition, exposure-response relationship, immunotherapy, renal function, individualized dosing, amyloid load
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