Population pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema

Population pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema

Anthony S Basile,1 Matthew M Hutmacher,2 Kenneth G Kowalski,2 Kuan Y Gandelman,3 Dana J Nickens1 1Clinical Pharmacology, Specialty Care Business Unit, Pfizer Inc, San Diego, CA, USA; 2Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA; 3Clinical Pharmacology, World Wide Biopharmaceuticals, Pfizer...

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Autores principales: Basile AS, Hutmacher MM, Kowalski KG, Gandelman KY, Nickens DJ
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2015
Materias:
Ophthalmology
RE1-994
Acceso en línea:https://doaj.org/article/c12c2369c69545bb9abac183533439d1
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spelling oai:doaj.org-article:c12c2369c69545bb9abac183533439d12021-12-02T07:47:15ZPopulation pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema1177-5483https://doaj.org/article/c12c2369c69545bb9abac183533439d12015-02-01T00:00:00Zhttp://www.dovepress.com/population-pharmacokinetics-of-pegaptanib-sodium-macugenreg-in-patient-peer-reviewed-article-OPTHhttps://doaj.org/toc/1177-5483 Anthony S Basile,1 Matthew M Hutmacher,2 Kenneth G Kowalski,2 Kuan Y Gandelman,3 Dana J Nickens1 1Clinical Pharmacology, Specialty Care Business Unit, Pfizer Inc, San Diego, CA, USA; 2Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA; 3Clinical Pharmacology, World Wide Biopharmaceuticals, Pfizer Inc, New York, NY, USA Objective: Population pharmacokinetic modeling of pegaptanib was undertaken to determine influence of renal function on apparent clearance. Methods: In a randomized, double-masked multicenter trial, intravitreal pegaptanib (0.3, 1.0, or 3.0 mg/eye) was administered in patients with diabetic macular edema every 6 weeks for 12–30 weeks. A one-compartment model with first-order absorption, distribution volume, and clearance was used to characterize the pegaptanib plasma concentration–time profile. Results: In 58 patients, increases in area under the concentration–time curve (AUC) to end of the dosing interval (AUC0–tau) and maximum concentration with repeat doses were <6%, indicating minimal plasma accumulation. Sex and race did not have clinically significant effects on pegaptanib exposure. In the final model, the AUC extrapolated to infinite time and maximum concentration increased by ≥50% in older patients (aged >68 years) relative to younger patients due to decreases in creatinine clearance (CRCL), a significant predictor of clearance. Pegaptanib clearance was reduced by 29% when CRCL decreased by 50%. The change in exposure with CRCL (range, 0–190 mL/minute) was < 10-fold with 0.3–3.0 mg doses. Conclusion: While pegaptanib clearance and AUC were significantly influenced by CRCL, the predicted exposure in patients with renal insufficiency or renal failure shows no evidence that a dose adjustment is warranted, given the tenfold margin of safety observed over the dose range of 0.3–3.0 mg. Keywords: clearance, diabetic macular edema, pegaptanib, population pharmacokinetics, renal function Basile ASHutmacher MMKowalski KGGandelman KYNickens DJDove Medical PressarticleOphthalmologyRE1-994ENClinical Ophthalmology, Vol 2015, Iss default, Pp 323-335 (2015)
institution DOAJ
collection DOAJ
language EN
topic Ophthalmology
RE1-994
spellingShingle Ophthalmology
RE1-994
Basile AS
Hutmacher MM
Kowalski KG
Gandelman KY
Nickens DJ
Population pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema
description Anthony S Basile,1 Matthew M Hutmacher,2 Kenneth G Kowalski,2 Kuan Y Gandelman,3 Dana J Nickens1 1Clinical Pharmacology, Specialty Care Business Unit, Pfizer Inc, San Diego, CA, USA; 2Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA; 3Clinical Pharmacology, World Wide Biopharmaceuticals, Pfizer Inc, New York, NY, USA Objective: Population pharmacokinetic modeling of pegaptanib was undertaken to determine influence of renal function on apparent clearance. Methods: In a randomized, double-masked multicenter trial, intravitreal pegaptanib (0.3, 1.0, or 3.0 mg/eye) was administered in patients with diabetic macular edema every 6 weeks for 12–30 weeks. A one-compartment model with first-order absorption, distribution volume, and clearance was used to characterize the pegaptanib plasma concentration–time profile. Results: In 58 patients, increases in area under the concentration–time curve (AUC) to end of the dosing interval (AUC0–tau) and maximum concentration with repeat doses were <6%, indicating minimal plasma accumulation. Sex and race did not have clinically significant effects on pegaptanib exposure. In the final model, the AUC extrapolated to infinite time and maximum concentration increased by ≥50% in older patients (aged >68 years) relative to younger patients due to decreases in creatinine clearance (CRCL), a significant predictor of clearance. Pegaptanib clearance was reduced by 29% when CRCL decreased by 50%. The change in exposure with CRCL (range, 0–190 mL/minute) was < 10-fold with 0.3–3.0 mg doses. Conclusion: While pegaptanib clearance and AUC were significantly influenced by CRCL, the predicted exposure in patients with renal insufficiency or renal failure shows no evidence that a dose adjustment is warranted, given the tenfold margin of safety observed over the dose range of 0.3–3.0 mg. Keywords: clearance, diabetic macular edema, pegaptanib, population pharmacokinetics, renal function 
format article
author Basile AS
Hutmacher MM
Kowalski KG
Gandelman KY
Nickens DJ
author_facet Basile AS
Hutmacher MM
Kowalski KG
Gandelman KY
Nickens DJ
author_sort Basile AS
title Population pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema
title_short Population pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema
title_full Population pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema
title_fullStr Population pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema
title_full_unstemmed Population pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema
title_sort population pharmacokinetics of pegaptanib sodium (macugen®) in patients with diabetic macular edema
publisher Dove Medical Press
publishDate 2015
url https://doaj.org/article/c12c2369c69545bb9abac183533439d1
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AT kowalskikg populationpharmacokineticsofpegaptanibsodiummacugenreginpatientswithdiabeticmacularedema
AT gandelmanky populationpharmacokineticsofpegaptanibsodiummacugenreginpatientswithdiabeticmacularedema
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