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


CONCLUSIONS
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.
Clinical Pharmacology, Specialty Care Business Unit, Pfizer Inc, San Diego, CA, USA.
Anthony S
AS
Basile
Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA.
Matthew M
MM
Hutmacher
Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA.
Kenneth G
KG
Kowalski
Clinical Pharmacology, World Wide Biopharmaceuticals, Pfizer Inc, New York, NY, USA.
Kuan Y
KY
Gandelman
Clinical Pharmacology, Specialty Care Business Unit, Pfizer Inc, San Diego, CA, USA.
Dana J
DJ
Nickens
clearance; diabetic macular edema; pegaptanib; population pharmacokinetics; renal function