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QUANTITATIVE CLINICAL PHARMACOLOGY

Population Pharmacokinetic and Pharmacodynamic Analysis of Pegloticase in Subjects With Hyperuricemia and Treatment-Failure Gout

Corinne Seng Yue, MSc, William Huang, PhD, Michelle Alton, BA, Allan N. Maroli, PhD, Royce W. Waltrip, MD, David Wright, PhD and Marika Di Marco, PhD

From the Université de Montréal, Montréal, Québec, Canada (Ms Seng Yue); Savient Pharmaceuticals Inc, East Brunswick, NJ (Dr Huang, Mrs Alton, Dr Maroli, Dr Waltrip, Dr Wright); and MDS Pharma Services, St-Laurent, Québec, Canada (Dr Di Marco).

Pegloticase is designed to convert urate into the easily excretable allantoin to treat hyperuricemia in gout. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of pegloticase in 40 gout patients. Pegloticase was administered as intravenous infusions every 2 weeks at 4- and 8-mg doses or every 4 weeks at 8- or 12-mg doses for 12 weeks. Serum pegloticase concentrations, plasma urate, and serum antibody response were determined. Population pharmacokinetics and pharmacodynamics analyses were performed. Data were modeled simultaneously, and covariates were investigated (age, gender, race, body weight, ideal body weight, and antibody response). The dosing regimens to maintain uric acid levels below the therapeutic target of 6 mg/dL were then predicted by the model. The pharmacokinetics were best described by a 1-compartment linear model, while the pharmacodynamics model was fitted as a direct effect of pegloticase on uric acid concentrations with a suppressive maximum effect attributed to drug (Emax) function. Pegloticase suppressed uric acid levels up to 83%. Weight only affected clearance and volume of distribution. No covariates affected pharmacodynamics. Simulation suggests pegloticase administered at 8 mg every 2 or 4 weeks as 2-hour intravenous infusions will maintain uric acid levels well under 6 mg/dL.

Key Words: Uricase • pharmacokinetics • pharmacodynamics • population modeling • uric acid • PEG

Address for reprints: Corinne Seng Yue, MSc, Université de Montréal, Faculté de pharmacie, Pavillon Jean Coutu, 2940 Chemin de la polytechnique, Montreal, Quebec, H3T 1J4 Canada; e-mail: corinne.seng.yue{at}umontreal.ca.


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