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TRADITIONAL AND POPULATION PHARMACOKINETICS OF ABETIMUS SODIUM IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS WITH A HISTORY OF RENAL DISEASE
M. D. Linnik*1, T. Joh2, A. M. O'Rourke1
1Research and Development, 2Biostatistics, La Jolla Pharmaceutical Company, San Diego, United States
Background / Purpose: AAbetimus sodium (Riquent®) is an oligonucleotide-based investigational drug designed to treat patients with lupus nephritis by specifically reducing anti-dsDNA antibody levels.
Objectives: One trial evaluated traditional PK after single- and repeat-dose of abetimus in SLE patients. A second trial characterized the potential effect of several baseline variables on exposure to abetimus in SLE patients using a population PK based approach.
Methods: For assessment of traditional PK, one group of 8 patients received weekly i.v. 100 mg doses of abetimus for 11 weeks. Blood samples were drawn for concentration determination following the week 1 and week 8 doses. A second group of 8 patients received single doses of 25 mg (week 1), 200 mg (week 2) and then weekly 100 mg doses (weeks 3 through 10) with blood samples drawn following doses 1-3 and dose 8. For the population PK analysis, 202 SLE patients were administered i.v. weekly 100 mg abetimus for up to 25 weeks. Up to 3 plasma samples were collected on weeks 1, 9 and 17 for concentration determination. Nonlinear mixed-effects modeling was used to develop a population PK model with covariates including age, weight, height, BSA, BMI, race, gender, estimated creatinine clearance, SGPT and SGOT. Individual PK parameters were calculated by the posterior conditional estimation technique of NONMEM.
Results: In both trials abetimus was well tolerated. Non-compartmental analysis of the traditional PK data revealed a predictable and reproducible exposure pattern. There was no evidence of exposure-dependent effect as mean t1/2 of 1.1 hours was identical after administration of the 1st and 8th doses of 100 mg. Cmax and AUC values were 30 μg/ml and 22 μg*h/ml, respectively. Exposure to abetimus as assessed by Cmax and AUC was dose-linear, and the mean half-life ranged from 0.8 to 1.1 hours for the dose range between 25 to 200 mg. In the population PK analysis, the best model was a two-compartmental model in which inter-compartmental clearance was affected by sex, a finding that was considered likely artifactual as the patient population was predominantly female. The population PK model estimated t1/2 of 0.9 h, AUC of 33 μg*h/ml, CL of 3.2 L/h and Vss of 4 L. The PK of abetimus was not affected by any other baseline parameters.
Conclusions: The traditional abetimus PK in SLE patients was dose-linear and unaffected by repeat administration. The parameter estimates from population PK model were in agreement with the traditional PK estimates. The population PK model showed inter-compartment clearance was affected by gender, but the effect is unlikely to be of clinical significance. The PK of abetimus was not affected by age, race, body size, renal or hepatic function.
American Society of Nephrology
Saturday, November 3, 2007 10:00 AM
Poster Session: Outcomes and Treatments in the Glomerular Diseases (10:00 AM-12:00 PM)
Poster Board Number: SA-PO1019
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