Population pharmacokinetic and pharmacodynamic modeling of acetazolamide in peritoneal dialysis patients and healthy volunteers.

PURPOSE: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of acetazolamide (ACTZ) in peritoneal dialysis patients, ACTZ 500 mg was administered intravenously to 7 healthy subjects (HV) and 8 peritoneal dialysis patients (CAPD). METHODS: Population PK/PD modeling was performed with ACTZ serum (total and unbound), urine and dialysate concentrations, intra-ocular pressure (IOP) and covariates. A multi-compartment PK model (accounting for non-linear protein binding) and an inhibitory Emax (maximal change in IOP) PD model were selected. RESULTS: As expected, renal clearance (which almost equals total body clearance) was severely decreased in CAPD (1.2 vs 80.3 L/h) and the elimination half-life of total ACTZ was prolonged (20.6 vs 3.4 hours). The protein binding was significantly altered with a mean free fraction 4.2% in HV and 8.6% in CAPD. Moreover protein binding of ACTZ was concentration dependent in both HV and CAPD. Despite a higher free fraction of ACTZ, the Emax was lower in CAPD: 4.4±1.4 vs 7.4±2.8 mmHg. CONCLUSION: Both PK and PD are significantly altered in dialysis patients.