PHARMACOKINETICS AND PHARMACODYNAMICS OF ACETAZOLAMIDE IN PATIENTS WITH TRANSIENT INTRAOCULAR-PRESSURE ELEVATION

Objective: To characterize the pharmacokinetics and pharmacodynamics o f acetazolamide in patients with transient intraocular pressure (IOP) elevation and to provide individual patients with the optimal dosage r egimen for this drug. Methods: We studied 17 patients with transient I OP elevation, who were given 62.5-500 mg acetazolamide orally as singl e or repetitive doses. Plasma acetazolamide concentration and IOP were measured at approximately 1, 3, 5, and 9 h after the last acetazolami de administration. Pharmacokinetics and pharmacodynamics were analyzed by nonlinear mixed-effect modeling using the program NONMEM. Results: The plasma concentration profile of acetazolamide was characterized b y a one-compartment model with first-order absorption. The apparent or al clearance was related to the creatine clearance (CCR) which was est imated by the Cockcroft and Gault equation, as follows: 0.0468.CCR1.h( -1). The estimated apparent oral volume of distribution, first-order a bsorption rate constant, and absorption lag time were 0.231 1.kg(-1) 0 .821.h(-1), and 0.497 h, respectively. IOP after oral acetazolamide ad ministration was characterized by an E-max model. The maximal effect i n lowering the IOP (E-max) was 7.2 mmHg, and the concentration corresp onding to 50% of the maximal effect (EC50) was 1.64 mu g.ml(-1). As 70 % of E-max was achieved at a plasma concentration of 4 mu g.ml(-1), th is concentration was considered satisfactory for lowering IOP. The rec ommended dosage nias calculated so that the minimum plasma concentrati on at steady state exceeded this target concentration; 350 mg t.i.d., 135 mg t.i.d., 125 mg b.i.d., and 115 mg once daily for the patients w ith CCR values of 70, 50, 30, and 10 ml.min(-1) respectively. Conclusi on: Measuring plasma concentrations of acetazolamide and subsequent ph armacokinetic and pharmacodynamic analyses are useful for estimating i ts concentration-dependent effectiveness in lowering the IOP in indivi dual patients. The dosage regimen presented in this study is expected to improve the benefits of acetazolamide pharmacotherapy in most elder ly patients with transient rises in IOP following intraocular surgery.