Optimal use of amiodarone (AMD) requires information regarding the drug's pharmacokinetics and the influence of various factors on the drug's disposition. This study was conducted to establish the role of patient characteristic in estimating doses of AMD using nonlinear mixed effects modeling in Japanese patients treated with oral therapy.Methods:
Serum concentrations of AMD were determined by high-performance liquid chromatography. The 151 serum trough concentrations from 23 patients receiving repetitive oral AMD were collected. Analysis of the pharmacokinetics of AMD was accomplished using a 1-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on AMD disposition was investigated.Results:
Estimates generated by nonlinear mixed effects modeling indicated that the clearance of AMD was influenced by the demographic variables: total body weight (TBW), daily dosage of AMD (DD), body mass index (BMI), gender (GEN), duration of AMD dosing (DUR), and patient clearance factor (Concθ; Conc = serum trough concentration of AMD). The final pharmacokinetic parameters were CL/F (L/h) = 0.072·TBW·Conc−1.01·1.95DD≧200·0.931BMI≧25·1.37GEN·DUR−0.016, and Vd/F (L) = 78.4·TBW, where CL is total body clearance and Vd is volume of distribution. As all doses were given orally, it was impossible to assess the bioavailability (F). DD ≧200 is an indicator variable that has a value of 1 if the patient is receiving more than 200 mg daily dosage of AMD, and 0 otherwise. BMI ≧25 is an indicator variable that has a value of 1 if the BMI is 25 kg/m2 and over, and 0 otherwise. GEN is an indicator variable that has a value of 1 if the patient is woman, and 0 otherwise.Conclusions:
The authors developed new population pharmacokinetic parameters. Clinical application of the findings in the present study to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect.