Effect of obesity on serum amiodarone concentration in Japanese patients: population pharmacokinetic investigation by multiple trough screen analysis

Abstract

Population pharmacokinetic analysis confirms that obesity affects the pharmacokinetics of AMD.

Population Pharmacokinetic Investigation for Optimization of Amiodarone Therapy in Japanese Patients

“…The predictions of the serum AMD concentrations were made with the previous model of Fukuchi et al 16 Figure 1, where the data points of high concentration are underestimated. It was expected that the clearance varied with AMD concentration.…”

“…AMD has been reported to accumulate in most body tissues, particularly adipose tissue, and has an extremely long blood elimination half-life. 15 Previously, 16 the authors reported the influence of obesity on the pharmacokinetics of AMD with nonlinear mixed effect modeling (NONMEM) computer program 17 using the multiple-trough screen approach. [12][13][14] Thus, blood concentration of AMD would vary considerably among patients treated with the drug and the true extent of tissue accumulation of AMD was largely unanticipated.…”

Evaluation of factors affecting epidermal growth factor receptor tyrosine kinase inhibitor-induced hepatotoxicity in Japanese patients with non-small cell lung cancer: a two-center retrospective study

“…Oda et al also reported that BMI ≥ 25.0 was a risk factor for the occurrence of hepatotoxicity in patients with EGFR-mutated NSCLC undergoing gefitinib monotherapy [20], in accordance with the present results. In obese patients, it was commonly reported that the activity of CYP3A4 was decreased [29][30][31][32], although CYP2D6 and 1A2 were not affected [29,30], and that the clearance of CYP3A4 substrates fentanyl and amiodarone was decreased [33,34]. Since gefitinib is metabolized mainly by CYP3A4, and partially by CYP3A5, 2D6, 1A1, and 1A2 [35][36][37], reduced CYP3A4 activity in obese patients is expected to cause reduced clearance of gefitinib, which would lead to earlier occurrence of hepatotoxicity compared to patients with normal BMI.…”

The Link Between Atrial Fibrillation and Obesity

“…For example, it has been shown that clearance of amiodarone was significantly reduced in those with BMI >25 kg/m 2 . [16] Higher shock energy was needed for increased first-shock success when transthoracic direct current cardioversion was studied in overweight and obese individuals.…”