Masaru Samura1,2, Keisuke Takada2, Risako Yamamoto1, Hayato Ito1, Fumio Nagumo2, Masaki Uchida2, Takenori Kurata2, Sakura Koshioka2, Yuki Enoki3, Kazuaki Taguchi1, Ryuji Higashita4, Norifumi Kunika5, Koji Tanikawa2, Kazuaki Matsumoto1. 1. Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. 2. Department of Pharmacy, Yokohama General Hospital, 2201-5 Kuroganecho, Aoba-ku-shi, Yokohama, Kanagawa, 225-0025, Japan. 3. Division of Pharmacodynamics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. enoki-yk@pha.keio.ac.jp. 4. Wound care center, Yokohama General Hospital, 2201-5 Kuroganecho, Aoba-ku, Yokohama-shi, Kanagawa, 225-0025, Japan. 5. Internal Medicine, Yokohama General Hospital, 2201-5 Kuroganecho, Aoba-ku, Yokohama-shi, Kanagawa, 225-0025, Japan.
Abstract
PURPOSE: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose. METHODS: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration-time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated. RESULTS: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05-0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20-60 mL/min and aged 65-95 years were calculated as 200-500 mg q24h. CONCLUSION: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.
PURPOSE: This study evaluated the population pharmacokinetics of daptomycin in nonobese elderly patients with hypoalbuminemia and chronic kidney disease (CKD) using the glomerular filtration rate estimated from cystatin C (eGFRcys) and estimated its optimal dose. METHODS: We performed population pharmacokinetic analysis of the unbound concentrations of daptomycin. The probability of target attainment of 90% for achieving an area under the concentration-time curve of unbound daptomycin at steady state/ minimum inhibitory concentration ratio of ≥66.6 was stochastically simulated. RESULTS: In the population pharmacokinetic analysis of 25 patients aged ≥65 years, the two-compartment model using eGFRcys and age as covariates of clearance in central compartment of unbound daptomycin were optimal. The unbound fraction rate (fu) was 0.05-0.14. According to the Monte Carlo simulation, the optimal doses for patients with eGFRcys of 20-60 mL/min and aged 65-95 years were calculated as 200-500 mg q24h. CONCLUSION: These results suggest that establishing the dose using total concentrations may result in under- or overestimation caused by alterations in fu. The optimal dose for nonobese elderly patients with hypoalbuminemia and CKD depends on eGFRcys and age, and a standard dose may be insufficient for some patients.
Authors: Shu Jin Tan; Matthew Cockcroft; Sam Salman; Laurens Manning; Madhu Page-Sharp; Glenn Arendts; Timothy M E Davis; Brioni R Moore; Kevin T Batty Journal: Antimicrob Agents Chemother Date: 2020-09-21 Impact factor: 5.191