PK/PD analysis of biapenem in patients undergoing continuous hemodiafiltration

Abstract

BackgroundContinuous hemodiafiltration (CHDF) is used as renal replacement therapy for critically ill patients with renal failure, and to treat hypercytokinemia. Since CHDF also clears therapeutic agents, drug pharmacokinetics (PK) should be dependent upon CHDF conditions. Although the antibiotic biapenem (BIPM) is used in patients undergoing CHDF, the optimal therapeutic regimen in such patients has not been fully clarified. In this study, we investigated the PK of BIPM in patients with various levels of renal function undergoing CHDF with polysulfone (PS) membrane, and used PK models to identify the optimal administration regimen.MethodsBIPM (300 mg) was administered by infusion in patients undergoing CHDF (n = 7). Blood and filtrate-dialysate were collected for compartment and non-compartment analysis.ResultsThe sieving coefficient of PS membrane was 1.00 ± 0.06 (mean ± S.D., n = 7), and CHDF clearance of BIPM was found to be the sum of the dialysate flow rate (QD) and filtrate flow rate (QF). Non-CHDF clearance showed inter-individual variability (4.82 ± 2.48 L/h), depending on residual renal function and non-renal clearance. Based on the average PK parameters obtained with a compartmental model, maximal kill end point (over 40 % T > MIC4 μg/mL) was achieved with regimens of 300 mg every 6 h, 300 mg every 8 h, and 600 mg every 12 h. Monte Carlo simulation indicated that 300 mg infusion for 1 h every 6 h was optimal, and the probability of target attainment at MIC2 μg/mL was 90.2 %.ConclusionsOur results establish the optimal regimen of BIPM in patients with various levels of renal function undergoing CHDF with a PS membrane.

Recommendation of Antimicrobial Dosing Optimization During Continuous Renal Replacement Therapy

“…Flucloxacillin Ultrafiltration rate: 57 ± 9 ml/min 4.0 g q8h (Meyer et al, 2003) --1 g q8h 1h infusion (Onichimowski et al, 2020b) Dialysate rate: 20-35 ml/kg/h 2 g q12 h; or Loading dose:1 g, Maintenance dose:500 mg q8 h; or Loading dose:1 g LD, Maintenance dose:1 g q12 h (Shaw and Mueller, 2017) Dialysate rate:35 ml/kg/h 1 g q8h 1h infusion (Onichimowski et al, 2020b) Dialysate rate: 0.7-1 L/h 0.25 q24h for MIC ≤2 mg/L >0.5 g q8h for MIC = 16 mg/L (Kawano et al, 2015) Dialysate rate: 30 ml/kg/h 1 g q8h or 2 g q8h or 3 g continuous infusion q24h (Grensemann et al, 2020) Ultrafiltration rate: 22 ± 12 ml/kg/h Dialysate rate: 23 ± 9 ml/kg/h 1 g q12h (MIC ≤1 mg/L) (Seyler et al, 2011) Ultrafiltration rate: 2 L/h Dialysate rate: 1 L/h 500 mg q8h (MIC ≤4mg/L) (Varghese et al, 2015) Ultrafiltration rate: 1.5-2 L/h Dialysate rate: 1-1.5 L/h 1 g q8h Imipenem Ultrafiltration rate: 52 ± 14 ml/kg/h 1.0 g q6h Ultrafiltration rate: 20 or 37 ml/kg/h 0.5 g q6h for MIC ≤2 mg/L, 1.0 g q6h for MIC 4-16 mg/L (Li and Xie, 2019) Dialysate rate: 20 or 37 ml/kg/h 0.5 g q6h for MIC ≤2 mg/L, 1.0 g q6h for MIC 4-16 mg/L (Li and Xie, 2019) Combined flow rate: 20 or 37 ml/kg/h 0.5 g q6h for MIC ≤2 mg/L, 1.0 g q6h for MIC 4-16 mg/L (Li and Xie, 2019) Panipenan CLtot (ml/min) = (1.2 creatinine clearance + 66.5) +0.86 (dialysate rate+ ultrafiltration rate) CLtot <80 ml/min, 0.5 q12h or 1.0 g q15h; 80 ≤ CLtot ≤120 ml/min, 0.5 q8h or1.0 g q12h; 120 ≤ CLtot ≤160 ml/min, 0.5 g q6h or1.0 g q8h (Hayakawa et al, 2006) Biapenan --Ultrafiltration rate: 1,000 ml/h Dialysate rate: 500 ml/h 300 mg q6h (Akashita et al, 2015) (Continued) (Eyler et al, 2014) Combined flow rate: 36-51 ml/h/kg 500 mg q24h, 750 mg q24h, 500 mg q12h, or 1,000 mg q24h (Eyler et al, 2014)…”

“…Early study showed that the minimum dosages to achieve T > MIC of more than 30% at filtrate-dialysate flow rates of 1.4, 2.8, and 5.6 L/h were 300 mg q12 h, 600 mg q12 h, and 600 mg q12 h, respectively (Ikawa et al, 2008). Biapenem 300 mg q6h might be an appropriate dose under continuous hemodiafiltration (ultrafiltration rate: 1,000 ml/h, dialysate rate: 500 ml/h) (Akashita et al, 2015). Both MICs of pathogens and CRRT effluent flow rates should be considered during biapenem dosing adjustment.…”

Case report: therapeutic monitoring of vancomycin in an acute liver failure patient with anuria under high-flow continuous hemodiafiltration

“…Clearance never exceeds the liquid inflow rate to dialyzer (Q B in ) or the dialysis outflow rate (Q HDF = Q F + Q D ), and the slower flow is rate-determining in blood purification therapy [ 4 , 15 – 17 ]. If Q B in < Q D + Q F and assuming complete removal of the drug from the blood, the maximum clearance is defined by Q B in .…”

Biapenem: Clinical and Microbiological Characteristics and the Place of The New Carbapenem In The Treatment of Severe Infections In The Hospital. Clinical Pharmacologists' Point of View

“…Биапенем эффективно удаляется из плазмы во время проведения заместительной почечной терапии (ЗПТ) при сепсисе -продлённой веновенозной гемофильтрации и вено-венозной гемодиафильтрации (ВВГДФ) [43][44][45][46]. Во время проведения ВВГДФ период полувыведения из плазмы крови и фильтрата-диализата составил 3,0 и 3,2 ч, Клиренс ВВГДФ был 1,53 л/ч, а клиренс, не связанный с ВВГДФ -4,9 л/ч.…”

“…Во время проведения ВВГДФ период полувыведения из плазмы крови и фильтрата-диализата составил 3,0 и 3,2 ч, Клиренс ВВГДФ был 1,53 л/ч, а клиренс, не связанный с ВВГДФ -4,9 л/ч. На основании фармакодинамического моделирования 90% вероятность достижения фармакодинамической цели (40% T > MIC 2 мг/л ) достигалась при назначении биапенема в дозе 300 мг каждые 6 ч при проведении ЗПТ [43]. В другой работе [44] клиренс биапенема, связанный с ВВГВФ, был 1,3 л/м, а клиренс, не связанный с ВВГДФ -6,1 л/ч.…”