nd in vitro models of infection. For relebactam theratio of the 24-hour unbound plasma relebactam AUC to imipenem/relebactam MIC (fAUC 0 – 24 hr/MIC)best predicts the activity of relebactam in animal and in vitro models of infection.
Cardiac ElectrophysiologyAt a dose 4.6 times the recommended dose, relebactam does not prolong the QTc interval to a clinicallyrelevant extent.
12.3 Pharmacokinetics
The steady-state pharmacokinetic parameters of imipenem, cilastatin, and relebactam in patients withactive bacterial infection with CLcr 90 mL/min or greater following administration of the recommended dosage are summarized in Table 4. Pharmacokinetic parameters were similar for single- andmultiple-dose administration due to minimal accumulation.
Table 4: Population Pharmacokinetic Model Based Steady State Mean (±SD) PlasmaPharmacokinetic Parameters of Imipenem 500 mg/Cilastatin 500 mg plus Relebactam 250 mg AfterMultiple Intravenous Infusions Every 6 Hours in Patients with CLcr 90 mL/min or GreaterImipenem Relebactam
AUC0-24hr (µM-hr) 573.9 (321.2) 427.3 (190.3)
Cmax (µM) 104.3 (61.4) 64.0 (27.3)
CL (L/hr) 15.3 (8.3) 8.0 (3.6)
AUC0-24hr=area under the concentration time curve from 0 to 24 hours
Cmax=maximum concentration
CL=plasma clearance
Distribution
The binding of imipenem and cilastatin to human plasma proteins is approximately 20 % and 40 %,respectively. The binding of relebactam to human plasma proteins is approximately 22 % and isindependent of concentration at a range of 5 to 50 µM.
The steady-state volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and19.0 L, respectively, in subjects following multiple doses infused over 30 minutes every 6 hours.
Elimination
Imipenem and relebactam are eliminated from the body by the kidneys with a mean (± SD) half-life of 1(± 0.5) hour and 1.2 (± 0.7) hours, respectively.
Metabolism
Imipenem, when administered alone, is metabolized in the kidneys by dehydropeptidase, resulting in lowlevels of imipenem recovered in human urine. Cilastatin, an inhibitor of this enzyme, effectively preventsrenal metabolism so that when imipenem and cilastatin are given concomitantly, adequate concentrations
of imipenem are achieved in the urine to enable antibacterial activity.
Relebactam is minimally metabolized. Unchanged relebactam was the only drug-related componentdetected in human plasma.
Excretion
Imipenem, cilastatin, and relebactam are mainly excreted by the kidneys.
Following multiple-dose administration of imipenem 500 mg, cilastatin 500 mg, and relebactam 250 mg tohealthy male subjects, approximately 63 % of the administered imipenem dose, and 77 % of theadministered cilastatin dose are recovered as unchanged parent drugs in the urine. The renal excretion ofimipenem and cilastatin involves both glomerular filtration and active tubular secretion. Greater than 90 %of the administered relebactam dose was excreted unchanged in human urine. The unbound renal
clearance of relebactam is greater than the glomerular filtration rate, suggesting that in addition toglomerular filtration, active tubular secretion is involved in the renal elimination, accounting for ~ 30 % ofthe total clearance.
Specific Populations
No clinically significant differences in the pharmacokinetics of imipenem, cilastatin, or relebactam wereobserved based on age, gender, or race/ethnic |
