Imipenem, Cilastatin and Relebactam

The bactericidal activity of imipenem results from the inhibition of penicillin binding proteins (PBPs) leading to inhibition of peptidoglycan cell wall synthesis.

Cilastatin limits the renal metabolism of imipenem and does not have antibacterial activity.

Relebactam is a non-beta lactam inhibitor of Ambler class A and class C beta-lactamases, including class A Klebsiella pneumoniae carbapenemase (KPC) and extended-spectrum beta-lactamases (ESBLs), and class C (AmpC-type) beta-lactamases including Pseudomonas-Derived Cephalosporinase (PDC). Relebactam does not inhibit class B enzymes (metallo-beta-lactamases) or class D carbapenemases. Relebactam has no antibacterial activity.

Resistance

Mechanisms of resistance in Gram-negative bacteria that are known to affect imipenem/relebactam include the production of metallo-beta-lactamases or oxacillinases with carbapenemase activity.

Expression of certain alleles of the class A beta-lactamase Guiana extended-spectrum beta-lactamase (GES) and overexpression of PDC coupled with loss of imipenem entry porin OprD may confer resistance to imipenem/relebactam in P. aeruginosa. The expression of efflux pumps in P. aeruginosa does not affect activity of either imipenem or relebactam. Mechanisms of bacterial resistance that could decrease the antibacterial activity of imipenem/relebactam in Enterobacterales include porin mutations affecting outer membrane permeability.

Antibacterial activity in combination with other antibacterial agents

In vitro studies have demonstrated no antagonism between imipenem/relebactam and amikacin, azithromycin, aztreonam, colistin, gentamicin, levofloxacin, linezolid, tigecycline, tobramycin, or vancomycin.

Susceptibility testing breakpoints

Minimum inhibitory concentration (MIC) breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) are as follows:

Pharmacokinetic/pharmacodynamic relationship

Time that unbound plasma concentrations of imipenem exceed the imipenem/relebactam minimum inhibitory concentration (% fT > MIC) has been shown to best correlate with efficacy. The ratio of the 24-hour unbound plasma relebactam AUC to imipenem/relebactam MIC (fAUC/MIC) has been determined to be the index that best predicts activity of relebactam.

General introduction

The steady-state pharmacokinetic parameters of imipenem, cilastatin, and relebactam in healthy adults with normal renal function (CrCl 90 mL/min or greater), after multiple 30-minute intravenous infusions of 500 mg imipenem/500 mg cilastatin + 250 mg relebactam administered every 6 hours are summarised in Table 1. The steady-state pharmacokinetic parameters of imipenem and relebactam in patients with cIAI or cUTI and HAP or VAP with normal renal function (90 mL/min≤ CrCl <150 mL/min) after multiple 30-minute intravenous infusions of 500 mg imipenem/500 mg cilastatin + 250 mg relebactam administered every 6 hours are summarised in Tables 2 and 3, respectively. Pharmacokinetic parameters were similar for single- and multiple-dose administration due to minimal accumulation.

The C_max and AUC of imipenem, cilastatin, and relebactam increase in proportion to dose. The elimination half-lives (t_½) of imipenem, cilastatin, and relebactam are independent of dose.

Table 1. Steady-state geometric mean (% geometric co-efficient of variation) plasma pharmacokinetic parameters of imipenem, cilastatin, and relebactam after multiple intravenous 30-minute infusions of 500 mg imipenem/500 mg cilastatin + 250 mg relebactam every 6 hours in healthy adults:

^* Arithmetic mean (standard deviation) reported for t_1/2
AUC_0–6hr = area under the concentration time curve from 0 to 6 hours; C_max = maximum concentration; CL = plasma clearance; t_1/2 = elimination half-life

Table 2. Population pharmacokinetic model based steady-state geometric mean (% geometric co-efficient of variation) plasma pharmacokinetic parameters of imipenem and relebactam after multiple intravenous 30-minute infusions of 500 mg imipenem/500 mg cilastatin/250 mg relebactam every 6 hours in cIAI or cUTI patients with CrCl 90 mL/min or greater:

^* Arithmetic mean (standard deviation) reported for t_1/2
AUC_0–24hr = area under the concentration time curve from 0 to 24 hours; C_max = maximum concentration; CL = plasma clearance; t_1/2 = elimination half-life

Table 3. Population pharmacokinetic model based steady-state geometric mean (% geometric co-efficient of variation) plasma pharmacokinetic parameters of imipenem and relebactam after multiple intravenous 30-minute infusions of 500 mg imipenem/500 mg cilastatin + 250 mg relebactam every 6 hours in HAP or VAP patients with CrCl 90 mL/min or greater:

AUC_0-24hr = area under the concentration time curve from 0 to 24 hours; C_max = 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 is independent of concentration.

The steady-state volume of distribution of imipenem, cilastatin, and relebactam is 24.3 L, 13.8 L, and 19.0 L, respectively, in subjects following multiple doses infused over 30 minutes every 6 hours.

The penetration into pulmonary epithelial lining fluid (ELF) expressed as the total ELF-to-unbound plasma exposure ratio was 55% and 54% for imipenem and relebactam, respectively.

Biotransformation

Imipenem, when administered alone, is metabolised in the kidneys by dehydropeptidase-I, resulting in low levels of imipenem (average of 15-20% of the dose) recovered in human urine. Cilastatin, an inhibitor of this enzyme, effectively prevents renal metabolism so that when imipenem and cilastatin are given concomitantly, adequate levels of imipenem (approximately 70% of the dose) are achieved in the urine to enable antibacterial activity.

Cilastatin is mainly eliminated in the urine as unchanged parent drug (approximately 70-80% of the dose), with 10% of the dose recovered as an N-acetyl metabolite, which has inhibitory activity against dehydropeptidase-I comparable to the parent medicinal product.

Relebactam is cleared primarily via renal excretion as unchanged parent drug (greater than 90% of the dose) and is minimally metabolised. Unchanged relebactam was the only drug-related component detected in human plasma.

Elimination

Imipenem, cilastatin, and relebactam are mainly excreted by the kidneys.

Following multiple-dose administration of 500 mg imipenem, 500 mg cilastatin, and 250 mg relebactam to healthy male subjects, approximately 63% of the administered imipenem dose, and 77% of the administered cilastatin dose are recovered as unchanged parent in the urine. The renal excretion of imipenem 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 mean renal clearance for relebactam is 135 mL/min, close to the plasma clearance (148 mL/min), indicating nearly complete elimination of relebactam by the renal route. The unbound renal clearance of relebactam is greater than the glomerular filtration rate, suggesting that in addition to glomerular filtration, active tubular secretion is involved in the renal elimination, accounting for ~30% of the total clearance.

Linearity/non-linearity

The pharmacokinetics of relebactam are linear across the 25 mg to 1150 mg dose range studied for a single intravenous administration, and 50 mg to 625 mg dose range studied for multiple intravenous administration every 6 hours up to 7 days. Minimal accumulation of imipenem, cilastatin or relebactam was observed following multiple 30-minute intravenous infusions of relebactam (50 to 625 mg) co-administered with 500 mg imipenem/500 mg cilastatin every 6 hours up to 7 days in healthy adult males with normal renal function.

Drug metabolizing enzymes

Studies evaluating the potential for imipenem or cilastatin to interact with CYP450 enzymes have not been conducted.

Relebactam at clinically relevant concentrations does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in vitro in human liver microsomes. Relebactam showed no potential for in vitro induction of CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes. Thus, relebactam is unlikely to cause clinical drug-drug interactions via CYP-mediated pathways.

Imipenem, cilastatin, and relebactam are all cleared primarily via renal excretion unchanged, with metabolism as a minor elimination route. Thus, imipenem/cilastatin/relebactam is unlikely to be subject to drug-drug interactions when co-administered with CYP inhibitors or inducers.

Membrane transporters

Relebactam does not inhibit the following hepatic and renal transporters in vitro at clinically relevant concentrations: OATP1B1, OATP1B3, OAT1, OAT3, OCT2, P-gp, BCRP, MATE1, MATE2K, or BSEP.

Relebactam is actively secreted into the urine. It is not a substrate of OAT1, OCT2, P-gp, BCRP, MRP2, or MRP4 transporters, but is a substrate of OAT3, OAT4, MATE1 and MATE2K transporters. The active tubular secretion accounts for only approximately 30% of the total clearance of relebactam, thus, the extent of drug-drug interaction due to inhibition of the tubular transporters is expected to be of minimal clinical significance, which was confirmed with a clinical drug-drug interaction study with probenecid and imipenem/cilastatin/relebactam.

Special populations

Renal impairment

In a clinical pharmacokinetic study and population pharmacokinetic analysis, clinically relevant differences in exposure (AUC) were observed for imipenem, cilastatin, and relebactam based on the extent of renal impairment. In the clinical study, imipenem geometric mean AUCs were up to 1.4-fold, 1.5-fold, and 2.5-fold higher in patients with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects with normal renal function. The respective cilastatin geometric mean AUCs were up to 1.6-fold, 1.9-fold, and 5.6-fold higher. Relebactam geometric mean AUCs were up to 1.6-fold, 2.2-fold, and 4.9-fold higher in patients with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects with normal renal function. In patients with End Stage Renal Disease (ESRD) on haemodialysis, imipenem, cilastatin, and relebactam are efficiently removed by haemodialysis.

To maintain systemic exposures similar to patients with normal renal function, dose adjustment is recommended for patients with renal impairment. ESRD patients on haemodialysis should receive imipenem/cilastatin/relebactam after haemodialysis session.

Hepatic impairment

Imipenem, cilastatin, and relebactam are primarily cleared renally; therefore, hepatic impairment is not likely to have any effect on imipenem/cilastatin/relebactam exposures.

Elderly/gender

In a geriatric/gender study and population pharmacokinetic analysis no clinically relevant differences in exposure (AUC) were observed for imipenem, cilastatin, and relebactam based on age or gender, apart from the effect of renal function.

Race

Only a limited number of non-white patients were included in the clinical studies, but no major effect of race on imipenem, cilastatin, and relebactam pharmacokinetics is expected.

Imipenem/cilastatin

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity studies. Animal studies showed that the toxicity produced by imipenem, as a single entity, was limited to the kidney. Co-administration of cilastatin with imipenem in a 1:1 ratio prevented the nephrotoxic effects of imipenem in rabbits and monkeys. Available evidence suggests that cilastatin prevents the nephrotoxicity by preventing entry of imipenem into the tubular cells.

A teratology study in pregnant cynomolgus monkeys given imipenem/cilastatin sodium at doses of 40/40 mg/kg/day (bolus intravenous injection) resulted in maternal toxicity including emesis, inappetence, body weight loss, diarrhoea, abortion, and death in some cases. When doses of imipenem/cilastatin sodium (approximately 100/100 mg/kg/day or approximately 3 times the recommended daily human intravenous dose) were administered to pregnant cynomolgus monkeys at an intravenous infusion rate which mimics human clinical use, there was minimal maternal intolerance (occasional emesis), no maternal deaths, no evidence of teratogenicity, but an increase in embryonic loss relative to control groups.

Long term studies in animals have not been performed to evaluate carcinogenic potential of imipenem/cilastatin.

Relebactam

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproduction toxicity, or genotoxicity. Carcinogenicity studies have not been conducted with relebactam.

Relebactam administered intravenously to lactating rats at a dose of 450 mg/kg/day (GD 6 to LD 14), was excreted into the milk with concentration of approximately 5 % that of maternal plasma concentrations.

Animal studies show that relebactam given as a single entity caused renal tubular degeneration in monkeys at AUC exposure 7-fold the human AUC exposure at the maximum recommended human dose (MRHD). Renal tubular degeneration was shown to be reversible after dose discontinuation. There was no evidence of nephrotoxicity at AUC exposures less than or equal to 3-fold the human AUC exposure at the MRHD.