Jannik Vollmer (1), Juan Quevedo (2), Nathalie Dunkel (2), Anne Santerre Henriksen (3), Matthias Machacek (1)
(1) LYO-X AG, Basel, Switzerland (2) Advanz Pharma UK, London, United Kingdom (3) Maxel Consulting, Jyllinge, Denmark
Introduction: Cefepime (FEP)-enmetazobactam (ENM) is a new fixed dose combination treatment for the treatment of urinary tract infections (cUTI) (and nosocomial pneumonia) in adults which gained recent a positive opinion in the EU and approval in the US. FEP is a cephalosporin which exerts bactericidal activity by inhibiting peptidoglycan cell wall synthesis. The most frequent mechanism of resistance in Enterobacterales is the expression of Class A extended-spectrum β-lactamases. ENM binds to β-lactamases and prevents the hydrolysis of FEP. FEP-ENM showed broad-spectrum activity against multidrug-resistant Enterobacterales and has demonstrated superiority to piperacillin/tazobactam for the treatment of cUTI [1].
Objectives: The objective of this study was to characterize the ENM and FEP population pharmacokinetics (PK) from the combined phase I, II and III trials, including the intra-patient correlation of ENM and FEP PK parameters.
Methods: Plasma PK samples were available from a total of 663 subjects in three phase 1 (n=132), one phase 2 (n=43) and one phase 3 (n=488) clinical trials. The population included healthy volunteers, subjects with renal impairment and patients with cUTI.
A compartmental population PK modelling approach was used to characterize the FEP and ENM PK. For model development, a stepwise model building was employed. First, the PK for each analyte was characterized separately. This included the structural, covariate and error model. In a final step, a combined FEP/ENM population PK model was developed. In the combined population PK model, the covariance of FEP and ENM random effects of central volumes of distribution and clearances were assessed. In order to obtain an accurate estimation of the between subject variability in the cUTI patient population separate inter-individual variabilities for healthy and cUTI patients were estimated.
Results: The PK of both compounds was best described using two-compartmental models with linear clearance from the central compartment (V1). Statistically significant covariates for both, FEP and ENM, were de-indexed eGFR on Cl, age on V1, and body weight (BW) on V1 and V2. ENM PK covariates additionally included eGFR and sex on V2, and cUTI infection on V1.
The central volume of distribution of patients with cUTI was 11.4 L for FEP and 13.4 L for ENM. Clearances were estimated to 5.95 L/h for FEP and 7.68 L/h for ENM. Both clearances were found to depend on de-indexed eGFR with covariate coefficients (β) close to 1 (βENM = 0.898 and βFEP = 0.84), suggesting that renal filtration is the predominant clearance mechanism. The terminal elimination half-life in infected patients was 2.2 hours for FEP and 2.0 hours for ENM.
Strong correlations between the FEP and ENM clearances (r = 0.934) and between the FEP and ENM central volume of distribution (r = 0.963) were identified. PK in infected subjects was found to be more variable as characterized by a higher inter-individual variability on the V1 and the clearance of FEP and ENM in infected subjects versus non-infected subjects.
Conclusions: A combined population PK model was developed for FEP and ENM. The same dosing frequency for both compounds is justified based on the highly similar PK as shown by the comparable PK parameter estimates and the high inter-compound correlations of the random effects. During the development BW-allometry on different parameters was tested. A purely data-driven approach identified BW as a covariate on V1 only. This was likely due to the sparse sampling the phase 3 study which did not allow to robustly estimate parameters describing the distribution into the peripheral compartment. The final model included BW as a covariate on central and peripheral compartments assuming equal allometric parameters on V1 and V2. The final model was judged to be adequate for Monte-Carlo-Simulations (MCSs) for dose selection to achieve the desired probability of target attainment (PTA) and test if any dose adjustments are required for the identified covariates to maintain the PTA.
References:
[1] Kaye KS, Belley A, Barth P, Lahlou O, Knechtle P, Motta P, Velicitat P. Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial. JAMA. 2022 Oct 4;328(13):1304-1314. doi: 10.1001/jama.2022.17034. PMID: 36194218; PMCID: PMC9533186.
Reference: PAGE 32 (2024) Abstr 10971 [www.page-meeting.org/?abstract=10971]
Poster: Drug/Disease Modelling - Infection