(T-123) Monte-Carlo simulations to assess the probability of target attainment for cefepime and enmetazobactam in patients with complicated urinary tract infections

Juan Quevedo, - – Global Medical Advisor, Advanz Pharma UK, London, United Kingdom; Nathalie Dunkel, - – Director Global Clinical Development, Advanz Pharma UK, London, United Kingdom; Anne Santerre Henriksen, PhD – Managing Partner, Maxel Consulting, Jyllinge, Denmark; Matthias Machacek, Dr. – Managing Director, LYO-X AG, Basel, Switzerland

Objectives: Cefepime (FEP)-enmetazobactam (META) is a new fixed dose combination treatment approved by the FDA for the treatment of complicated urinary tract infections (cUTI) in adults. The pharmacokinetics (PK) of META and FEP have been characterized using a compartmental population PK modelling approach using the combined phase I, II and III data. The objective of this study was to assess the clinical relevance of the PK covariates to support the dose selection and to assess whether dose adjustments are required.

Methods: Clinical relevance of the PK covariates was assessed by testing their effect on exposure (C_max and AUC_0-24h) and on the probability of target attainment (PTA). For each covariate group, 4’000 subjects were generated for Monte-Carlo simulations (MCS). Random sampling was done from the joint individual FEP and META PK parameter distributions. This method considered that in the same subject the distribution and elimination of FEP and META were correlated and was therefore more likely to provide realistic MCS results. The joint FEP-META PTA, which is the fraction of subjects who simultaneously attained the PK/PD target for both FEP and META was computed from the MCS. The PK/PD targets were 60 or 68% fT >MIC for FEP and 45% fT >C_T=2mg/L for META.



Results: Renal clearance, as quantified by estimated glomerular filtration rate (eGFR), was the only covariate with a clinically significant effect on PTA. The proposed dosing for patients with cUTI with an eGFR of 60 to 149 mL/min in the EU and 60 to 129 mL/min in the US is 2 grams of FEP and 0.5 grams of META given every 8 hours as a 2-hour IV infusion. For patients with augmented renal clearance (ARC, eGFR ≥130 mL/min in the US, ≥150 mL/min in the EU), the infusion time is increased to 4 hours. For patients with an eGFR of < 60 mL/min, the dose is reduced. Additionally, for patients with severe renal impairment (eGFR 15 – 29 mL/min) and end stage renal disease (eGFR < 15 mL/min), the dosing interval is reduced. Simulations confirmed that this dosage achieved adequate PTAs while maintaining the exposure within the range confirmed to be safe in the phase 3 trial.

Conclusions: Renal clearance was found to be the only covariate requiring dose adjustments. The proposed dosing for FEP/META based on renal function ensures an adequate exposure that is safe as well as effective in patients with normal renal function, as well as in patients with increased or decreased renal function. Using a population PK model that simultaneously described the META and FEP PK and included the intra-patient correlation of PK parameters allowed to robustly estimate the PTAs without the need for approximate methods.

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