C Fornari (1), E Borella (1), C Piana (1), B Pizà -Vallespir (1), A Nuti (1), A Tuccio (1), K Fusaro (2), P Mazzei (1), A Capriati (1), and A Pellacani (1)
(1) Menarini Ricerche SpA, Italy, (2) Melinta Therapeutics, US
Objectives: Vaborem [1] (Vabomere in the US [2]) is a fixed combination of the carbapenem antibiotic meropenem with the beta-lactamase inhibitor vaborbactam. Vaborem was developed to treat serious Gram-negative infections, including those caused by bacteria resistant to currently available carbapenems. It is approved by EMA to treat adult patients with complicated urinary tract infection (cUTI) and other complicated infections, at a dose up to meropenem 2000 mg – vaborbactam 2000 mg every 8 hours (q8h), with each dose given over 3 hour infusion. The product is also approved (with the same regimen) by the FDA, for adult patients with cUTI. Vaborem PK is currently under investigation in the paediatric population in the TANGOKIDS study [3], in patients aged from birth to <18 years and with known/suspected bacterial infections, for which are receiving antibiotic treatment, or who are receiving peri-operative prophylactic antibiotics. Under the assumptions of (i) a similar disease and disease progression, (ii) a similar response to treatment, and (iii) a similar PK-PD relationship between adults and children, children are expected to respond similarly to adults when the same exposure levels are achieved [4,5,6]. The objective of this analysis was to identify the most appropriate Vaborem dosing regimen for each paediatric age group. To this aim, the percentage of time during the dosing interval for which its free drug plasma concentration exceeds the minimum inhibitory concentration, which is the PKPD index that best correlates with meropenem efficacy, together with the probability of target attainment (PTA) were evaluated in each paediatric age group.
Methods: A model-based approach centered on PK bridging and extrapolation principles [7,8] was applied to develop two popPK models for meropenem and vaborbactam using data of children aged from 3 months to <18 years (available from TANGOKIDS study). To support model development, extensive PK data in adults from previous studies [9,10] were leveraged together with available meropenem data in neonates from the literature [11,12]. Body weight (BW) and creatinine clearance (CLcr, mL/min/1.73) were introduced as covariates according to allometric scaling principles [13], to capture the effect of weight and age-dependent changes in the disposition of meropenem and vaborbactam in children. Prior distributions derived from the adult population were applied to inform the estimation of PK parameters in children [7,8], to address identifiability issues due to sparse PK sampling in TANGOKIDS study. A range of potential regimens was evaluated that could result in exposures within the adult therapeutic window. Simulations with the final models were used to assess the PTA of these regimens and confirm the paediatric dose rationale.
Results: Bridging PK from adults to children based on allometric principles allowed the characterization of Vaborem disposition in paediatric patients of TANGOKIDS study. The final popPK models consisted in two-compartment models with a zero-order intravenous infusion, first-order elimination, and a proportional error term. BW and CLcr well described the changes in systemic exposure due to developmental processes. Model-based simulations of Vaborem concentration vs. time profiles in a virtual population of approximately 15000 paediatric patients from birth (including pre-terms) to <18 years were used to identify the most optimized dosing regimen for each paediatric age group that would ensure the appropriate exposure and TA for the treatment of infections caused by Enterobacterales, KPC-producing Enterobacterales, and P. aeruginosa. The following age-and-weight-based paediatric dosing regimens are proposed: (i) 2000/2000 mg q8h infused over 180 minutes for children weighing >50 kg (adult dose), (ii) 40 mg/kg q8h infused over 210 minutes for children aged >3 months and weighing <50 kg, (iii) 30 mg/kg q8h infused over 210 minutes, for infants older than 14 days, and (iv) 20 mg/kg q8h infused over 210 minutes, for infants younger than 14 days. These results provided a preliminary evaluation of Vaborem exposure in children younger than 3 months, waiting for data in neonates to be generated in TANGOKIDS study.
Conclusions: A model-based analysis was implemented to identify Vaborem dosing regimens to be administerd in paediatric patients, from neonates to adolescents, for the treatment of infections caused by Enterobacterales, KPC-producing Enterobacterales, and P. aeruginosa, in children.
References:
[1] Vaborem product infomation: https://www.ema.europa.eu/en/documents/product-information/Vaborem-epar-product-information_en.pdf
[2] Vabomere U.S. Prescribing Information.
[3] NCT02687906 Dose-finding, Pharmacokinetics, and Safety of VABOMERE in Pediatric Subjects With Bacterial Infections (TANGOKIDS). https://clinicaltrials.gov/ct2/show/NCT02687906
[4] European Medicines Agency, “European Medicines Agency, Reflection paper on the use of extrapolate on in the development of medicines for paediatrics. EMA/189724/2018.”
[5] E. M. Agency, “European Medicines agency, Ich Topic E11: clinical Investigation of Medicinal Products in the Paediatric Population. cPMP/Ich/2711/99, 2001.”
[6] E. M. Agency, “European Medicines Agency; Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections to address paediatric specific clinical data requirements, Committee for Human Medicinal Products (CHMP); EMA/CHMP.” 2018.
[7] M. Cella, F. G. De Vries, D. Burger, M. Danhof, and O. Della Pasqua, “A model-based approach to dose selection in early pediatric development,” Clin. Pharmacol. Ther., vol. 87, no. 3, pp. 294–302, 2010
[8] S. D’Agate, F. T. Musuamba, and O. Della Pasqua, “Dose Rationale for Amoxicillin in Neonatal Sepsis When Referral Is Not Possible,” Front. Pharmacol., vol. 11, no. September, pp. 1–14, 2020, doi: 10.3389/fphar.2020.521933
[9] D.C. Griffith, M. Sabet, Z. Tarazi, O. Lomovskaya, M.N. Dudley, “Pharmacokinetics/pharmacodynamics of vaborbactam, a novel beta-lactamase inhibitor, in combination with meropenem,” Antimicrob. Agents Chemother. vol. 63, no. 1, pp. 01659-18, 2019
[10] C.M. Rubino, S.M. Bhavnani, J.S. Loutit, E.E. Morgan, D. White, M.N. Dudley, D.C. Griffith, “Phase 1 study of the safety, tolerability, and pharmacokinetics of vaborbactam and meropenem alone and in combination following single and multiple doses in healthy adult subjects,” Antimicrob Agents Chemother vol. 62, no. 62, pp. e02228-17, 2018
[11] B. Smith and et al, “Population Pharmacokinetics of Meropenem in Plasma and Cerebrospinal Fluid of Infants with Suspected or Complicated Intra-Abdominal Infections,” Pediatr Infect Dis, vol. 30, no. 10, pp. 844–849, 2011, doi: 10.1097/INF.0b013e31822e8b0b
[12] FDA, “NIH National Institute of Child Health and Human Development (A0009) – Clinical Study Report – FDA-2011-N-0918-0006.” 2012
[13] B. J. Anderson and N. H. G. Holford, “Mechanistic basis of using body size and maturation to predict clearance in humans,” Drug Metab. Pharmacokinet., vol. 24, no. 1, pp. 25–36, 2009
Reference: PAGE 29 (2021) Abstr 9658 [www.page-meeting.org/?abstract=9658]
Poster: Drug/Disease Modelling - Paediatrics