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: Oritavancin is a novel, semi-synthetic, lipoglycopeptide antibiotic, indicated for the treatment of adult subjects with acute bacterial skin and skin structure infections (ABSSSI), caused or suspected to be caused by Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (S. aureus) [1]. In adults it is administered as a 1200 mg single dose by intravenous (IV) infusion over 3 hours [2]. In paediatric subjects, the pharmacokinetic (PK) of oritavancin was investigated in the ORKIDS study [3] in patients aged between 3 months and < 18 years. Under the assumptions of (i) similar disease and disease progression, (ii) similar response to treatment, and (iii) similar pharmacokinetic-pharmacodynamic (PK-PD) relationship between adults and children, children are expected to respond similarly to adults when the same target exposure levels are achieved [4,5,6]. Leveraging extensive oritavancin adult PK data [7], we implemented a model-based approach [8] to identify the paediatric doses that would ensure in the paediatric population oritavancin exposures within the therapeutic window of adult patients with ABSSSI. Lastly, the probability of target attainment (PTA) in children was evaluated to confirm whether the recommended dosing based on the model-based approach would ensure appropriate target attainment across all age groups in the paediatric population.
Methods: A popPK model for oritavancin in children was developed leveraging extensive PK data from adults and using allometric principles as basis to characterise oritavancin disposition in the paediatric population [8, 9]. Baseline demographic factors describing body size (e.g. body weight, lean body mass) were introduced as covariates into the model to capture the effect of developmental growth on oritavancin PK in children. The model was used to estimate the relevant PK parameters in paediatric patients from ORKIDS study. Lastly, simulations with the final model in a paediatric population of 10000 subjects from birth to <18 years of age were used to identify a dosing regimen that would result in an exposure range similar to the efficacious and safe exposure range attained in adults. PTA was also estimated for each tested dose to confirm the dose rationale.
Results: The extrapolation of PK from adults to children, based on allometric principles, allowed the characterization of the disposition of oritavancin in the paediatric population. The final popPK model consisted in a 3-compartment model, where the infused drugs follows a zero-order input and a first-order elimination. A proportional error model was used. Lean body mass was introduced as a covariate on all PK parameters. Model-based simulations of oritavancin concentration vs. time profiles in a virtual paediatric population of 10000 children from birth to <18 years of age, showed that a 15 mg/kg dose infused intravenously over 3 hours provides the appropriate exposure for the treatment of Gram-positive microorganisms, including methicillin-resistant S. aureus, across all age groups. These results were further corroborated by percent probabilities of PKPD target attainment above 90% for all age groups at the minimum inhibitory concentration (MIC) of 0.12 mg/L, which is oritavancin susceptibility breakpoint for S. aureus.
Conclusions: A model-based analysis was implemented to identify the oritavancin dose to be administered in pediatric patients. A dose of 15 mg/kg, administered as a single 3 hour infusion, was considered to be adequate in children of all age groups, from neonates to adolescents, for the treatment of Gram-positive microorganisms, including methicillin-resistant S. aureus.
References:
[1] S. Rosenthal, A. G. Decano, A. Bandali, D. Lai, G. E. Malat, and T. E. Bias, “Oritavancin (Orbactiv) a new-generation lipoglycopeptide for the treatment of acute bacterial skin and skin structure infections,” Drug Forecast, vol. 43, no. 3, pp. 143–147, 2018
[2] ORITAVANCIN® Package Insert May 2019.
[3] NCT02134301 Open-Label, Dose-Finding, Pharmacokinetics, Safety and Tolerability Study of Oritavancin in Pediatric Patients with Suspected or Confirmed Bacterial Infections
[4] European Medicines Agency, “European Medicines Agency, Reflection paper on the use of extrapolation 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] C.M. Rubino, S.M. Bhavnani, G. Moeck, S.E. Bellibas and P.G. Ambrose, “Population pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials,” Antimicrob. Agents Chemother. vol. 59, no. 6, pp. 3365–3372, 2015.
[8] 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
[9] 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 9659 [www.page-meeting.org/?abstract=9659]
Poster: Drug/Disease Modelling - Paediatrics