Tomás Sou (1,2), Edgars Liepins (3), Jon Hansen (4), Solveiga Grinberga (3), Maria Backlund (2), Onur Ercan (5), Anna Petersson (5), Diarmaid Hughes (5), Magdalena Tomczak (6), Malgorzata Urbas (6), Dorota Zabicka (6), Carina Vingsbo Lundberg (4), Sven N. Hobbie (7), Lena E. Friberg (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Department of Pharmacy, Uppsala University, Uppsala, Sweden, (3) Latvian Institute of Organic Synthesis, Riga, Latvia, (4) Statens Serum Institute, Copenhagen, Denmark, (5) Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden, (6) Department of Epidemiology and Clinical Microbiology, National Medicines Institute, Warsaw, Poland, (7) Institute of Medical Microbiology, University of Zurich, Zurich, Switzerland
Objectives: Predictions of human dose for antibiotics are commonly based on 24h response in mouse infection models, ignoring the dynamics of bacterial growth and killing. Preclinical profiling has identified the aminoglycoside apramycin as a suitable candidate for development into a new human therapeutic. Apramycin has been shown to evade almost all mechanisms of clinically relevant aminoglycoside resistance. In this study, we applied translational pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) modelling to predict an efficacious human dose for apramycin using i) in-vivo data from a mouse thigh infection model, and (ii) in-vitro time-kill data, in combination with human PK predicted from allometric scaling and knowledge on earlier aminoglycosides.
Methods: PK models were fitted to the preclinical PK data of apramycin available from four different species (mouse, rat, guinea pig, and dog). The estimated PK parameters were allometrically scaled to obtain typical PK parameter values for humans. For antimicrobial efficacy, in vitro time-kill data from four E. coli strains were available and semi-mechanistic PKPD models were fitted to describe the killing of bacteria at various drug concentrations. Bacterial count data on in-vivo efficacy at 24h in the mouse thigh infection model, as well as information on natural growth rate without drug exposure, was available for the same four E. coli strains. The PK model for mouse, and the predicted PK in humans, were then connected to the final PKPD model to predict the growth and killing of bacteria in mice and in humans. A suitable human efficacious dose was derived through the classical approach based on 95% probability of target attainment (PTA), where the target is derived based on the response observed in mice, and, through a modelling approach based on the PKPD model developed from the in-vitro time-kill experiments.
Results: In the PK analysis, 1-compartment models described the plasma concentration-time profiles of the preclinical species. Based on allometric scaling, the typical values of clearance and volume of distribution in humans are expected to be 7.67 L/h and 21.2 L, respectively. These values are similar to the typical population PK parameters of the aminoglycoside gentamicin reported in the literature [1]. For in-vivo efficacy, the required fAUC/MIC targets for stasis and 1-log kill in the neutropenic mouse thigh infection model were 50 and 106, respectively. The PKPD model predicted the time-kill data well with strain specific differences in susceptibility, maximum bacterial load and the rate of resistance development. The human efficacious dose predicted from the PKPD-model and the ‘classical’ PK/PD target approach both supported an apramycin daily dose of 30 mg/kg/day for patients with a typical kidney function of 80 ml/min.
Conclusions: Translational PK and PKPD modelling was successfully applied to analyse the data on apramycin from in-vitro time-kill experiments. The estimated human efficacious dose aligned well with the expected dose from in-vivo studies on apramycin. The agreement of the two methods support an anticipated efficacious dose of 30 mg/kg to be studied in patients.
References:
[1] Xuan D, Nicolau DP, Nightingale CH. Population pharmacokinetics of gentamicin in hospitalized patients receiving once-daily dosing. Int J Antimicrob Agents. 2004;23(3):291-4.
Reference: PAGE 28 (2019) Abstr 8890 [www.page-meeting.org/?abstract=8890]
Poster: Drug/Disease Modelling - Infection