Vo Thanh1, Eman El-Khateeb1, Khaled Abduljalil1, Frederic Bois1
1Certara
Objectives: Finding an optimal dosage regimen for achieving the desired efficacy and safety can be challenging because of the variability of PK/PD parameters that usually leads to subtherapeutic effects or toxicity. The objective of this work is to assess the performance of a dose finding tool that was implemented within the Simcyp Simulator V24 to support the decision-making in the selection of safe and effective dosage regimens, taking into account variability in the PK/PD targets as well as physiological differences of the selected population. Our tool allows a wide range of PK and PD targets for selection including PK or PD time profiles at any time or steady state; PK or PD summary parameters such as Cmax, AUC or PD response Rmax as well as PKPD indices [2], composited of PK/PD parameters and point estimates of the effect. The performance of this tool was assessed by evaluating the probability of PK/PD target attainment. Methods: The dose finding tool available within the Simcyp Simulator [1] was used to predict PK and PD parameters using theophylline and ciprofloxacin from the Simulator library as probe compounds for whom clinical PK/PD data are available. For theophylline, the target was a Cmax within the therapeutic range of 10–20 mg/L, while for ciprofloxacin it was log10-transformed counts of CFU below 4. The PD effect of ciprofloxacin is modelled using a logistic growth function linking plasma concentration profiles to its antimicrobial efficacy. Simulations for both compounds were verified with observed exposure data [3,4] as well with the observed response for ciprofloxacin [5]. Several doses per compound (Theophylline: 3, 5, 7, 10, 15 mg/kg, Ciprofloxacin: 500, 750, 1000, 1250, 1500 mg twice daily) or dosing time intervals (Ciprofloxacin: 500mg every 4.5, 6, 8, 12 h) were simulated. Monte Carlo simulation was employed to capture variability in the PK/PD parameters for each dosing regimen. The probability of target attainment, computed as the percentage of individuals within the population reaching the PK/PD target, was used to support the decision-making of candidate dosing regimens. Results: Theophylline PBPK model shows that a dose of 7mg/kg would give the highest probability of 83% in maintaining the Cmax in the therapeutic range of 10 – 20 mg/L. For ciprofloxacin PBPK/PD model, the logistic-growth model described the reduction in the forming of bacteria measured in log10 CFU. Ciprofloxacin administered as 500 mg with a dosing time interval of 4.5h gave the best outcome (reduction in log10 CFU below 4) with a probability of 72%. Conclusions: The developed dose finding tool can be utilised to support the selection of effective dosage regimens based on PK/PD targets, which could be exposure-effect profiles, summary PK and PD parameters or composite PK/PD indices and their variability. It can be of potential application to assess dose recommendations in special populations with impaired organ functions (cirrhosis, renal insufficiency) or in populations with limited metabolic capacity, e.g., neonates. References [1] M. Jamei et al. (2009). Expert opinion on drug metabolism & toxicology 5 (2):211–223. [2]J. W. Mouton et al. (2005). Journal of Antimicrobial Chemotherapy. 55:601–607. [3]J. G. Gillum et al. (1996). Antimicrobial Agents and Chemotherapy 40(8), pp. 1866–9. [4]K. T. Batty et al. (1995). Br J Clin Pharmacol, 39(3), pp. 305–11. [5]A. K. Meagher et al. (2004), Antimicrobial Agents and Chemotherapy 48(6), pp. 2061–2068.
Reference: PAGE 33 (2025) Abstr 11698 [www.page-meeting.org/?abstract=11698]
Poster: Methodology - Other topics