Extrapolation and pharmacokinetic protocol design optimization for ceftriaxone as an exemplar for the development of...

Ceftriaxone is a cephalosporin commonly used for the treatment of acute, severe infections; however, there are conflicting data on its disposition properties in children, making it a suitable case study for the evaluation of the appropriateness of extrapolation approaches based on exposure matching principles for paediatric patients and exploring the relevance of optimized protocol designs to characterize the pharmacokinetics in prospective studies in children.

Data from 12 healthy adults receiving ceftriaxone (1 g IV) were available for the purpose of this investigation. A nonlinear mixed effects modelling approach was implemented in conjunction with ED-optimality to identify suitable sampling schemes in children. In addition, estimates were derived of the probability of target attainment across the relevant weight range. Predictions were compared with published pharmacokinetic data and established dosing recommendations for children.

A two-compartment model with first-order elimination best described the data, with body weight as a covariate on clearance (0.97 L/h) and Vss (8.83 L). Doses derived through exposure matching were substantially lower than those currently recommended. A sampling scheme with four samples per subject (t = 0.17-0.25 h, 0.7-1.2 h, 5.1-5.6 h and 11.5-12.0 h postdose) was identified for the assessment of the pharmacokinetics of ceftriaxone in children.

Our case study reveals the importance of considering factors other than developmental growth and maturation when extrapolating the efficacy of compounds such as ceftriaxone based on matching exposure and PKPD principles. It also highlights the need for optimized, informative study protocols for the accurate description of drug disposition properties in children.