Michael Tagen: No financial relationships to disclose
Objectives: Oritavancin is a glycopeptide antibiotic approved in adults for the treatment of acute bacterial skin and skin structure infections (ABSSSI) with a single intravenous dose of 1200 mg IV. Sparse pharmacokinetic (PK) data are available from two ongoing pediatric studies with age groups of 0 to < 3 months, 3 months to < 2 years, 2 to < 6 years, 6 to < 12 years, and 12 to < 18 years. Tested pediatric dosages included 15 and 20 mg/kg IV. The objective of this analysis was to characterize the pediatric PK of oritavancin with a population PK (popPK) model and perform stochastic simulations to support pediatric dose selection.
Methods: Sparse PK data from pediatric patients (N=85, including 3 patients aged < 3 months) were combined with sparse PK data from two pivotal Phase 3 studies of adult patients with ABSSSI (N=297). A three-compartment model with linear elimination was fit to the combined dataset using the Markov Chain Monte Carlo (MCMC) algorithm in Pumas software. Parameter estimates from a previous popPK model [1] were used as Bayesian priors. This model was developed with data from adult Phase 1, Phase 2 and earlier Phase 3 studies (N=560 subjects) with mostly dense PK sampling. After fitting the base model, weight was assessed as a covariate on clearance and volume parameters. Stochastic simulations were performed using a virtual population (N=1000 per sex and year of age) created by sampling from CDC growth chart weight distributions. Probability of target attainment (PTA) was assessed against Staphylococcus aureus using previously established AUC(0-72)/minimum inhibitory concentration (MIC) ratio targets.
Results: The base model using Bayesian priors was successfully fit to the combined adult and pediatric dataset. All MCMC diagnostics showed adequate convergence of the chains. Mean post-hoc parameter estimates showed a strong trend with body weight and age. The allometric effect of body weight was estimated on clearance and volumes of distribution, with intercompartmental clearance exponents fixed to 0.75. The estimated allometric exponents were close to the typical exponents (0.75 for clearance and 1 for volumes of distribution). The final model showed no further trend of mean post-hoc estimates with body weight or age. It adequately described the PK of each age group, as demonstrated by an age-stratified visual predictive check (VPC). Stochastic simulations of 15 mg/kg, the maximum tolerated dose in pediatrics, predicted that infants aged birth to < 3 months have a geometric mean AUC(0-72) 0.65-fold of adults. Geometric mean Cmax and AUC(72-168), which may also be associated with efficacy, were 0.49-fold and 0.54-fold of adult values, respectively. PTA analysis of exposures in infants aged birth to < 3 months following a 15 mg/kg dose showed a reduced probability of efficacy against Staphylococcus aureus at an MIC of 0.25 ug/mL.
Conclusions: The PK of oritavancin in pediatric and adult patients with ABSSSI was adequately described by a Bayesian three-compartment model. No trend of age with clearance was identified after controlling for the effect of body weight. Simulated exposures in infants aged birth to < 3 months of age were potentially sub-therapeutic at the maximum tolerated dose of 15 mg/kg.
Citations: [1] Rubin CM, Van Wart SA, Bhavnani SJ, Ambrose PG, McCollam JS, Forrest A. Oritavancin population pharmacokinetics in healthy subjects and patients with complicated skin and skin structure infections or bacteremia. 2009. Antimicro Agents Chemother, 53:4422-8.
Keywords: pediatrics, population pharmacokinetics, Bayesian
