Development of a Pediatric Physiologically-Based Pharmacokinetic Model of Clindamycin Using Opportunistic Pharmacokinetic Data

Abstract

Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool used to characterize maturational changes in drug disposition to inform dosing across childhood; however, its use is limited in pediatric drug development. Access to pediatric pharmacokinetic data is a barrier to widespread application of this model, which impedes its development and optimization. To support the development of a pediatric PBPK model, we sought to leverage opportunistically-collected plasma concentrations of the commonly used antibiotic clindamycin. The pediatric PBPK model was optimized following development of an adult PBPK model that adequately described literature data. We evaluated the predictability of the pediatric population PBPK model across four age groups and found that 63-93% of the observed data were captured within the 90% prediction interval of the model. We then used the pediatric PBPK model to optimize intravenous clindamycin dosing for a future prospective validation trial. The optimal dosing proposed by this model was 9 mg/kg/dose in children ≤5 months of age, 12 mg/kg/dose in children >5 months-6 years of age, and 10 mg/kg/dose in children 6-18 years of age, all administered every 8 h. The simulated exposures achieved with the dosing regimen proposed were comparable with adult plasma and tissue exposures for the treatment of community-acquired methicillin-resistant Staphylococcus aureus infections. Our model demonstrated the feasibility of using opportunistic pediatric data to develop pediatric PBPK models, extending the reach of this powerful modeling tool and potentially transforming the pediatric drug development field.

Trial registration: ClinicalTrials.gov NCT01431326.

Figure 1

Model building workflow for pediatric PBPK model.

Figure 2

Mean observed (dots) and simulated (lines) plasma concentrations and fractions of the drug excreted unchanged in urine in healthy adults: (A): clindamycin concentration in plasma, and clindamycin and clindamycin phosphate fractions in urine after a 30-min intravenous infusion of 600 mg clindamycin phosphate; (B): clindamycin phosphate concentration in plasma and fraction in urine after IV administration of 600 mg clindamycin phosphate every 6 hours; (C): clindamycin concentration in plasma and fraction in urine after IV administration of 600 mg clindamycin phosphate every 6 hours; (D): clindamycin phosphate concentration in plasma and fraction in urine after IV administration of 1200 mg clindamycin phosphate every 12 hours; (E): clindamycin concentration in plasma and fraction in urine after IV administration of 1200 mg clindamycin phosphate every 12 hours.

Figure 2

Mean observed (dots) and simulated (lines) plasma concentrations and fractions of the drug excreted unchanged in urine in healthy adults: (A): clindamycin concentration in plasma, and clindamycin and clindamycin phosphate fractions in urine after a 30-min intravenous infusion of 600 mg clindamycin phosphate; (B): clindamycin phosphate concentration in plasma and fraction in urine after IV administration of 600 mg clindamycin phosphate every 6 hours; (C): clindamycin concentration in plasma and fraction in urine after IV administration of 600 mg clindamycin phosphate every 6 hours; (D): clindamycin phosphate concentration in plasma and fraction in urine after IV administration of 1200 mg clindamycin phosphate every 12 hours; (E): clindamycin concentration in plasma and fraction in urine after IV administration of 1200 mg clindamycin phosphate every 12 hours.

Figure 2

Mean observed (dots) and simulated (lines) plasma concentrations and fractions of the drug excreted unchanged in urine in healthy adults: (A): clindamycin concentration in plasma, and clindamycin and clindamycin phosphate fractions in urine after a 30-min intravenous infusion of 600 mg clindamycin phosphate; (B): clindamycin phosphate concentration in plasma and fraction in urine after IV administration of 600 mg clindamycin phosphate every 6 hours; (C): clindamycin concentration in plasma and fraction in urine after IV administration of 600 mg clindamycin phosphate every 6 hours; (D): clindamycin phosphate concentration in plasma and fraction in urine after IV administration of 1200 mg clindamycin phosphate every 12 hours; (E): clindamycin concentration in plasma and fraction in urine after IV administration of 1200 mg clindamycin phosphate every 12 hours.

Figure 3

Observed (dots) and simulated (lines) plasma concentration-time profiles of clindamycin phosphate and clindamycin following IV administration of 600 mg clindamycin phosphate every 6 hours in healthy adults. Solid lines represent geometric mean of the simulated data. The shaded area represents geometric mean ± geometric SD for the simulated data. Symbols represents mean and SD for the observed data.

Figure 4

Simulated total drug exposure as concentration versus time curve from zero to infinity after a single dose (AUC_inf) with age-based clindamycin dosage regimens.