Physiologically Based Pharmacokinetic Modeling and Dose Adjustment of Teicoplanin in Pediatric Patients With Renal Impairment

Abstract

The pharmacokinetics of teicoplanin differs in children as compared with adults, and especially in renally impaired pediatric patients. Inappropriate empirical antibacterial therapy may lead to treatment-related antibacterial resistance and increased toxicity, making adjustment of the dosage regimen essential. In the present study, physiologically based pharmacokinetic (PBPK) models were developed to define the appropriate dosage regimen for pediatric patients with differing renal function. Our PBPK models accurately predicted teicoplanin exposures in both adult and pediatric subjects after single and multiple intravenous infusions, with a <1.36-fold error between predicted and observed data, and all observed data were within minimal and maximal data of the corresponding population simulation. The area under the plasma concentration-time curve was predicted to increase 1.25fold, 1.95-fold, and 2.82-fold in pediatric patients with mild, moderate, and severe renal impairment, respectively, relative to that of healthy children. Subsequently, the results of Monte Carlo simulations indicated that the recommended dosing of 12, 9.5, 6, and 4 mg/kg at 12-hour intervals would be appropriate in pediatric patients with normal renal function and in those with mild, moderate, and severe renal impairment, respectively, at a susceptible minimum inhibitory concentration <2 mg/L. In conclusion, our PBPK model with an incorporated Monte Carlo simulation can provide improved guidance on dosing in pediatric patients with differing renal function and provide a basis for precision therapy with teicoplanin.

Predicting the correct dose in children: Role of computational Pediatric Physiological‐based pharmacokinetics modeling tools

“…Verified PBPK models of drugs are presented in support of pediatric dose prediction (Figure 4 ): 13 articles reported results from P‐PBPK models, which are presented in support of dose selection, 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 five articles were on the optimization of dosage in the design of future pediatric clinical studies, 3 , 29 , 43 , 44 , 45 and six articles reported findings from studies on determining dose regimens. 46 , 47 , 48 , 49 , 50 , 51 Fourteen publications were on some special pediatric populations and uncommon diseases with an assessment of renal impairment, 52 , 53 , 54 , 55 , 56 children with obesity, 57 , 58 , 59 , 60 and pediatric patients with severe coronavirus disease 2019 (COVID‐19) disease. 61 , 62 , 63 , 64 , 65 Consistent with this trend, several big research funding/grants for computational pharmaceutics worldwide were launched (Table 1 ).…”

Lamivudine and Emtricitabine Dosing Proposal for Children with HIV and Chronic Kidney Disease, Supported by Physiologically Based Pharmacokinetic Modelling

“…In this study, we demonstrated that PBPK modelling might be a useful tool to predict the PK of compounds that are renally cleared in paediatric subjects with CKD. Other studies have successfully used PBPK modelling to simulate PK of renally excreted drugs in paediatric CKD populations by solely reducing the GFR of the virtual population, as compounds included in these studies did not undergo tubular secretion like 3TC and FTC [ 37 , 38 , 39 , 40 ]. Ye et al applied PBPK modelling to predict PK of ertapenem in paediatric CKD populations, considering both glomerular filtration and tubular secretion [ 41 ].…”

Physiologically Based Pharmacokinetic (PBPK) Model-Informed Dosing Guidelines for Pediatric Clinical Care: A Pragmatic Approach for a Special Population

“…A scenario in which altered PK is expected can necessitate a dose adjustment. With PBPK modeling, it is not only possible to study the effect of age on drug PK, an additional effect of, for example, co-medication, ethnicity, renal impairment or obesity on a drug's PK profile can also be investigated [25][26][27].…”