Mizuno, T; Fukuda, T; Emoto, C; Mobberley-Schuman, PS; Hammill, AM; Adams, DM; Vinks, AA. Developmental pharmacokinetics of sirolimus: Implications for precision dosing in neonates and infants with complicated vascular anomalies. Pediatric Blood and Cancer. 2017; 64(8):e26470-e26470.
Sirolimus is the first drug shown to be efficacious and tolerable in pediatric patients with complicated vascular anomalies. However, evidence-based dosing information for neonates and infants is lacking. The purpose of this study was to develop age appropriate dosing regimens that incorporate developmental changes in drug elimination in these very young children. The developed algorithms in combination with concentration measurements will for the first time allow sirolimus precision dosing in young children with vascular anomalies.
Alloway, RR; Vinks, AA; Fukuda, T; Mizuno, T; King, EC; Zou, Y; Jiang, W; Woodle, ES; Tremblay, S; Klawitter, J; Christians, U. Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial. PLoS medicine. 2017; 14(11):e1002428-e1002428.
Professional transplant societies and publications voiced skepticism of the FDA approval process of generic immunosuppressants, such as tacrolimus, based on healthy volunteer data translated to transplant recipients. Using a six-way crossover bioequivalence study design, we showed equivalence between tacrolimus innovator and two generic products in kidney or liver transplant recipients using FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus shown in healthy volunteers translates to kidney and liver transplant recipients.
Emoto, C; Johnson, TN; McPhail, BT; Vinks, AA; Fukuda, T. Using a Vancomycin PBPK Model in Special Populations to Elucidate Case-Based Clinical PK Observations. CPT: Pharmacometrics and Systems Pharmacology. 2018; 7(4):237-250.
Changes in physiological factors are important considerations to explain observed large variability in vancomycin pharmacokinetics (PK). This study systematically studied the effects of multiple factors on vancomycin PK as measured in diseased and pediatric populations. The pediatric model includes development of both renal and non-renal elimination pathways . The developed models predicted the concentration-time profiles very well with renal function, cardiac output, and protein binding as major factors influencing vancomycin PK.
Xiong, Y; Fukuda, T; Knibbe, CAJ; Vinks, AA. Drug Dosing in Obese Children Challenges and Evidence-Based Strategies. Pediatric Clinics of North America. 2017; 64(6):1417-1438.
Pathophysiologic alterations associated with obesity can predict changes in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, but drug-specific properties, disease progression, and the need to consider other comorbidities. Appropriate weight-based descriptors serve as important factors for estimating critical PK parameters as part of dose calculations. Future research should focus on pediatric population PK/PD studies to allow evidence-based dosing in obese children.
Dong, M; Mizuno, T; Vinks, AA. Opportunities for model-based precision dosing in the treatment of sickle cell anemia. Blood Cells, Molecules, and Diseases. 2017; 67:143-147.
Hydroxyurea is a potent disease-modifying therapy for both children and adults with sickle cell anemia (SCA). Patients are carefully titrated to maximum tolerated dose (MTD), but current dose escalation is empirical and by trial-and-error and often results in a lengthy process. We studied pharmacokinetically guided precision dosing of hydroxyurea to more rapidly achieve individual maximum tolerated dose. This manuscript provides an overview of quantitative modeling approaches including Bayesian adaptive control for the precision dosing of hydroxyurea. Future research directions should focus on integrating specific safety and other clinical outcome endpoints into dose selection decision making.