Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review

Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. L-arginine, an endogenous amino acid, was reported in clinical studies in adults to improve cardiovascular function in hypertension, pulmonary hypertension, pre-eclampsia, angina, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because of hepatic first-pass metabolism avoidance and longer circulation time. Although not yet well studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases of children. However, optimal clinical development of arginine or citrulline in children is dependent on more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the pre-clinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as baseline variation of arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are not enough to inform the optimal design of clinical studies, especially those in children. Successful bench to bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic-pharmacodynamic studies, along with pharmacometric approaches

State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development

Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug–drug interactions, real-time assessment of pharmacokinetic–safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and reliability of these techniques are well established

State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development

Physiologically based pharmacokinetic modeling and simulation is an important tool for predicting the pharmacokinetics, pharmacodynamics, and safety of drugs in pediatrics. Physiologically based pharmacokinetic modeling is applied in pediatric drug development for first-time-in-pediatric dose selection, simulation-based trial design, correlation with target organ toxicities, risk assessment by investigating possible drug–drug interactions, real-time assessment of pharmacokinetic–safety relationships, and assessment of non-systemic biodistribution targets. This review summarizes the details of a physiologically based pharmacokinetic modeling approach in pediatric drug research, emphasizing reports on pediatric physiologically based pharmacokinetic models of individual drugs. We also compare and contrast the strategies employed by various researchers in pediatric physiologically based pharmacokinetic modeling and provide a comprehensive overview of physiologically based pharmacokinetic modeling strategies and approaches in pediatrics. We discuss the impact of physiologically based pharmacokinetic models on regulatory reviews and product labels in the field of pediatric pharmacotherapy. Additionally, we examine in detail the current limitations and future directions of physiologically based pharmacokinetic modeling in pediatrics with regard to the ability to predict plasma concentrations and pharmacokinetic parameters. Despite the skepticism and concern in the pediatric community about the reliability of physiologically based pharmacokinetic models, there is substantial evidence that pediatric physiologically based pharmacokinetic models have been used successfully to predict differences in pharmacokinetics between adults and children for several drugs. It is obvious that the use of physiologically based pharmacokinetic modeling to support various stages of pediatric drug development is highly attractive and will rapidly increase, provided the robustness and reliability of these techniques are well established

Therapeutic Potential of Citrulline as an Arginine Supplement: A Clinical Pharmacology Review

Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. L-arginine, an endogenous amino acid, was reported in clinical studies in adults to improve cardiovascular function in hypertension, pulmonary hypertension, pre-eclampsia, angina, and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because of hepatic first-pass metabolism avoidance and longer circulation time. Although not yet well studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases of children. However, optimal clinical development of arginine or citrulline in children is dependent on more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the pre-clinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as baseline variation of arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are not enough to inform the optimal design of clinical studies, especially those in children. Successful bench to bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic-pharmacodynamic studies, along with pharmacometric approaches

Tacrolimus Population Pharmacokinetics in Paediatric Kidney Transplant Patients

Objectives: 1. To describe the pharmacokinetics (PK) of tacrolimus in paediatric kidney transplant recipients. 2. To determine the relationship between measures of tacrolimus exposure and renal function. 3. To determine if there were any differences in either the PK or pharmacodynamics (PD) of tacrolimus in brand versus generic formulations. Methods: Data from 1999-2014 were extracted from the electronic medical records from Intermountain Healthcare network. Data were available on 95 paediatric patients with kidney transplant taking oral tacrolimus. Reliable data was available in 77 patients. Using the individual predicted PK parameters from the population model several exposure metrics were derived for each dosing interval including; Cmin, Cmax and partial AUCs (2, 4, 6, 8, 10, 12h). We investigated the relationship between tacrolimus exposure and creatinine clearance in the first 30 days post-transplantation, using a simple slope-intercept model as well as an Emax model. Results: A total of 598 concentrations of tacrolimus were available for analysis. A one-compartment model described the final PK model, the significant covariates on clearance were haematocrit, body weight and post-transplant day. A total of 43 patients had data in the first 30 days post-transplant with a total of 470 creatinine concentrations available. The model that best described the relationship between tacrolimus exposure and creatinine clearance was an Emax model using a partial AUC of 4 hours. The significant covariates of this analysis were age, albumin, and formulation of the ED50 equivalent partial AUC 4h. The generic formulation (Sandoz) had a 35% increase partial AUC50 4h compared to the brand formulation. Conclusions: In the present work we developed a population PK model for tacrolimus in pediatric kidney transplant recipients the significant covariates have been previously identified [1]. We also determined an exposure-response relationship between tacrolimus and creatinine clearance. This relationship was influenced by patients age and albumin concentrations. Furthermore, we show that there is a difference in the pharmacodynamic effects of tacrolimus when comparing the brand formulation to the generic

Tacrolimus Population Pharmacokinetics in Paediatric Kidney Transplant Patients

Objectives: 1. To describe the pharmacokinetics (PK) of tacrolimus in paediatric kidney transplant recipients. 2. To determine the relationship between measures of tacrolimus exposure and renal function. 3. To determine if there were any differences in either the PK or pharmacodynamics (PD) of tacrolimus in brand versus generic formulations. Methods: Data from 1999-2014 were extracted from the electronic medical records from Intermountain Healthcare network. Data were available on 95 paediatric patients with kidney transplant taking oral tacrolimus. Reliable data was available in 77 patients. Using the individual predicted PK parameters from the population model several exposure metrics were derived for each dosing interval including; Cmin, Cmax and partial AUCs (2, 4, 6, 8, 10, 12h). We investigated the relationship between tacrolimus exposure and creatinine clearance in the first 30 days post-transplantation, using a simple slope-intercept model as well as an Emax model. Results: A total of 598 concentrations of tacrolimus were available for analysis. A one-compartment model described the final PK model, the significant covariates on clearance were haematocrit, body weight and post-transplant day. A total of 43 patients had data in the first 30 days post-transplant with a total of 470 creatinine concentrations available. The model that best described the relationship between tacrolimus exposure and creatinine clearance was an Emax model using a partial AUC of 4 hours. The significant covariates of this analysis were age, albumin, and formulation of the ED50 equivalent partial AUC 4h. The generic formulation (Sandoz) had a 35% increase partial AUC50 4h compared to the brand formulation. Conclusions: In the present work we developed a population PK model for tacrolimus in pediatric kidney transplant recipients the significant covariates have been previously identified [1]. We also determined an exposure-response relationship between tacrolimus and creatinine clearance. This relationship was influenced by patients age and albumin concentrations. Furthermore, we show that there is a difference in the pharmacodynamic effects of tacrolimus when comparing the brand formulation to the generic

An Evaluation of Vancomycin Area Under the Curve Estimation Methods for Children Treated for Acute Pulmonary Exacerbations of Cystic Fibrosis Due to Methicillin‐Resistant Staphylococcus aureus

The prevalence of pulmonary methicillin‐resistant Staphylococcus aureus infections in patients with cystic fibrosis (CF) has increased over the last 2 decades. Two concentrations—a postdistributive and a trough—are currently used to estimate the area under the curve (AUC) of vancomycin, an antibiotic routinely used to treat these infections, to achieve the target AUC/minimum inhibitory concentration of ≥400 mg·h/L in ensuring optimal dosing of this drug. This study evaluated precision and bias in estimating vancomycin AUCs obtained either from a population pharmacokinetic (PK) model by using a single trough concentration or from standard PK equation–based 2‐point monitoring approach. AUCs were either obtained from a single trough concentration–fitted model or derived from a model fitted by 2 concentration points. Children ≥2 years of age with CF received intravenous vancomycin at 2 centers from June 2012 to December 2014. A population PK model was developed in Pmetrics to quantify the between‐subject variability in vancomycin PK parameters, define the sources of PK variability, and leverage information from the population to improve individual AUC estimates. Twenty‐three children with CF received 27 courses of vancomycin. The median age was 12.3 (interquartile range [IQR] 8.5–16.6) years. From the individual vancomycin PK parameter estimates from the population PK model, median AUC was 622 (IQR 529–680) mg·h/L. Values were not significantly different from the AUC calculated using the standard PK equation‐based approach (median 616 [IQR 540–663] mg·h/L) (P = .89). A standard PK equation‐based approach using 2 concentrations and a population PK model‐based approach using a single trough concentration yielded unbiased and precise AUC estimates. Findings suggest that options exist to implement AUC‐based pediatric vancomycin dosing in patients with CF. The findings of this study reveal that several excellent options exist for centers to implement AUC‐based pediatric vancomycin dosing for patients with CF