Prediction of Drug Clearance in Children: an Evaluation of the Predictive Performance of Several Models

Mahmood, Iftekhar; Staschen, Carl-Michael; Goteti, Kosalaram

doi:10.1208/s12248-014-9667-7

Cited by 46 publications

(111 citation statements)

References 43 publications

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“…The substantial prediction error introduced by exponent 0.75 in GFR observed in this study is in line with the observations noted in other studies for the prediction of drug clearances in the aforementioned age groups (4,38,40,41). In this study, however, it was observed that the predictive power of exponent 0.75 for GFR was comparable with other models in children >1 year of age (this will not be true for the prediction of drug clearances and generally exponent 0.75 provides a good prediction of drug clearances in children >5 years of age).…”

Section: Discussionsupporting

confidence: 93%

“…Both these models have been proposed for the prediction of drug clearances in pediatrics (4,(8)(9)(10)(11). Although the BDE model was developed based on inulin clearance, the model's predictive power was comparable for GFR based on inulin and creatinine clearance.…”

Section: Discussionmentioning

confidence: 99%

“…Using the data of Rubin et al (2), Hayton (3) developed an allometric model incorporating the maturation and growth of renal function that could be used to predict GFR in different age groups. Although Hayton suggested a fixed exponent of 0.662 for GFR, it is possible that a single exponent cannot describe the GFR data across all age groups (4). This phenomenon has been observed with the clearances of drugs when allometric models were developed across different age groups (4).…”

Section: Introductionmentioning

confidence: 99%

“…Although Hayton suggested a fixed exponent of 0.662 for GFR, it is possible that a single exponent cannot describe the GFR data across all age groups (4). This phenomenon has been observed with the clearances of drugs when allometric models were developed across different age groups (4).…”

Section: Introductionmentioning

confidence: 99%

“…The BDE model has been applied to predict clearance of morphine (8), propofol (9,10), and busulfan (11). Besides BDE model, another empirical model called age-dependent exponent (ADE) model has been developed for the prediction of drug clearance from preterm neonates to adults (4). Both BDE and ADE models predict clearances of drugs based on allometric exponents which change with body weight or age.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models

Mahmood

Staschen

2016

AAPS J

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Abstract. The objective of this study was to evaluate the predictive performance of several allometric empirical models (body weight dependent, age dependent, fixed exponent 0.75, a data-dependent single exponent, and maturation models) to predict glomerular filtration rate (GFR) in preterm and term neonates, infants, children, and adults without any renal disease. In this analysis, the models were developed from GFR data obtained from inulin clearance (preterm neonates to adults; n = 93) and the predictive performance of these models were evaluated in 335 subjects (preterm neonates to adults). The primary end point was the prediction of GFR from the empirical allometric models and the comparison of the predicted GFR with measured GFR. A prediction error within ±30% was considered acceptable. Overall, the predictive performance of the four models (BDE, ADE, and two maturation models) for the prediction of mean GFR was good across all age groups but the prediction of GFR in individual healthy subjects especially in neonates and infants was erratic and may be clinically unacceptable.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models

Mahmood

Staschen

2016

AAPS J

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Animal‐to‐Human Dose Translation of ANTHRASIL for Treatment of Inhalational Anthrax in Healthy Adults, Obese Adults, and Pediatric Subjects

Beliveau,

Rubets,

Bojan

et al. 2023

Clin Pharma and Therapeutics

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Anthrax Immune Globulin Intravenous (AIGIV [ANTHRASIL]), was developed for the treatment of toxemia associated with inhalational anthrax. It is a plasma product collected from individuals vaccinated with anthrax vaccine and contains antitoxin IgG antibodies against Bacillus anthracis protective antigen. A pharmacokinetic (PK) and exposure–response model was constructed to assess the PKs of AIGIV in anthrax‐free and anthrax‐exposed rabbits, non‐human primates and anthrax‐free humans, as well as the relationship between AIGIV exposure and survival from anthrax, based on available preclinical/clinical studies. The potential effect of anthrax on the PKs of AIGIV was evaluated and estimates of survival odds following administration of AIGIV protective doses with and without antibiotic co‐treatment were established. As the developed PK model can simulate exposure of AIGIV in any species for any dosing scenario, the relationship between the predicted area under the concentration curve of AIGIV in humans and the probability of survival observed in preclinical studies was explored. Based on the simulation results, the intravenous administration of 420 U (units of potency as measured by validated Toxin Neutralization Assay) of AIGIV is expected to result in a > 80% probability of survival in more than 90% of the human population. Additional simulations suggest that exposure levels were similar in healthy and obese humans, and exposure in pediatrics is expected to be up to approximately seven‐fold higher than in healthy adults, allowing for doses in pediatric populations that ranged from one to seven vials. Overall, the optimal human dose was justified based on the PK/pharmacodynamic (PD) properties of AIGIV in animals and model‐based translation of PK/PD to predict human exposure and efficacy.

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Multistep Unified Models Using Prior Knowledge for the Prediction of Drug Clearance in Neonates and Infants

Tegenge

Mahmood

Jiang

et al. 2018

The Journal of Clinical Pharma

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Allometric approaches are widely used for interspecies scaling for the prediction of pharmacokinetic (PK) parameters during drug development. The concept of allometry can also be extended to predict PK parameters from adults to children. Three methods for extrapolating pediatric clearance were developed and evaluated using the clearance values of 4 drugs. The first method was established using a simple allometric (SA) model with estimated coefficient and exponent based on data ranging from children older than 2 years to adult. Then we developed a unified multistep single-exponent (MSE) and multistep body-weight-dependent exponent (MBDE) models. The major steps in these 2 new methods include generating pseudopredicted clearance for unobserved new populations such as preterm neonates, term neonates, and infants. Subsequent steps involve incorporating the pseudopredicted clearance with the actual PK data from older children and adults. All 3 models were then used to predict drug clearance in children ≤2 years old (N = 278). Drug clearance was predicted with mean absolute error of 29.6, 14.2, and 12.9 using SA, MSE, MBDE, respectively. The root mean square error was 65.9, 29.8, 24.7 for SA, MSE, MBDE, respectively. Approximately 41%, 72%, and 74% of the children's clearance data were within 0.5 to 1.5-fold of the observed values when drug clearance was extrapolated using SA, MSE, and MBDE models, respectively. The present multistep unified extrapolation approaches improved the prediction of clearance from preterm neonates to 2 years of age and may have practical use for first-in-pediatric dose selection.

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Prediction of Drug Clearance in Children: an Evaluation of the Predictive Performance of Several Models

Cited by 46 publications

References 43 publications

Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models

Prediction of Human Glomerular Filtration Rate from Preterm Neonates to Adults: Evaluation of Predictive Performance of Several Empirical Models

Animal‐to‐Human Dose Translation of ANTHRASIL for Treatment of Inhalational Anthrax in Healthy Adults, Obese Adults, and Pediatric Subjects

Multistep Unified Models Using Prior Knowledge for the Prediction of Drug Clearance in Neonates and Infants

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