A Bodyweight-Dependent Allometric Exponent for Scaling Clearance Across the Human Life-Span

Wang, Chenguang; Peeters, Mariska Y. M.; Allegaert, Karel; Oud-Alblas, Heleen J. Blussé van; Krekels, Elke H. J.; Tibboel, Dick; Danhof, Meindert; Knibbe, Catherijne A. J.

doi:10.1007/s11095-012-0668-x

Cited by 69 publications

(120 citation statements)

References 40 publications

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“…In this study, the exponents of allometry in younger children were >1 and decreased with increasing age. This observation reconciles with the observations of the BDE models (8)(9)(10)(11) as well as the nature of allometric exponents as observed by Brody, Wiesner, McMahon, and Bonner (52)(53)(54).…”

Section: Discussionsupporting

confidence: 91%

“…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%

“…Recent studies by many investigators have shown that the concept of quarter-power law or so-called theoretical allometry (fixed exponents of 0.25, 0.75, or 1.0) is incorrect (43)(44)(45)(46)(47)(48)(49)(50)(51). The exponents of allometry for drug clearance in preterm and term neonates are generally >1 (4,(8)(9)(10)(11)39). Therefore, it is not surprising that even for GFR the exponent 0.75 (model 3) provided a very poor prediction (systematic over-prediction by hundreds of percent) of GFR in preterm, term, and children ≤1 year of age as compared to exponent 1.15, 1.0, or 0.9, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have indicated that a single allometric exponent does not describe the entire data (body weight versus drug clearance or volume of distribution) across all age groups (4,(8)(9)(10)(11). This was demonstrated by some recently published population PK studies.…”

Section: Discussionmentioning

confidence: 99%

“…The maturation model has been applied to predict clearance of several drugs such as morphine (5), propofol (6), and midazolam (7). 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).…”

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: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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Model Informed Development of VRC01 in Newborn Infants Using a Population Pharmacokinetics Approach

Nikanjam

Cunningham

et al. 2020

Clin Pharma and Therapeutics

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VRC01 is a first-in-class, potent, broadly neutralizing antibody that targets the CD4 binding site of gp120 on HIV-1 viruses, and is under development as a novel HIV therapeutic. This study utilized population pharmacokinetic (PK) modeling to characterize VRC01 PK to guide dosing selection for ongoing phase II clinical trials in pediatric patients. Combining VRC01 PK data from 3 adult and 1 infant clinical trials, a total of 1,475 VRC01 serum concentrations from 100 participants were used in the analysis (40 infants and 60 adults). VRC01 was administered either i.v. or s.c. (1-40 mg/kg). All infants received s.c. doses as compared with 13% s.c. and 87% i.v. in adults. The data were well-described by a two-compartment model. Clearance was 37% higher in adults with HIV infection and 83% lower in infants than adults. Subcutaneous bioavailability was 55% in adults. Rapid absorption was seen in infants indicating therapeutic levels could be achieved quickly. Monte Carlo simulations were used to determine optimal dosing and demonstrated 40 mg/kg s.c. at weeks 0, 2, 6, and 10 would maintain VRC01 levels at the suppressive target concentration of 50 μg/mL for the first 14 weeks of life in infants. The current analysis provides new insight into differences in monoclonal antibody PK between infants and adults and demonstrates the utility of a population PK approach in informing drug development for infant populations. Antiretroviral therapy (ART) has dramatically reduced vertical transmission of HIV. However, many infants are newly infected each year, with an estimated 160,000 acquiring HIV globally in 2018. 1 Late diagnosis of maternal HIV, incomplete adherence to ART, infection with ART-resistant virus, and breastmilk transmission account for the majority of current new infections. 1 Broadly neutralizing antibodies (bNAbs) are a novel class of therapies characterized by long half-lives, which require infrequent

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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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A Bodyweight-Dependent Allometric Exponent for Scaling Clearance Across the Human Life-Span

Cited by 69 publications

References 40 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

Model Informed Development of VRC01 in Newborn Infants Using a Population Pharmacokinetics Approach

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

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