Pediatric Drug Safety Research Articles

Application of Quantitative Systems Pharmacology to Pediatric Drug Safety Assessment.

Application of Quantitative Systems Pharmacology to Pediatric Drug Safety Assessment.

Pediatric Drug Safety Surveillance: A 10-Year Analysis of Adverse Drug Reaction Reporting Data in Calabria, Southern Italy.

IntroductionThe paucity of pediatric clinical trials has led to many medicines frequently prescribed to children without a license for use in pediatrics, resulting in an increased risk of adverse drug reactions. Pharmacovigilance databases remain, among others, a valuable tool for evaluating pediatric drug safety in the real-life setting.ObjectiveWe aimed to characterize pediatric adverse drug reactions reported in the Italian Pharmacovigilance database coming from the Calabria region (Southern Italy) over 10 years.MethodsAll Individual Case Safety Reports (ICSRs) concerning individuals aged under 18 years were extracted from 2010 to 2019. Duplicate and vaccine ICSRs were excluded. The remaining ICSRs were analyzed with respect to patients’ demographic data, suspected drugs, and category of adverse drug reactions across different age groups.ResultsAmong 6529 selected ICSRs, 395 pediatric ICSRs corresponding to 556 adverse drug reactions were analyzed. From 2010 to 2015, an increasing number of ICSRs were observed, but the reporting rate decreased after 2015. The highest proportion of ICSRs concerned children and adolescents. Around 52% of ICSRs involved boys: a trend observed in all age groups excluding newborns. Sixty ICSRs were serious and among them, 75% required hospitalization mainly in children and adolescents. Most of the ICSRs were issued by physicians (64.1%), followed by other healthcare professionals (22.5%) and pharmacists (9.9%). Anti-infective agents for systemic use and skin disorders were, respectively, the most frequently reported drug group and adverse drug reaction category.ConclusionsThis study provides an overview of adverse drug reactions reported in the pediatric population of the Calabria region and emphasizes the need for strengthening the surveillance in specific age subgroups and on given drugs in relation to their pattern of use.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-022-01232-w.

A database of pediatric drug effects to evaluate ontogenic mechanisms from child growth and development

Adverse drug effects (ADEs) in children are common and may result in disability and death, necessitating post-marketing monitoring of their use. Evaluating drug safety is especially challenging in children due to the processes of growth and maturation, which can alter how children respond to treatment. Current drug safety-signal-detection methods do not account for these dynamics. We recently developed a method called disproportionality generalized additive models (dGAMs) to better identify safety signals for drugs across child-development stages. We used dGAMs on a database of 264,453 pediatric adverse-event reports and found 19,438 ADEs signals associated with development and validated these signals against a small reference set of pediatric ADEs. Using our approach, we can hypothesize on the ontogenic dynamics of ADE signals, such as that montelukast-induced psychiatric disorders appear most significant in the second year of life. Additionally, we integrated pediatric enzyme expression data and found that pharmacogenes with dynamic childhood expression, such as CYP2C18 and CYP27B1, are associated with pediatric ADEs. We curated KidSIDES, a database of pediatric drug safety signals, for the research community and developed the Pediatric Drug Safety portal (PDSportal) to facilitate evaluation of drug safety signals across childhood growth and development. This study was supported by grants from the National Institutes of Health (NIH).

C4c: Paediatric pharmacovigilance: Methodological considerations in research and development of medicines for children - A c4c expert group white paper.

Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population-specific factors (e.g., more frequent use of off-label/unlicensed drugs). In recognition of these challenges, a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life-cycle of medicinal products which are described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development, safety data collection and analysis. Furthermore, they describe the specific details of post-marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record-linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit-risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life-cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs.

AS3MT Polymorphism: A Risk Factor for Epilepsy Susceptibility and Adverse Drug Reactions to Valproic Acid and Oxcarbazepine Treatment in Children From South China.

Epilepsy is a common neurologic disorder characterized by intractable seizures, involving genetic factors. There is a need to develop reliable genetic markers to predict the risk of epilepsy and design effective therapies. Arsenite methyltransferase (AS3MT) catalyzes the biomethylation of arsenic and hence regulates arsenic metabolism. AS3MT variation has been linked to the progression of various diseases including schizophrenia and attention deficit or hyperactivity disorder. Whether genetic polymorphism of AS3MT contributes to epilepsy remains unclear. In this study, we investigated the association of AS3MT gene polymorphism with susceptibility to epilepsy in children from south China. We also explored the effect of AS3MT variation on the safety of antiepileptic drugs. Genotypic analysis for AS3MT rs7085104 was performed using samples from a Chinese cohort of 200 epileptic children and 244 healthy individuals. The results revealed a genetic association of AS3MT rs7085104 with susceptibility to pediatric epilepsy. Mutant homozygous GG genotype exhibited a lower susceptibility to childhood epilepsy than AA genotype. Carriers of AS3MT rs7085104 AA genotype exhibited a higher risk of digestive adverse drug reactions (dADRs) in children when treated with valproic acid (VPA) or oxcarbazepine (OXC). Additionally, bioinformatics analysis identified eight AS3MT target genes related to epilepsy and three AS3MT-associated genes in VPA-related dADRs. The effects of AS3MT on epilepsy might involve multiple targets including CNNM2, CACNB2, TRIM26, MTHFR, GSTM1, CYP17A1, NT5C2, and YBX3. This study reveals that AS3MT may be a new gene contributing to epileptogenesis. Hence, analysis of AS3MT polymorphisms will help to evaluate susceptibility to pediatric epilepsy and drug safety.

Improving Pediatric Drug Safety in Prehospital Emergency Care-10 Years on.

ObjectivesThe Pediatric Emergency Ruler (PaedER) is a height-based drug dose recommendation tool that was reported to reduce life-threatening medication errors by 90%. The PaedER was introduced into the Cologne Emergency Medical Service (EMS) in 2008 along with educational measures, publications, and lectures for pediatric drug safety. We reviewed the impact of these continuously ongoing measures on medication errors after 10 years.MethodsThe PaedER was introduced and distributed to all 14 emergency ambulances and 2 helicopters staffed with emergency physicians in the city of Cologne in November 2008. Electronic records and medical protocols of the Cologne EMS over two 20-month periods from March 2007 to October 2008 and March 2018 to October 2019 data sets were retrieved. The administered doses of either intravenous, intraosseous, intranasal, or buccal fentanyl, midazolam, ketamine, or epinephrine were recorded. Primary outcome measure was the rate of severe drug dosing errors with a deviation from the recommended dose of greater than 300%.ResultsA total of 59 and 443 drug administrations were analyzed for 2007/08 and 2018/19, respectively. The overall rate of drug dosing errors decreased from 22.0% to 9.9% (P = 0.014; relative risk reduction, 55%). Four of 5 severe dosing errors for epinephrine were avoided (P < 0.021; relative risk reduction, 78%). Documentation of patient’s weight increased from 3.2% in 2007/08 to 30.5% in 2018/19 (P < 0.001).ConclusionsThe distribution of the PaedER combined by educational measures significantly reduced the rates of life-threatening medication errors in a large EMS. Those results should motivate further initiatives on pediatric drug safety in prehospital emergency care.

Evaluating risk detection methods to uncover ontogenic-mediated adverse drug effect mechanisms in children

BackgroundIdentifying adverse drugs effects (ADEs) in children, overall and within pediatric age groups, is essential for preventing disability and death from marketed drugs. At the same time, however, detection is challenging due to dynamic biological processes during growth and maturation, called ontogeny, that alter pharmacokinetics and pharmacodynamics. As a result, methodologies in pediatric drug safety have been limited to event surveillance and have not focused on investigating adverse event mechanisms. There is an opportunity to identify drug event patterns within observational databases for evaluating ontogenic-mediated adverse event mechanisms. The first step of which is to establish statistical models that can identify temporal trends of adverse effects across childhood.ResultsUsing simulation, we evaluated a population stratification method (the proportional reporting ratio or PRR) and a population modeling method (the generalized additive model or GAM) to identify and quantify ADE risk at varying reporting rates and dynamics. We found that GAMs showed improved performance over the PRR in detecting dynamic drug event reporting across child development stages. Moreover, GAMs exhibited normally distributed and robust ADE risk estimation at all development stages by sharing information across child development stages.ConclusionsOur study underscores the opportunity for using population modeling techniques, which leverage drug event reporting across development stages, as biologically-inspired detection methods for evaluating ontogenic mechanisms.

Drug Safety in Labeling for Pediatric Drug Development and Dose Selection in Submissions to the US Food and Drug Administration.

Pediatric safety evaluations are an essential part of a pediatric drug development program. Communication of the results of these safety evaluations is primarily accomplished by labeling of the drug either during the initial pediatric drug development program, or during the postmarketing period after drug approval for pediatric patients. During drug development, the dose-adverse drug event (ADE) relationship is an important part of the evaluation, but a consideration for pediatric ADEs that are unrelated to drug dosage must be maintained. Examples of dose-related and non-dose-related ADEs are presented. The failure to label a product for pediatric use has been safety related for a number of development programs. The US Food and Drug Administration's Pediatric Advisory Committee is a primary source of the pediatric postmarketing safety review and has been associated with a number of labeling changes through its ongoing review process. Pediatric drug safety remains a critical part of the assessment of dose-effect relationship in the pediatric patient population during the drug development and postmarketing surveillance process.

Analysis of the reporting of adverse drug reactions in children and adolescents in Germany in the time period from 2000 to 2019.

The objective of this study was to analyse reports on adverse drug reactions (ADRs) from Germany in the particularly vulnerable patient group of children and adolescents. Reporting characteristics, demographic parameters and off-label use were examined among others. The ratio of ADR reports per number of German inhabitants and the ratio of ADR reports per number of German inhabitants exposed to drugs were calculated and compared. These parameters were examined to derive trends in reporting of ADRs. 20,854 spontaneous ADR reports for the age group 0–17 years were identified in the European ADR database EudraVigilance for the time period 01.01.2000–28.02.2019 and analysed with regard to the aforementioned criteria. 86.5% (18,036/20,854) of the ADR reports originated from Healthcare Professionals and 12.2% (2,546/20,854) from non-Healthcare Professionals. 74.4% (15,522/20,854) of the ADR reports were classified as serious. The proportion of ADR reports per age group was 11.8% (0–1 month), 11.0% (2 months—1 year), 7.4% (2–3 years), 9.3% (4–6 years), 25.8% (7–12 years), and 34.8% (13–17 years) years, respectively. Male sex slightly dominated (51.2% vs. 44.8% females). Only 3.5% of the ADR reports reported off-label use. The annual number of ADR reports increased since 2000, even if set in context with the number of inhabitants and assumed drug-exposed inhabitants. The pediatric population declined in the study period which argues against its prominent role for the increase in the total number of ADR reports. Instead, among others, changes in reporting obligations may apply. The high proportion of serious ADR reports underlines the importance of pediatric drug safety.

No population left behind: Improving paediatric drug safety using informatics and systems biology.

Adverse drugs effects (ADEs) in children are common and may result in disability and death. The current paediatric drug safety landscape, including clinical trials, is limited as it rarely includes children and relies on extrapolation from adults. Children are not small adults but go through an evolutionarily conserved and physiologically dynamic process of growth and maturation. Novel quantitative approaches, integrating observations from clinical trials and drug safety databases with dynamic mechanisms, can be used to systematically identify ADEs unique to childhood. In this perspective, we discuss three critical research directions using systems biology methodologies and novel informatics to improve paediatric drug safety, namely child versus adult drug safety profiles, age‐dependent drug toxicities and genetic susceptibility of ADEs across childhood. We argue that a data‐driven framework that leverages observational data, biomedical knowledge and systems biology modelling will reveal previously unknown mechanisms of pediatric adverse drug events and lead to improved paediatric drug safety.

Off-Label Antibiotic Use in the Pediatric Population: A Population-based Study in Taiwan

This study investigated the epidemiology and determinants of off-label antibiotic use in children in Taiwan. This was a retrospective, population-based study using the 2002-2005 Taiwan's National Health Insurance Research Database (NHIRD). The study subjects consisted of children under 12 years old. The prescriptions of antibiotics were retrieved from the pharmacy claims of NHIRD. Multivariable logistie regression models were used to assess the associations between patients' and providers' demographics and off-label use of antibiotics. Among 66,446 antibiotic prescriptions identified, off-label use accounted for 33.33%. The percentages of off-label use varied, with time trend, dispensing type. patient characteristics, physician characteristics and institution characteristics, Off- label use of antibiotics is very common among Taiwanese children. especially in the cases whose prescriptions were issued by senior and experienced physicians as well as those from private, non-teaching or regional hospitals. Off-label use can seriously affect pediatric drug safety and health, and are worthy of more concern and discussion. In addition, the study in the future would still need to explore the possible root causes of off label use.

Validity of administrative claims-based algorithms for ventricular arrhythmia and cardiac arrest in the pediatric population.

Identify administrative claims-based algorithms for capturing out-of-hospital ventricular arrhythmias (VA) and cardiac arrests (CA) due to cardiac causes in the pediatric population with high positive-predictive value (PPV). Within a single pediatric center, a retrospective cohort of patients hospitalized or seen in the emergency room for VA or CA were identified from the electronic health records. Eligible encounters were blindly reviewed and linked to administrative data, including ICD-9/ICD-10 codes. Test characteristics, including PPV, for different diagnostic and procedure codes were generated using a 50% training sample. The gold standard was definite or suspected out-of-hospital VA or CA due to cardiac cause verified based on clinical criteria. Algorithms with the highest PPV were then applied to a 50% validation sample to validate performance. From 2004-2017, 598 encounters met eligibility criteria. 174 (29%) had an outcome of interest, with remainder being an inpatient event or CA due to other cause. Within the training sample (n = 263), VA codes in primary position had a PPV 94% (95%CI 81%-99%) with low sensitivity (44%, 95%CI 33%-56%). CA codes in any position or VA codes in nonprimary positions had low PPV (18%-19%, 31% respectively). Applying the top three performing algorithms to the validation sample (n = 252) yielded similar PPV values. Contrary to adults, algorithms including a CA code do not perform well for identifying out-of-hospital VA and CA due to cardiac cause in the pediatric populations. Researchers should be aware of the potential implications for future pediatric drug safety studies for these outcomes.

Preparation of Cangai oil transfersomes patches and its in vitro evaluation

L_9(3~4) orthogonal experiment design was used to optimize the preparation of the patches,and investigate its affecting factors and skin irritation. Eugenol was taken as the index component to study the release behavior in vitro and percutaneous penetration of Cangai oil transfersomes patches by HPLC.The results showed that the optimal prescription for preparing Cangai oil transfersomes patches were Eudragit E100 0.6 g, succinic acid 0.08 g,triethyl citrate 0.25 g,glycerol 0.2 g.Patches prepared by the preferred preparation had a flat appearance without obvious bubbles.The initial adhesion was 18.33±2.52, the stickiness was(30.01±2.45) min,and the peel strength was(5.62±0.95) kN·m~(-1).The results of affecting factors experiment showed the order of factors affecting its adhesion was humidity&gt;temperature&gt;lighting,and the skin irritation test results showed no significant skin irritation after 24 h of single administration. The results of drug release behavior in vitro showed that the release and the percutaneous penetration of both Cangai oil patches and Cangai oil transfersomes patches conformed to the Higuchi equation.The release amount of eugenol were 80.66% and 82.25% at 72 h, with no significant difference. The cumulative permeation area of eugenol per unit area reached(0.195 6±0.065 9),(0.131 0±0.045 5) mg·cm~(-2) at 72 h, with significant differences(P&lt;0.05).The experiment results proved that the preparation process of Cangai oil transfersomes patches was stable,and the prepared patches had a good adhesion. At the same time,the preparation of transfersomes patches could alleviate and control the release of the drug to a certain extent, and provide a certain experimental basis for clinical pediatric drug safety.

A computational method to quantitatively measure pediatric drug safety using electronic medical records

BackgroundDrug safety in children is a major concern; however, there is still a lack of methods for quantitatively measuring, let alone to improving, drug safety in children under different clinical conditions. To assess pediatric drug safety under different clinical conditions, a computational method based on Electronic Medical Record (EMR) datasets was proposed.MethodsIn this study, a computational method was designed to extract the significant drug-diagnosis associations (based on a Bonferroni-adjusted hypergeometric P-value < 0.05) among drug and diagnosis co-occurrence in EMR datasets. This allows for differences between pediatric and adult drug use to be compared based on different EMR datasets. The drug-diagnosis associations were further used to generate drug clusters under specific clinical conditions using unsupervised clustering. A 5-layer quantitative pediatric drug safety level was proposed based on the drug safety statement of the pediatric labeling of each drug. Therefore, the drug safety levels under different pediatric clinical conditions were calculated. Two EMR datasets from a 1900-bed children’s hospital and a 2000-bed general hospital were used to test this method.ResultsThe comparison between the children’s hospital and the general hospital showed unique features of pediatric drug use and identified the drug treatment gap between children and adults. In total, 591 drugs were used in the children’s hospital; 18 drug clusters that were associated with certain clinical conditions were generated based on our method; and the quantitative drug safety levels of each drug cluster (under different clinical conditions) were calculated, analyzed, and visualized.ConclusionWith this method, quantitative drug safety levels under certain clinical conditions in pediatric patients can be evaluated and compared. If there are longitudinal data, improvements can also be measured. This method has the potential to be used in many population-level, health data-based drug safety studies.

Pediatric drug safety signal detection of non-chemotherapy drug-induced neutropenia and agranulocytosis using electronic healthcare records

ABSTRACTObjectives: This study aimed to develop a procedure to explore the adverse drug reaction signals of drug-induced neutropenia (DIN) or drug-induced agranulocytosis (DIA) in children using an electronic health records (EHRs) database.Methods: A two-stage design was presented. First, the suspected drugs to induce DIN or DIA were selected. Second, the associations were evaluated by a retrospective cohort study.Results: Ten and five drugs were potentially identified to be associated with DIN and DIA, respectively. Finally, five (oseltamivir, chlorpheniramine, vancomycin, meropenem, and ganciclovir) and two (chlorpheniramine, and vancomycin) drugs were found to be associated with DIN and DIA, respectively. Of these, the association between oseltamivir and neutropenia (P = 9.83 × 10–9; OR, 2.10; 95% CI, 1.62−2.69) was considered as a new signal for both adults and children. Chlorpheniramine-induced neutropenia (P = 3.01 × 10–8; OR, 1.59; 95% CI, 1.35−1.87) and agranulocytosis (P = 3.16 × 10–7; OR, 3.76; 95% CI, 2.25−6.26) were considered as new signals in children. Other drugs associated with DIN or DIA were confirmed by previous studies.Conclusion: A method to detect signals for DIN and DIA has been described. Several pediatric drugs were found to be associated with DIN or DIA.

Adverse Drug Reactions in Children: Pediatric Pharmacy and Drug Safety.

An underappreciated problem in child health is the risk for adverse drug reactions (ADRs). While there is an impression that children are at a lower risk than adults for ADRs, in fact a number of factors germane to pediatric therapy place certain groups of children at a high risk for adverse events associated with therapy. Given the importance of drug safety, an understanding of a diagnostic classification for ADRs and of how to approach a possible ADR clinically are key skills for pediatric pharmacists. As drug therapy for children evolves, becomes more complex, and begins to use novel molecules and biologicals there will be an increasing need for pediatric pharmacists to be more involved in clinical care, education, and research specific to drug safety.

Review of the Methods to Obtain Paediatric Drug Safety Information: Spontaneous Reporting and Healthcare Databases, Active Surveillance Programmes, Systematic Reviews and Meta-analyses.

Knowledge of drugs safety collected during the pre-marketing phase is inevitably limited because the randomized clinical trials (RCTs) are rarely designed to evaluate safety. The small and selective groups of enrolled individuals and the limited duration of trials may hamper the ability to characterize fully the safety profiles of drugs. Additionally, information about rare adverse drug reactions (ADRs) in special groups is often incomplete or not available for most of the drugs commonly used in the daily clinical practice. In the paediatric setting several highimpact safety issues have emerged. Hence, in recent years, there has been a call for improved post-marketing pharmacoepidemiological studies, in which cohorts of patients are monitored for sufficient time in order to determine the precise risk-benefit ratio. In this review, we discuss the current available strategies enhancing the post-marketing monitoring activities of the drugs in the paediatric setting and define criteria whereby they can provide valuable information to improve the management of therapy in daily clinical practice including both safety and efficacy aspects. The strategies we cover include the signal detection using international pharmacovigilance and/or healthcare databases, the promotion of active surveillance initiatives which can generate complete, informative data sets for the signal detection and systematic review/meta-analysis. Together, these methods provide a comprehensive picture of causality and risk improving the management of therapy in a paediatric setting and they should be considered as a unique tool to be integrated with post-marketing activities.

Masking by vaccines in pediatric drug safety signal detection in the EudraVigilance database.

Postmarketing drug safety surveillance relies upon measures of disproportionate reporting in spontaneous reporting systems. It has been hypothesized that products or events reported frequently may "mask" signals. We analyzed the masking effect of vaccines in pediatrics in the EudraVigilance database by conducting disproportionality analysis in the full database (containing vaccine exposures) and in a restricted set (excluding vaccine exposures). We measured performance of the reporting odds ratio (ROR) in both data sets using a pediatric-specific drug reference set and in the absence of a reference set. We assessed masking effects across age groups and conducted a classification tree (CART) analysis. Removal of vaccines decreased the ROR values both in negative and positive controls. Exceptions were drug-event combinations including outcomes frequent in vaccine reports. When restricted to positive control associations, removal of vaccine-related events resulted in increased ROR values for events commonly reported following vaccination. For events rarely associated with vaccination, ROR values decreased for all age groups, especially infants. Analysis in the absence of a reference set showed decrease in ROR following vaccine removal and CART revealed that change in ROR with vaccine removal depended upon age and proportion of reports including a vaccine. Removal of vaccines for signal detection in a pediatric population has an impact on ROR, dependent upon the reporting frequency of the event of interest in combination with vaccines. We recommend stratification by age and removal of vaccine exposures if the investigated adverse drug reactions include those typically reported in association with vaccines for the age strata.

Pediatric Prehospital Medication Dosing Errors: A National Survey of Paramedics

ABSTRACTBackground: Pediatric drug dosing errors occur at a high rate in the prehospital environment. Objective: To describe paramedic training and practice regarding pediatric drug administration, exposure to pediatric drug dose errors and safety culture among paramedics and EMS agencies in a national sample. Methods: An electronic questionnaire was sent to a random sample of 10,530 nationally certified paramedics. Descriptive statistics were calculated. Results: There were 1,043 (9.9%) responses and 1,014 paramedics met inclusion criteria. Nearly half (43.0%) were familiar with a case where EMS personnel delivered an incorrect pediatric drug dose. Over half (58.5%) believed their initial paramedic program did not include enough pediatric training. Two-thirds (66.0%) administered a pediatric drug dose within the past year. When estimating the weight of a pediatric patient, 54.2% used a length-based tape, while 35.8% asked the parent or guardian, and 2.5% relied on a smart phone application. Only 19.8% said their agency had an anonymous error-reporting system and 50.7% believed they could report an error without fear of disciplinary action. For solutions, 89.0% believed an EMS-specific Broselow-Luten Tape would be helpful, followed by drug dosing cards in milliliters (83.0%) and changing content of standardized pediatric courses to be more relevant (77.7%). Conclusion: This national survey demonstrated a significant number of paramedics are aware of a pediatric dosing error, safety systems specific to pediatric patients are lacking, and that paramedics view pediatric drug cards and eliminating drug calculations as helpful. Pediatric drug-dosing safety in the prehospital environment can be improved.

Effect of Age on The Hepatocellularity Number for Wistar rats.

Recently there has been a substantial increase in the number of juvenile animal toxicity studies that are conducted to support pediatric drug safety evaluation. Adequate design of juvenile toxicity studies in rats, for instance with respect to dose levels per age group, requires an understanding of age-dependent pharmacokinetics. In vitro-in vivo extrapolation (IVIVE) and physiologically based pharmacokinetic (PBPK) modeling can help to anticipate age-dependent drug exposure in juvenile toxicity studies provided age-dependent profiles for animal physiology and scaling factors are available. For instance, when hepatocytes are used to predict hepatic drug clearance, the hepatocellularity (number of hepatocytes per gram liver, HPGL) is required as one of the scaling factors. Although HPGL is known for adult rats, information on the influence of age on HPGL is missing. The present work profiles the hepatocellularity number in male Wistar rats as a function of age. Using the NADPH-cytochrome P450 reductase (NCR) activity method, the mean HPGL for the adult rat (8 weeks) was 104 × 10(6) cells/gram liver (relative standard deviation 17%). This value was calculated as a ratio between NRC activities in liver homogenates and suspended hepatocytes. The HPGL values were significantly higher (p <0.001) for rat pups until 3 weeks of age compared with adults. Our results revealed that the HPGL value showed a rapid decrease after 3 weeks (end of weaning), essentially reaching adult values by 4 weeks. This age-dependent HPGL profile will be instrumental for hepatic drug clearance prediction when designing juvenile toxicity studies in Wistar rats.