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Identification of markers involved in drug disposition is crucial for drugs with a narrow therapeutic index. Individual genomic differences can affect the pharmacology of some drugs and participate to inter-individual variability in drug response. Pharmacogenetics is a useful tool in clinical practice for dosage adjustment and to limit drug toxicities. In pediatrics, physiological changes can also influence the disposition of drugs in infants, children and adolescents. The importance of ontogeny translates into different responses to the same drug in children and adults. Thus, interactions between the maturation of metabolism enzymes or transporters and genetics have a major impact on drug exposure leading to age-specific dosage requirements. This review aims to describe implementation of pharmacogenetics in personalized medicine and specifies pediatric characteristics with ethical considerations., (Copyright © 2018 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Individual genomic differences may affect drug disposition and effects of many drugs, and identification of biomarkers are crucial to personalize dosage and optimize response. In children, developmental changes associated with growth and maturation translate into different relationships between genotype and phenotype and different responses to treatment compared to adults. This review aims to summarize some developmental aspects of pharmacogenetics, based on practical examples., (© 2018 Elsevier Inc. All rights reserved.)

Background: The backbone of drug therapy used in acute lymphoblastic leukemia (ALL) in children includes 6-mercaptopurine (6-MP). Intracellular metabolism of this prodrug is a key component of the therapeutic response. Many metabolizing enzymes are involved in 6-MP disposition and active 6-MP metabolites are represented by 6-thioguanine nucleotides (6-TGN) and methylated metabolites primarily methylated by the thiopurine S-methyltransferase enzyme (TPMT). The genetic polymorphism affecting TPMT activity displays an important inter-subject variability in metabolites pharmacokinetics and influences the balance between 6-MP efficacy and toxicity: patients with high 6-TGN levels are at risk of myelosuppression while patients with high levels of methylated derivates are at hepatotoxic risk. However, the genetic TPMT polymorphism does not explain all 6-MP adverse events and some severe toxicities leading to life-threatening conditions remain unexplained. Additional single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in 6-MP metabolism and 6-MP transporters may also be responsible for this inter-individual 6-MP response variability., Aim: This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.

This article aims to provide an overview of the current situation regarding pharmacogenetic and pharmacogenomic (PG) studies in pediatrics, with a special focus on the role of PG data in the regulatory decision-making process. Despite the gap in pharmacogenetic research due to the lack of translational studies in adults and children, several technologies exist in drug development and biomarkers validation, which could supply valuable information concerning labeling and dosing recommendations. If performed under strict good clinical practice quality criteria, such findings could be included in the submission package of new chemical entities and used as additional information for prescribers, supporting further evaluation and understanding of the efficacy and safety profile of new medicines. Even though regulatory authorities may be aware of the potential role of PG in medical practice and guidances are available about the integration of PG in drug development, most data obtained from PG studies are not used by prescribers. The challenge is to better understand whether PG markers can be used to assess potential differences in drug response during the clinical program, so PG data can be integrated into the regulatory decision-making process, enabling the introduction of labeling information that promotes optimal dosing in the pediatric population.

Pharmacogenetic polymorphisms that change the amino acid sequences in coding regions only account for part of the interindividual differences in disease susceptibility and drug response. Additional pharmacogenomic and epigenetic factors are also involved. In children, pharmacogenetic studies are limited, although it has been clear for many years that the interactions between developmental patterns of drug-metabolizing enzymes and transporters have a major impact on dose exposure with age-specific dosage requirements. This article will analyze the factors affecting variability in drug response in children and focus on the pharmacogenetic polymorphisms of immunosuppressants, antidepressants, anticancer and anti-inflammatory drugs. Additional pharmacogenetic and epigenetic studies should be performed to allow the individualization of therapy in children.

The area of pharmacogenetics (PGt) is evolving rapidly. However, ongoing efforts in this field are not aligned with the requirements for the inclusion of clinically relevant findings into the label, especially with reference to paediatric indications. Clinical research in children poses unique issues from a practical and technical perspective, but many challenges can be overcome by applying advanced study design and data analysis methods. When investigating the role of PGt factors on treatment effect, all features that influence drug response must be taken into account. Yet, PGt often has a privileged status in research protocols, with PGt factors evaluated independently from other determinants of response, instead of being regarded as other demographic or clinical covariates (e.g., age, renal function). At present, guidelines to incorporate PGt findings into label statements are lacking in part because this is a new and incompletely understood area. This situation is no longer acceptable. To achieve the potential that PGt can offer to drug development and ultimately to drug prescription, academia, industry and regulatory agencies need to pool resources on the revision of study design and data analysis requisites, bringing in model-based methodologies to enable accurate interpretation of results and provide appropriate labelling recommendations.

Aims: Azathioprine (AZA) and 6‐mercaptopurine are prescribed in acute lymphoblastic leukaemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6‐thioguanine (6TGN) and 6‐methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation. Methods: The first paediatric TDM samples received during year 2021 were analysed, whatever indication and thiopurine drug. Target concentration ranges were 200–500, <6000 pmol/8 × 108 RBC for 6TGN and 6MMPN. Results: Children (n = 492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (P <.0001). ALL received 6‐mercaptopurine (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti‐inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [interquartile range: 142.5; 309.6] and 1144.6 [419.4; 3574.3] pmol/8 × 108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine aminotransaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant. Conclusion: TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow‐up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome. [ABSTRACT FROM AUTHOR]

Thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) are used extensively in pediatric and adult patients with inflammatory and neoplastic diseases. They are metabolized to 6-thioguanine nucleotides (6-TGN) or to 6-methyl-mercaptopurine nucleotides (6-MMPN). The balance between 6-TGN and 6-MMPN is highly variable and monitoring is recommended, but its benefit in outcome gives rise to conflicting results, potentially increased by differences in quantifying 6-MP metabolism. Our aim was to report (1) the HPLC-UV procedure used in our laboratory to quantify red blood cells (RBCs) with 6-TGN and 6-MMPN (as its derivate: 6-MMP(d)) in patients treated with thiopurines and (2) additional tests, sometimes confirmatory, to improve method standardization. The comparison of two methods to count RBCs shows that metabolite concentrations were slightly lower in the washed and resuspended RBCs than in whole blood. Perchloric acid (0.7 M), dithiothreitol (DTT, final 0.013 M sample concentration) and 60 min hydrolysis were selected for acid hydrolysis. (3) Monitoring data from 83 patients receiving AZA or 6-MP showed that at steady state, only 53/183 (29%) had 6-TGN and 6-MMPN in the recommended therapeutic range. Our method is discussed in light of the technical conditions and sample stability data from 17 publications identified since the first analytical report in 1987. Monitoring data demonstrate, if required, that inter-patient variability in 6-TGN and 6-MMPN concentrations is high in samples from treated patients. [ABSTRACT FROM AUTHOR]

Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea and/or calcium channel blocker (CCB) co-administration. We report a renal transplant recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough concentration in both conditions, diarrhoea and CCB co-administration, and with genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our knowledge, this is the first case to be investigated for such polymorphisms. Clinicians should be reminded of the possibility of highly increased levels of tacrolimus in situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and their influence in high-risk situations when enzyme activity is already affected by enterocyte damage due to diarrhoea and CCB competition. Keywords Calcium channel blocker * Cytochrome P450 * Diarrhoea * P-glycoprotein * Polymorphisms * Renal transplant * Tacrolimus, Introduction Tacrolimus is a calcineurin inhibitor increasingly used for immunosuppression in renal transplantation [1]. Following oral administration, tacrolimus is preferentially absorbed in the duodenum and jejunum with highly variable pharmacokinetics [...]

What is known and objectives: Thiopurines are cornerstone drugs in the treatment of acute lymphoblastic leukaemia (ALL), but their use can be complicated by the incidence of life‐threatening leucopenia. Case description: We describe a case of a 6‐year‐old Chinese boy with B‐ALL receiving extremely low dose of 6‐mercaptopurine (only 4% of recommended dose) during the ALL maintenance therapy phase. What is new and conclusion: Complex pharmacogenetic tests and TDM should be recommended in children with complicated ALL to highlight the large individual variability in the responses to 6‐MP exposure and the associated adverse effects. [ABSTRACT FROM AUTHOR]

Aims: Chinese children are more susceptible to the development of thiopurine‐induced leukopenia compared with Caucasian populations. The aim of our study was to establish a 6‐mercaptopurine (6‐MP) dose–concentration–response relationship through exploration of pharmacogenetic factors involved in the thiopurine‐induced toxicities in Chinese paediatric patients afflicted by acute lymphoblastic leukaemia (ALL). Methods: Blood samples were obtained from ALL children treated with 6‐MP. We determined the metabolite steady‐state concentrations of 6‐MP in red blood cells (RBCs) by using high‐performance liquid chromatography. Pharmacogenetic analysis was carried out on patients' genomic DNA using the MassArray genotyping platform. Results: Sixty children afflicted by ALL who received 6‐MP treatment were enrolled in this study. The median concentration of 6‐thioguanine in patients afflicted by leukopenia was 235.83 pmol/8 × 108 RBCs, which was significantly higher than for patients unafflicted by leukopenia (178.90 pmol/8 × 108 RBCs; P = 0.029). We determined the population special target 6‐thioguanine threshold to have equalled 197.50 pmol/8 × 108 RBCs to predict leukopenia risk in Chinese paediatric patients afflicted by ALL. Among 36 candidate single nucleotide polymorphisms, our results indicated that NUDT15 (rs116855232) and IMPDH1 (rs2278293) were correlated with a 5.50‐fold and 5.80‐fold higher risk of leukopenia, respectively. MTHFR rs1801133 variants were found to have had a 4.46‐fold significantly higher risk of hepatotoxicity vs wild‐type genotype. Conclusion: Our findings support the idea that predetermination of genotypes and monitoring of thiopurine metabolism for Chinese paediatric patients afflicted by ALL is necessary to effectively predict the efficacy of treatments and to minimize the adverse effects of 6‐MP maintenance therapy. [ABSTRACT FROM AUTHOR]

Aims: Although substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic–pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug. Methods: Pharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment. Population pharmacokinetic–pharmacogenetic analysis of omeprazole and its metabolites was performed using NONMEM. Results: Data fitted a one‐compartment parent and metabolite model with first‐order absorption and elimination. CYP2C19 and CYP3A4 are predominantly involved in the metabolism of omeprazole despite their relatively low activities compared to adults. The clearance of omeprazole converted to 5‐hydroxy‐omeprazole (CLOMZ‐M1) increases with postnatal age. In CYP2C19 poor and intermediate metabolizers, model‐predicted CLOMZ‐M1 are 12.5% (5–95% percentile: 3–14.9%) and 44.9% (5–95% percentile: 29.9–72.6%) of the value in extensive/ultrarapid metabolizer, respectively. Model‐predicted absorption rate constant of omeprazole is 6.93 (5–95% percentile: 3.01–14.61) times higher in ABCB1 homozygous mutant patients, 1.86 (5–95% percentile: 0.86–3.47) times higher in ABCB1 heterozygous patients than that in ABCB1 homozygous wild‐type patients. Conclusions: Developmental pharmacogenetics of CYP2C19 was quantitatively described in neonates and young infants using omeprazole as a probe drug. Our findings emphasize the importance of semiphysiological developmental pharmacokinetic modelling approach when evaluating developmental pharmacogenetics of drugs with multiple routes of biotransformation. [ABSTRACT FROM AUTHOR]

Background and Objectives: Tacrolimus is a new prolonged-release once-daily formulation of the calcineurin inhibitor tacrolimus, currently used in adult transplant patients. As there are no pharmacokinetic data available in pediatric kidney transplant recipients, the aims of this study were to develop a population pharmacokinetic model of tacrolimus in pediatric and adolescent kidney transplant recipients and to identify covariates that have a significant impacts on tacrolimus pharmacokinetics, including CYP3A5 polymorphism. Methods: Pharmacokinetic samples were collected from 22 pediatric kidney transplant patients. Population pharmacokinetic analysis was performed using NONMEM. Pharmacogenetic analysis was performed on the CYP3A5 gene. Results: The pharmacokinetic data were best described by a one-compartment model with first order absorption and lag-time. The weight normalized oral clearance CL/F [CL/F/ (weight/70)] was lower in patients with CYP3A5*3/*3 as compared to patients with the CYP3A5*1/*3 (32.2 ± 10.1 vs. 53.5 ± 20.2 L/h, p = 0.01). Conclusions: The population pharmacokinetic model of tacrolimus was developed and validated in pediatric and adolescent kidney transplant patients. Body weight and CYP3A5 polymorphism were identified as significant factors influencing pharmacokinetics. The developed model could be useful to optimize individual pediatric tacrolimus dosing regimen in routine clinical practice. [ABSTRACT FROM AUTHOR]

• The pharmacogenetic polymorphisms of both TPMT and ITPA are associated with individual variability in 6-mercaptopurine (6-MP) intracellular metabolism. • The balance between red blood cell (RBC) 6-thioguanine nucleotide (6TGN) and 6-methylated metabolite (6-MMPN) concentrations has an important impact on efficacy in children treated for acute lymphoblastic leukemia. • Hepatotoxicity is a frequent complication of the association 6-MP and methotrexate during maintenance therapy. • RBC 6-TGN concentrations are dependant on TPMT genotype and age, while RBC 6-MMPN concentrations depend on TPMT and ITPA polymorphisms. • Children aged 6 years or less had lower RBC 6-TGN concentrations during maintenance therapy, demonstrating an age effect on 6-MP intracellular metabolism. • Hepatotoxicity is a frequent complication of the association of 6-MP and methotrexate. A 6-MMPN threshold of 5000 pmol/8 × 10 RBC was associated with an increased risk of hepatotoxicity. 6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase ( TPMT) and inosine triphosphate pyrophosphatase ( ITPA) on 6-MP metabolism and response. Sixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2+ 21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis. During maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 10RBC) than in older children (600 pmol/8 × 10RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862 pmol/8 × 10RBC), intermediate in wild-type patients and high (16468 pmol/8 × 10RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000 pmol/8 × 10RBC was associated with an increased risk of hepatotoxicity. In this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children. [ABSTRACT FROM AUTHOR]