Table 1.
Description of Studies About Impact of Pharmacogenetics on Pharmacokinetics and -Dynamics in Neonates and/or Infants
| Author, Year, Country | Study Aim | Setting | Study Design | Study Population | Sample Size (Male/Female) | Ethnicity or Nationality | Age (Days) | Effect on PK and/or PD |
|---|---|---|---|---|---|---|---|---|
| Allegaert et al 2008, Belgium31 | Determinants of tramadol O-demethylation | NICU | Cohort study | Neonates and young infants | N=86 (n/a) | - | 1–7 days: 45/86 8–28 days:22/86 >28 days: 19/86 |
PMA and CYP2D6 polymorphisms |
| Ansari et al 2010, Canada43 | GST polymorphism on busulfan | HSCT Unit | Cohort study | Children | N=4/28 infants (1/3) | - | <1 years: 0.5 y 1–4 years: 2.2 y >4 years: 10.4 y |
GSTM1 genotype was the best predictor of first-dose pharmacokinetic variability |
| Barnett et al 2021, UK20 | PK and PGx of cyclophosphamide (CYP2B6, CYP2C19) | Multicentre (8 UK centres) | Cohort study | Children | N=14/25 infants (10/15) | - | 0–6 months: 4/25 7–12 months:10/25 13–24 months: 11/25 |
No significant differences in cyclophosphamide clearance in patients <2 years |
| Blake et al 2007, USA30 | Ontogeny of Dextromethorphan O- and N-demethylation | Multicentre (6 Pediatric Pharmacology Research Unit) | Cohort study | Healthy infants | N=193 infants (95/98) | African american (n=81) European american (n=64) |
Between mean (SD), 14.4 (2.2) and 371.1 (18.2) days (Strength= repeated measurement) |
A strong correlation between CYP2D6 genotype and Dextromethorphan O-demethylation |
| Cao et al 2018, China64 | Association between TNF and MAPK8 polymorphisms and low response to HBV vaccines | A University Hospital | Cohort study | Infants | N=709 infants (374/335) | - | GA, mean (SD) Low responders: 39.0 (1.4) weeks High responders: 38.9 (1.4) weeks |
MAPK8 polymorphisms are associated with immune response to HBV vaccinations in infants |
| Chen et al 2014, China36 | Impact of CYP3A5 variants on tacrolimus disposition | LDLT Unit | Cohort study | Pediatrics | N=90 (52/38) | - | 10 (4–120) months | CYP3A5 genotyping both in recipient and donor, not ABCB1 or ACE is necessary for establishing a personalized tacrolimus dosage regimen |
| Elens et al 2016, the Netherlands63 | Impact of two SNPs on the response to opioid treatment (intubation setting) | NICU | Cohort study | Preterm infants 193 (185–200) days, equal to 26.4–28.6 weeks | N=34 (21/13) | - | 7.17 (4.10–10.23) days | KCNJ6 −1250A and COMT158Val alleles are predisposing to diminished opioid-induced pain relief |
| Enlund-Cerullo et al 2019, Finland65 | GC genotype–related differences in 25OHD concentrations | Maternity Hospital | RCT | Infants | N=913 (459/454) | - | GA, mean (SD) 40.2 (1.1) weeks | Vitamin D binding protein genotype affects 25OHD concentration |
| Fanta et al 2008, Finland53 | Variations in the ABCB1, ABCC2, SLCO1B1, CYP3A4, CYP3A5, or NR1I2 genes associated with the pharmacokinetics of cyclosporine | Children’s and Adolescents Hospital | Cohort study | Children and adolescents with renal transplant candidate | N=31/104 infants (66/38) | Finnish Caucasians (n=103) East African (n=1) |
0.72 (0.17) months | Age-related effect of ABCB1 polymorphism on oral bioavailability |
| Fukudo et al 2006, Japan35 | PopPK of tacrolimus and the effects of the MDR1 gene and the CYP3A4 and CYP3A5 on the oral clearance of tacrolimus | LDLT Unit | Retrospective observational study | Pediatric liver transplant recipients | N=130 (67/63) | - | Subpopulation PG data 1.3 (0.3–15) year |
The enterocyte MDR1 mRNA level and the CYP3A5*1 allele in the graft liver contribute differently to the interindividual variability in the oral clearance of tacrolimus after living-donor liver transplantation |
| Gao et al 2021, China18 | Evaluate the suitability of the current caffeine dosing regimen for the Chinese population using modelling and simulation approach. | NICU | Cohort study | Preterm newborns GA 28.3 (25–33.4) weeks |
N=99 (58/41) | - | 19.8 (10.8) days | CYP1A2 genotypes had no effect on caffeine clearance |
| Gorny et al 2010, Germany33 | CYP2D6 ultrarapid metabolism with ritonavir | Pediatric Oncology | Case report | Infant | N=1 | African | 6 months | Failure of ritonavir due to CYP2D6 ultrarapid metabolism |
| Guan et al 2019, China19 | Correlation between genetic polymorphisms and dexmedetomidine concentration levels | Children’s Hospital | Cohort study | Pediatrics | N=260 (120/140) | - | 28.82 (24.42) months aged 4–72 months | Correlation between CYP2A6 rs835309 activity and concentration of dexmedetomidine |
| Hahn et al 2019, USA62 | How does OCT1 ontogeny and genetic variation influence morphine disposition in neonatal patients? | NICU | Cohort study | Neonates | N=83 (53/30) | Caucasian (n=28) African American (n=11) Asian (n=1) |
14 days PMA 38.3 (24.9–57.3) months PNA 14 (1–212) days |
Morphine clearance follows a developmental trajectory in parallel with ontogeny of hepatic OCT1 protein expression |
| Hahn et al 2020, USA60 | The influence of MRP3 genetics on morphine clearance | Children’s Hospital | Retrospective study | Neonatal and pediatric patients | N=57/142 neonates (Fig 1 and 2 of relevance) | - | PMA: 24–58 weeks | Morphine clearance showed an identical but nonsignificant decreasing trend by MRP3 genotypes |
| Hamberg et al 2013, Sweden24 | Comparison of accuracy in dose prediction relative to published warfarin algorithms for children | Children’s Hospital | Cohort study | Pediatrics | N=64 (33/31) | Caucasian (n=53) Asian (n=6) African (n=2) |
4.3 years | The bridged PK/PD model performed prediction for warfarin maintenance dose CYP2C9, VKORC1 |
| Hill et al 2014, UK54 | Actinomycin D pharmacokinetics and investigate the impact of pharmacogenetic variation on the disposition | Multicentre | Cohort study | ≤21 years Children with cancer | N=9/158 infants (78/80) | White British (n=140) | 4.6 years | Body weight as the major determinant of actinomycin D clearance Variation in ABCB1 does not significantly impact on actinomycin D pharmacokinetics |
| Hronova et al 2016, Czech Republic56 | Effect of dosing and genetic factors on sufentanil- and midazolam-induced analgosedation and withdrawal syndrome | PICU | Retrospective study | Neonates and children over 3 months of age | N=30/48 neonates (17/13) | - | PMA: 40 (37–42) weeks | SNPs in the candidate genes COMT, PXR and ABCB1 affected the dosing of analgosedative drugs |
| Kato et al 2011, Japan67 | Effect of the genotype of VKORC1 on warfarin dose requirements | Children’s Hospital | Cohort study | Pediatrics | N=48 (33/15) | Japanese patients | 6.6 (5.8) years Range: 0.42–19.25 years |
VKORC1 genotype and age were major factors affecting the relationship between the weight-normalized warfarin dose |
| Keller et al 2014, Argentina45 | Evaluate the genotype and phenotype of NAT2 under isoniazid | Children’s Hospital | Cohort study | Pediatrics | N=25/88 infants | Argentinian patients | 4–23 months | A typical high proportion of rapid acetylators compared with other populations |
| Langaee et al 2021, USA42 | Relationship between genetic variations in relevant drug disposition genes and niverapine PK parameters | Children’s Hospital | Cohort study | Ghanaian children younger than 3 years old | N=53 | - | 1.6 (0.3–3.6) years | Genotyping for CYP2B6 rs3745274, and the NR1I2 rs6785049 G > A SNP (which encodes the transcriptional factor, pregnane X receptor), could improve prediction of nevirapine PK |
| Lee et al 2012, Korea27 | Effects of CYP2C19 genetic polymorphisms on phenobarbital PK | Children’s Hospital | Cohort study | Neonates and infants | N=44 (27/17) infants | - | 8 days-6 months (subgroup analysis < 4 months, or 4–6 months) | Phenobarbital PK were not significantly different among the groups with different CYP2C19 genotypes |
| Linakis et al 2018, USA50 | The role of genetic variability on the relevant metabolic pathways to determine which variants contribute to the variability observed in the PK profile of acetaminophen metabolites | NICU | Cohort study | Neonates | N=33 (19/14) | Non-Hispanic (n=22) Hsipanic (n=8) Declined to respond (n=3) |
6 (1–26) days Extreme preterm (10), preterm (6) and term cases (17) |
Pharmacogenetic effect of a sequence variations in the UGT1A9 promoter region on the metabolism of acetaminophen (glucuronide formation clearance) |
| Maagdenberg et al 2018, the Netherlands25 | Dosing algorithms for pediatric patients receiving acenocoumarol with and without genetic information | Multicentre (4 Pediatric Hospital) | Retrospective study | ≤ 18 years | N=4/166 infants (84/82) N=123/175, and 86/123 with valid data on weight and height, only 2 infants included |
European (n=141) Asian (n=4) African (n=4) |
Clinical cohort: 8.9 (4.2–13.3) years Genetic cohort: 9.2 (4.2–14.0) years (86 and 80 cases), only 2 infants included |
Genotypes of VKORC1, CYP2C9 and CYP2C18 to the algorithm increased variability in dose requirement to 61.8%. |
| Matic et al 2014, the Netherlands51 | Determine whether SNPs of OPRM1 118A>G (asn40asp), COMT 472G>A (val158met) and ARRB2 8622C>T are associated with morphine rescue in placebo | NICU | RCT | (Pre)term newborns on mechanical ventilation | N=64 neonates (39/25) | Caucasian (n=53) | PNA <3 days GA, rescue morphine:28.7 (27.3–31.4) weeks No rescue morphine: 30 (29.1–32.1) weeks in the placebo group |
Combined OPRM1 118A>G and COMT 472G>A genotype might serve as a predictor for the need of rescue morphine |
| Matic et al 2014, the Netherlands52 | Association between UGT2B7 polymorphism −900G>A (rs7438135, also known as-842G>A) with morphine kinetics | NICU | RCT | Preterm newborns on mechanical ventilation (<37wks) | N=15 neonates (8/7) | - | 0.14–7.4 days | GT2B7 −900G>A polymorphism significantly alters morphine PK (morphine, and morphine ratio’s, M3G/M and M6G/M |
| Matic et al 2016, the Netherlands61 | Effect of SLC22A1 (encoding the OCT1) genotype on tramadol PK | Children’s Hospital | Retrospective study | Neonates and infants | N=50 | Caucasian (n=45) | 7.0 (2.0–27) days | Additional role of SLC22A1/OCT1 genetics in M1 exposure OCT1 is already active early after birth OCT1 allelle frequency and CYP2D6 functional genes copies <2 or ≥2 |
| Pogliani et al 2012, Italy57 | Relationship between renal morphine toxicity and genetic background | Children’s Hospital | Case report | Premature infant | N=1 | Caucasian | Newborn | Effect of impaired P-glycoprotein activity due to C3435T polymorphism in the ABCB1 gene on accumulation of morphine within urothelial cells |
| Roberts et al 2016, USA59 | Determine the popPK of oral topotecan, specifically evaluating the effects of age and ABCG2 and ABCB1 on the Ka | Children’s Hospital | Cohort study | Infants and very young children | N=61 (38/23) | - | 2.37 (0.48–4.59) years | A possible role for the ABCG2 rs4148157 allele in the PK of oral topotecan |
| Schaaf et al 2005, South Africa46 | PK of isoniazid in relation to the NAT2 genotype. | Children’s Hospital | Cohort study | <13 years | N=18/64, 0–2 years | - | 3.8 years | Younger children eliminate isoniazid faster than older children for each genotype (NAT2) k decreases with age within each genotype |
| Shimizu et al 2018, Japan34 | Dihydrocodeine overdoses and PK modelling with genotyped as cytochrome P450 2D6*1/*10-*36 | Children’s Hospital | Case report | Neonate and 14-years old girl | N=2 | Japanese patients | 1 month | CYP2D6*1/*10-*36 genotype may not significantly contribute to the likelihood of dihydrocodeine overdose |
| Sridharan et al 2021, Kingdom of Bahrain41 | Prevalence of SNPs in the key CYP enzymes and their effect on urinary metabolites and serum acetaminophen concentrations | Children’s Hospital | Cohort study | Neonates | N=74 (38/36) | - | 4 (1–20) days | A significant prevalence of SNPs in the key CYP enzymes related to acetaminophen metabolism was observed Relevant, but in essence negative study (cyp isoenzymes focused) |
| Uesugi et al 2006, Japan37 | Liver transplants, CYP3A5 genotype in both recipients and donors, and the effect of the recipients’ polymorphism on the concentration/dose ratio of tacrolimus in patients after LDLT | LDLT Unit | Cohort study | General population | N=204 | - | 0.25–70 years | Intestinal CYP3A5, as well as hepatic CYP3A5, plays an important role in the first-pass effect of orally administered tacrolimus |
| Veeravigrom et al 2015, Thailand23 | Effext of CYP2C9 and CYP2C19 on phenytoin metabolism | Neurology Unit | Case Report | Infant | N=1 | - | 2 months | Phenytoin toxicity resulting from CYP2C9 gene polymorphism |
| Ward et al 2010, USA28 | PK profile of pantoprazole granules | Multicentre | RCT | Neonates with GERD | N=40 | White (n=30) Hispanic or Latino (n=8) African American (n=6) Asian (n=1) |
8.0 (1.3–19.6) weeks | Two patients with the CYP2C19 poor metabolizer genotype had a substantially higher AUC than extensive metabolizers |
| Xue et al 2014, China73 | Effect of CYP3A5 genotype on optimal dosage regimen in LDLT patients | LDLT Unit | Cohort study | Pediatrics | N=64 (39/25) | Chinese recipients and donors | 9–11 months | CYP3A5 genotype in both recipients and donors significantly affects tacrolimus PK after Liver transplantation |
| Yang et al 2011, China74 | The role of PGx determinants in the treatment of childhood ALL | University Hospital | Retrospective study | Pediatrics | N=7/105 infants (59/46) | Chinese patients | 0–1 years | Independent PGx determinants associated with treatment outcome (event free survival): ABCB1, MDR1, etc. |
| Yang et al 2015, China75 | Impact of SNPs of CYP3A5 and ABCB1 genotypes on tacrolimus PK | LDLT Unit | Retrospective study | Pediatrics | N=136 (74/62) | Chinese recipients and donors | 8–10 months | CYP3A5 (R and D) and ABCB1-1236 genotyping (R), in addition to recipient age, are necessary for establishing a more accurate tacrolimus dosage regimen |
| Zhao et al 2018, China29 | Effect of both age and PGx on developmental pattern of CYP2C19 in omeprazole | Children’s Hospital | Cohort study | (Pre)term Neonates and young infants with GERD | N=51 (24/27) | Caucasian (n=51) | 38 (7–87) days GA 31.3 (24–41 weeks) |
Both CYP2C19 genotype and age contribute to the developmental PK of omeprazole and its metabolites ABCB1 PG is relevant on the absorption rate constant |
| Zhu et al 2012, USA49 | İmpact of polymorphism of izoniazide PGx | Children’s Hospital | RCT | Infants | N=151 (71/80) | South African | 8.84 ± 8.03 (3.03–33.47) months | A different NAT2 enzyme maturation profile for each of the 3 acetylation groups, with the 70-kg body weight–normalized typical apparent clearance for the fast and intermediate acetylators increasing from 14.25 L/h and 10.88 L/h at 3 months of age to 22.84 L/h and 15.58 L/h at 24 months of age, respectively |
| Zielinska et al 1998, Poland48 | Comparison of the acetylation phenotype and NAT2 coding genotype in the prediction of idiosyncratic reaction to Cotrimoxazole | Children’s Hospital | Cohort study | Infants | N=20 (10/10) | - | 6.35 (2–12) months | The NAT2 genotype rather than phenotype provides the basis for the detection of hypersensitivity to Cotrimoxazole |
| Zwaveling et al 2008, the Netherlands76 | The contribution of genetic polymorphisms in the GST isozymes to the PK of busulfan | Multicentre HSCT | Retrospective study | Pediatrics | N=77 | - | 5 (0.2–23) years | Variability in PK of busulfan could not be related to polymorphisms in GST |
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| Allegaert et al 2008, Belgium31 | Impact of CYP2D6 polymorphism on IV tramadol disposition | Children’s Hospital | Cohort study | (Pre)term neonates and young infants | N=57 | - | 6 (1–149) days | A limited m-opioid receptor-mediated analgesic effect of M1 in preterm neonates and a CYP2D6 polymorphism dependent effect |
| Moreau et al 2012, France26 | The relative contributions of nongenetic and genetic factors (VKORC1, CYP2C9, and CYP4F2) on warfarin or fluindione dose requirements | Children’s Hospital | Cohort study | Pediatrics | N=118 (64/54) | - | 9 (3 months-18 years) years | Contribution of the VKORC1 and CYP2C9 genotypes to variations in warfarin response among children with cardiac disease |
| Ashton et al 2007, Australia44 | Polymorphisms in the genes encoding phase I and II drug metabolizing enzymes associated with the risk of relapse or death | Children’s Hospital | Double center Cohort study | Children with neuroblastoma | N=209 (122/87) <1 year: 86 (41%) |
- | 14.4 (0–13 years) months | NAT1*11 variant and the GSTM1 wild-type genotype contribute to a more favorable outcome in patients treated for neuroblastoma and are the first to demonstrate a relationship between NAT1 and GSTM1 genotypes in childhood neuroblastoma. |
| Gijsen et al 2011, the Netherlands40 | Relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality score on tacrolimus dose, steady-state trough concentrations, concentration/dose ratio | Children’s Hospital | Cohort study | Pediatric heart transplant recipients | N=39 (25/14) <1 year: 15 (38.5%) |
White (n=28) Asian (n=4) African American (n=2) |
6.0 years | First 14 days after heart transplantation, younger age and CYP3A5 expressor status were independently associated with higher tacrolimus dosing requirements and concentration/dose ratio |
| de Wildt et al 2011, Canada38 | The effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period | Children’s Hospital | Retrospective study | Pediatric liver recipients | N=42 for liver recipients | - | Liver recipients: 1.5 (0.05–14.8) years |
In liver recipients, variation in tacrolimus disposition appears related to age and ABCB1 genotype |
| Hawwa et al 2009, UK58 | Influence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements | Children’s Hospital | Cohort study | Pediatric liver transplant population | N=51 (27/24) | - | 2 (0.6–16) years | ABCB1 polymorphisms in the native intestine significantly influence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms may predispose them to nephrotoxicity over the first year posttransplantation |
| Durrmeyer et al 2010, France11 | CYP2C8/2C9 polymorphisms may predict ibuprofen response | NICU | Cohort study | Extremely preterm infants with PDA | N=111 (60/51) | Caucasian mother (n=49) Caucasian father (n=52) |
GA: 25.6–26.6 weeks | CYP2C polymorphism was not associated with PDA response to ibuprofen and this factor appears not appropriate to optimize the ductal closure rate by modulating ibuprofen dosing strategy |
| Zielinska et al 1999, Poland47 | Extent to which genotype coding for N-acetyltransferase agrees with acetylation phenotype | Children’s Hospital | Cohort study | Pediatrics | N=82 (57/25) <1 years: 37 (45%) |
Caucasian | 1 month-17 years | Disagreement between the acetylation phenotype and genotype is more often found in the group of children characterized by low AFMU/1X and that in small children only N-acetyltransferase genotype studies enable the detection of genetic acetylation defect |
| Wachman et al 2013, USA77 | SNPs in the OPRM1, ABCB1, and COMT genes are associated with length of hospital stay and the need for treatment of NAS. | Multicenter (5 tertiary care) | Cohort study | Infants | N=86 (51/35) | White (n=84) | GA ≥38 weeks: 70 (81%) | Variants in the OPRM1 and COMT genes were associated with a shorter length of hospital stay and less need for treatment |
| Wachman et al 2017, USA55 | Genetic variations in thePNOC and COMT genes of opioid-exposed mother infant pair | Multicenter (5 tertiary care) | Cohort study | Infants | N=113 (41/72) | White (n=99) | GA: 39 weeks | Differences in NAS outcomes depending on PNOC and COMT SNP genotype |
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| Lewis et al 2019, USA66 | Candidate SNPs in corticosteroid metabolism and response genes are associated with short-term phenotypic response to systemic corticosteroids | Multicenter | RCT | Preterm infants at high risk for BPD | N=80 (46/34) | White (n=39) African American (n=38) |
22.8–29.2 days | Genetic variability is associated with corticosteroid responsiveness with regard to respiratory status |
| Smith et al 2017, USA22 | Association between SNPs in CYP2C9 and the closure of PDA in response to indomethacin | NICU | Retrospective study | Preterm infants with PDA | Responders N=96 (53/43) Non-responders N=52 (27/25) |
White (n=123) Black (n=15) |
GA: 25.3–26.9 weeks | Association between two SNPs in CYP2C9, rs2153628 and rs1799853, and indomethacin response for the treatment of PDA |
| Rooney et al 2019, USA21 | Clinical and genetic factors associated with indomethacin treatment failure | Multicenter (3 NICU) | Cohort study | Preterm neonates with PDA | N=144 (75/69) | White (n=105) | 7–8 days | Age, surfactant use, and CYP2C9*2 influence indomethacin treatment outcome |