Table 4 Summary of studies on PPK analysis and current recommendations of VRC optimal dosing regimen in pediatric patients
From: Clinical application of voriconazole in pediatric patients: a systematic review
Study design | No. of samples | Age (years) | Reference | Country of study populations | Year | Target Ctrough (mg/L) | Software | Modeling | Significant covariates | The results of dose simulation or the recommendations of optimal dose regimen |
|---|---|---|---|---|---|---|---|---|---|---|
An open, multicenter, two-cohort study | 35 | 2–11 | Walsh et al. [32] | America, Costa Rica, Panama, and Britain | 2004 | / | NONMEM | A two-compartment disposition | WT, CYP2C19 genotype, ALT and ALP | 4 mg/kg required in children to achieve exposures was consistent with those in adults following 3 mg/kg |
Data from three open-label studies | 82 | 2-<12 | Karlsson et al. [33] | / | 2009 | / | NONMEM | A two-compartment disposition | CYP2C19 genotype and ALT | 7Â mg/kg IV or 200Â mg PO q12h |
A prospective study | 46 | 8 months-20.5 | Neely et al. [34] | America | 2010 | / | MM-USCPACK | A two-compartment Michaelis-Menten | Age | 7Â mg/kg IV or 200Â mg PO q12h |
Data from 5 previous PK studies | 112 | 2-<12 | Friberg et al. [35] | / | 2012 | / | NONMEM | A two-compartment with first-order absorption and mixed linear and nonlinear elimination | WT, age and CYP2C19 genotype | The IV loading dose of 9Â mg/kg in children to attain exposures was comparable to that in adults receiving 6Â mg/kg IV. Dosages of 4 and 8Â mg/kg IV q12h in children were akin to those in adults receiving 3 and 4Â mg/kg IV q12h. The 9Â mg/kg PO (maximum, 350Â mg) q12h paralleled the adult regimen of 200Â mg PO q12h. |
An open-label, multicenter, phase II study | 21 | 3–14 | Muto et al. [36] | Japan | 2015 | / | NONMEM | A two-compartment with first-order absorption and mixed linear and nonlinear elimination | Age and WT | / |
A phase II study | 23 | 0.5–21 | Gastine et al. [37] | Germany | 2018 | 1.0–6.0 | NONMEM | A two-compartment with first-order absorption, nonlinear Michaelis-Menten elimination | / | 9 mg/kg IV TID for up to 3 days |
A retrospective study | 55 | ≤ 18 | Carlesse et al. [38] | Brazil | 2019 | 1.0–6.0 | Pmetrics | A nonparametric population | / | / |
A single-institution, phase I study | 58 | ≤ 21 | Takahashi et al. [39] | America | 2021 | 1.5-5.0 | NONMEM | A two-compartment parent mixed linear/nonlinear | WT and CYP2C19 phenotype | For NMs: 16 mg/kg (< 15 kg), 12 mg/kg (15–30 kg), or 10 mg/kg (> 30 kg). Doses for PMs were 33–50% lower, while for UMs, doses were 25–50% higher. |
A retrospective study | 99 | 0.44–13.58 | Wang et al. [40] | China | 2021 | 1.0-5.5 | Phoenix NLME | A two-compartment with nonlinear Michaelis-Menten elimination | WT, CYP2C19 phenotype and omeprazole | For most children, two loading doses of 9 mg/kg q12h were recommended, while for children weighing ≤ 18 kg, three loading doses of 6-7.5 mg/kg q8h were suggested (except for PMs). The maintenance doses in PMs were reduced by about 30–40% compared to NMs. |
A single-institution, phase I study | 59 | < 21 | Takahashi et al. [41] | America | 2022 | / | NONMEM | A two-compartment linear elimination | CRP and ALB | / |
A retrospective study | 67 | 1.08–17.92 | Wu et al. [42] | China | 2022 | 0.5-5.0 | NONMEM | A one-compartment with first-order absorption and elimination | WT, CYP2C19 phenotype and ALB | Order of the recommended doses: NM > IM > PM. Children with lower WT should receive a higher dose, while those with lower ALB levels should receive a lower dose. |