Table 1.
Overview of identified M&S-based publications in pediatric oncology
| Drug | Study characteristics | Analysis characteristics | Reference | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Nr. Pat (P/A)† | Age (years)‡ | Type§ | Indication¶ | Objectives†† | Type‡‡ | Software§§ | Evaluation¶¶ | Model††† | Covariates‡‡‡ | ||
| 6-MP | 19/0 | 10 (3–17) | Study | ALL | PK-Cov | PPK | NM (FOCE) | VPC, SPLIT | 1cmt M:1cmt | BSA, PGTPMT | Hawwa et al. 58 |
| Actinomycin D | 36/0 | 1.6–20.3 | Study | Oth | PK-Cov Contaminations | PPK | NM (FOCE) | VPC | 3cmt | BWT, AGE | Edwards 82 |
| Asparaginase | 168/0 | 5.8 (4–10.2) | Retro | ALL | PK-Cov | PPK | NM (FO) | 1cmt | BSA | Hempel et al. 83 | |
| Asparaginase | NA/0 | NA | NA | ALL | PdrK-Cov, SimDose | PPK | NM (SIM) | 1cmt | Avramis et al. 84 | ||
| Asparaginase | 118/0 | 5 (1–9) | Study | ALL | PK-Cov | PPK | NM (NS) | 1cmtNL | Avramis et al. 85 | ||
| Asparaginase | 32/0 | 4.5 (1–14) | Study | ALL | PK-Cov | PPK | NM (FOCE) | VPC, PPC | 2cmt | BSA, BWT | Borghorst et al. 86 |
| Busulfan | 24/0 | 6.3 (0.3–16.7) | Study | HSCT | PK-Cov, SimDose | PPK | NM (FOCE) | BS | 1cmt | BWT | Booth et al. 36 |
| Busulfan | 24/0 | 6 (0.5–16.7) | Retro | HSCT | PK-Cov, SimDose | PPK | NM (FOCE) | BS | 1cmt | BWT | Nguyen et al. 87 |
| Busulfan | 48/0 | 10.4 (0.4–18.1) | Retro | HSCT | PK-Cov | PPK | NM (FOCE) | 1cmt | BSA | Schiltmeyer et al. 88 | |
| Busulfan | 12/62 | 5.8 (1.3–12) | Retro | HSCT | PK-Cov, TDM | PPK | NM (FOCE) | 1cmt | BWT, ALT, CMED | Sandstrom et al. 88 | |
| Busulfan | 20/0 | 1.1 (0.1–7.8) | Study | HSCT | PK-Cov, LSS | PPK | NM (NS) | 1cmt | BWT, DIS | Hassan et al. 89 | |
| Busulfan | 94/0 | 9.2 (0.4–18.8) | Meta | HSCT | PK-Cov, SimDose | PPK | NM (FOCE) | VPC, SPLIT | 1cmt | BSA, BWT | Trame et al. 33 |
| Busulfan | 77/0 | 5 (0.2–23) | Meta | HSCT | PK-Cov | PPK | NM (FOCE) | VPC | 1cmt | BWT, PGGST | Zwaveling et al. 90 |
| Busulfan | 29/0 | 5.6 (0.1–18.3) | Study | HSCT | PK-Cov, SimDose | PPK | NM (FOCE) | VPC | 1cmt | Age, PGGST | Johnson et al. 64 |
| Busulfan | 103/0 | 1.5 (0.2–11.3) | Study | HSCT | PK-Cov | PPK | NM (FOCE) | BS | 1cmt | BWT, Age, CMED, FRM, DIS | Nakamura et al. 91 |
| Busulfan | 100/0 | 0.1 (5.3–18.1) | Study | HSCT | PK-Cov | PPK | USCP (NPAG) | 1cmt | BWT, DIS | Bertholle et al. 92 | |
| Busulfan | 6/0 | 6 (1.5–14) | Study | HSCT | PK-Cov, LSS | PPK | NM (FOCE) | 1cmt | Cremers et al. 60 | ||
| Busulfan | 48/0 | 2.5 (0.2–15) | Meta | HSCT | PK-Cov, SimDose | PPK | NM (NS) | VPC, SPLIT | 1cmt | BWT | Paci et al. 93 |
| Busulfan | 245/0* | (0.2–26) | Meta | HSCT | PK-Cov | PPK | NM (FOCE) | BS | 2cmt | BWT | Bartelink 94 |
| Busulfan | 158/0* | (0.1–26) | Meta | HSCT | PK-Cov | PPK | NM (FOCE) | External evaluation | 2cmt | BWT | Bartelink 95 |
| Busulfan | 63/0 | 3.0 (0.7–13) | Study | HSCT | PK-Cov | PPK | NM (FOCE) | 1cmt | BWT | Veal 96 | |
| Carboplatin | 13/56 | 31 (2–60) | Meta | NBL, Oth | PK-Cov, SimDose | PPK | NM (FOCE) | 2cmt | HT, BWT, Age, CLCR, DUR | Lindauer et al. 97 | |
| Carboplatin | 75/75 | 6.5 (1.2–17.5) | Retro | MED, NBL, Oth | PK-Cov | PPK | MPK (NS) | 2cmt | BWT, SCR, NEPH | Urien et al. 98 | |
| Carboplatin | 57/57 | 5 (0.2–18) | Retro | CNS, NBL, Oth | PK-Cov | PPK | NM (NS) | PPC | 2cmt | BWT, SCR, NEPH | Chatelut et al. 99 |
| Cisplatin | NA/0 | NA | NA | PK-Cov | PBPK | NS (NA) | NA | PBPK | Evans et al. 25 | ||
| Clofarabine | 40/0 | 12.3 (2–19) | Meta | ALL, AML | PK-Cov | PPK | NM (FOCE) | BS | 2cmt | BWT, WBC | Bonate et al. 55 |
| Cyclofosfamide | 15/0 | 13.3 (5.4–21) | Study | STS | PK-Cov | PPK | NM (FOCE) | 1cmt | BSA, Sex | Chinnaswamy et al. 100 | |
| Cyclofosfamide | 22/0 | 3.2 (1.3–9.4) | Study | NBL | PK-Cov | PPK | NM (FO) | VPC | 1cmtNL M:1cmt | GFR | McCune et al. 61 |
| Cytarabine | 52/0 | (0.2–19) | Meta | ALL, AML, Oth | PK-Cov | PPK | NM (FO) | 2cmt M:1cmt | BSA, Age | Periclou et al. 101 | |
| Daunorubicin | 24/0 | 15.4 (2.8–23.2) | Retro | AML, Oth | PK-Cov | PPK | NM (FOCE) | 1cmt | BWT | Hempel et al. 102 | |
| Daunorubicin | 33/0 | (0.1–18.8) | Meta | AML | PK-Cov | PPK | NM (FO) | 2cmt M:1cmt | Hempel et al. 103 | ||
| Doxorubicin | 22/0 | 15 (3.3–21.5) | Study | Oth | PK-Cov | PPK | NM (NS) | 3cmt M:1cmt | BSA | Thompson et al. 62 | |
| Erlotinib | 46/42 | (2–19) | Meta | CNS | PK-Cov, SkinTox | PPK | NM (FOCE) | VPC | 1cmt | BWT, PGCYP, PGABC | White et al. 74 |
| Etoposide | NA/0 | NA | NA | PK-Cov | PBPK | PKSIM (NA) | NA | PBPK | Kersting et al. 24 | ||
| Etoposide | 67/0 | 3.5 (0.3–16.7) | Study | MED, NBL, Oth | PK-Cov | PPK | MLX (SAEM) | VPC | 2cmt | BWT | Urien et al. 104 |
| Etoposide | 31/0 | 8 (0.8–23.7) | Retro | NBL, Oth | PK-Cov | PPK | Ppharm (NS) | VPC | 3cmt | BWT | Wurthwein et al. 105 |
| Etoposide | NA/0 | NA | NA | PK-Cov, SimDose | SIM | Excel (NA) | NA | NA | Wurthwein et al. 106 | ||
| Etoposide | 26/0 | 8.5 (2.0–19.0) | Study | SLT | PK-Cov | PPK | NM (FOCE) | VPC | 1cmt | Baheti 107 | |
| Ifosfamide | 32/0 | (1–18) | Study | Oth | PK-Cov | PPK | NM (FO) | 1cmt M:1cmt | Kerbusch et al. 108 | ||
| Imatinib | 41/0 | (6–24) | Meta | PHL, SLT | PK-Cov | PPK | NM (FOCE) | PPC | 1cmt M:2cmt | BWT | Menon et al. 109 |
| Irinotecan | 11/0 | 12 (3–17) | Study | SLT | PK-Cov | PPK | NM (FOCE) | 2cmt | BWT | Kimura et al. 63 | |
| Irinotecan | 82/0 | (1–21) | Study | SLT, Oth | PK-Cov | PPK | NM (FOCE) | PPC | 2cmt M:2cmt | BWT | Thompson et al. 110 |
| Isotretinoin | 29/0 | 3.2 (1.1–18.7) | Study | NBL | PK-Cov | PPK | NM (FOCE) | 1cmt | Veal et al. 111 | ||
| Melphalan | 59/0 | 0 (0.3–18) | Study | HSCT | PK-Cov, LSS | PPK | NM (FOCE) | SPLIT | 2cmt | BWT, GFR, CMED | Nath et al. 112 |
| Methotrexate | 64/0 | 5 (1.6–16.8) | Retro | ALL, Oth | PK-Cov | PPK | NM (FOCE) | VPC | 2cmt | BWT, PGCT | Faganel et al. 113 |
| Methotrexate | 340/0 | 5 (0.4–17.8) | Study | ALL | PK-Cov, Relapse | PPK | NM (NS) | 2cmt | BWT | Johnsson et al. 79 | |
| Methotrexate | 69/0 | 6.7 (1–15) | Meta | ALL | PK-Cov, EFS | PPK | NM (NS) | 2cmt | Martelli et al. 80 | ||
| Methotrexate | 131/0 | (1.3–17.1) | Meta | ALL | PK-Cov, GITox | PPK | NM (FOCE) | 2cmt | BWT, Age, DIS | Buitenkamp et al. 75 | |
| Methotrexate | 118/0 | 7.4 (1.3–13.6) | Study | ALL | PK-Cov | PPK | NM (FOCE) | SPLIT | 2cmt | BSA, Age | Zhang et al. 114 |
| Methotrexate | 24/0 | 14.8 (10.8–18.8) | Retro | OSC | PK-Cov | PPK | NM (FOCE) | VPC, SPLIT | 2cmt | BWT, Age | Colom et al. 115 |
| Methotrexate | 79/0 | 6.9 (2–16) | Study | ALL | PK-Cov, LSS | PPK | NM (FOCE) | SPLIT | 2cmt | BWT | Plard et al. 116 |
| Methotrexate | 49/0 | 7 (0.5–17) | Retro | ALL | PK-Cov | PPK | NM (FOCE) | SPLIT | 2cmt | BWT, Age | Aumente et al. 117 |
| Methotrexate | NA/0 | NA | NA | PK-Cov | PBPK | BM (NA) | NA | PBPK | Li et al. 68 | ||
| Methotrexate | 23/0 | 6 (0.8–15) | Retro | ALL | PK-Cov, LSS | PPK | Ppharm (EM) | SPLIT | 2cmt | BWT, Age | Odoul et al. 118 |
| Methotrexate | 194/0 | NS (NS-NS) | Study | ALL | PK-Cov | PPK | ADAPT (MCPEM) | 2cmt M:2cmt | DIS | Panetta et al. 67 | |
| Methotrexate | 37/0 | 14 (4–21) | Retro | OSC, Oth | PK-Cov, MCT, RT, VOM | PPK | USCP (IT2B/NPEM) | 2cmt | Aquerreta et al. 76 | ||
| MK-0752 | 23/0 | 8.1 (2.6–17.1) | Study | CNS | PK-Cov | PPK | NM (FOCE) | 1cmt | Fouladi et al. 119 | ||
| Benzylguanine | 25/0 | NS (NS-21) | Study | CNS | PK-Cov, TDM | IPK | MLAB (NS) | 1cmt M:1cmt | Neville et al. 120 | ||
| Paclitaxel | 30/0 | (2.3–22.8) | Study | SLT | PK-Cov, NEUTR | IPK | ADAPT (ITS) | SPLIT | 2cmtNL | Sonnichsen et al. 70 | |
| Phenylacetate | 27/0 | 10 (1.4–20) | Study | Oth | PK-Cov, TDM | IPK | MLAB (NS) | 1cmtNL M:1cmt | Thompson et al. 121 | ||
| Prednisolone | 23/0 | 5.4 (2.4–15.2) | Study | ALL | PK-Cov, TDM | PPK | WNM (FO) | 2cmt | BSA | Petersen et al. 122 | |
| Pyrazoloacridine | 22/0 | (1–25) | Study | Oth | PK-Cov, NEUTR, TDM | IPK | MLAB (NS) | 2cmt | Berg et al. 69 | ||
| Temozolomide | 39/0 | 7.1 (0.7–21.9) | Study | CNS | PK-Cov | PPK | ADAPT (NS) | 1cmt M:1cmt | BSA, Age | Panetta et al. 123 | |
| Temozolomide | NA/0 | NA | NA | PK-Cov, LSS | OD | ADAPT (Unknown) | NA | Kirstein et al. 124 | |||
| Thioguanine | 18/0 | 18 (4–25) | Study | Oth | PK-Cov | IPK | MLAB (NS) | 2cmtNL | Kitchen et al. 125 | ||
| Topotecan | 162/0 | 9.1 (0.1–22) | Meta | MED, NBL, SLT, Oth | PK-Cov | PPK | NM (NS) | BS | 2cmt | BSA, Age, GFR, CMED | Schaiquevich et al. 126 |
| Topotecan | 6/0 | 4.9 (3.2–8.4) | Study | MED | PK-Cov | PPK | ADAPT (MAP) | 2cmt | Freeman et al. 127 | ||
| Topotecan | 40/0 | 12 (3–20) | Retro | SLT | PK-Cov, NEUTR | IPK | ADAPT (NS) | 2cmt | Zamboni et al. 71 | ||
| Topotecan | 17/0 | 12 (1–16) | Meta | CNS | PK-Cov | IPK | ADAPT (MAP) | 3cmt | Baker et al. 128 | ||
| Vincristine | 26/0 | (2–16) | Study | SLT | PK-Cov | PPK | NM (NS) | VPC, BS | 2cmt | PGCYP, PGABC | Guilhaumou et al. 129 |
| Vincristine | 70/0 | (1–16) | Study | ALL | PK-Cov | IPK | ADAPT (MAP) | 2cmt | Groninger et al. 130 | ||
| Vincristine | 17/0 | 3.8 (1.3–12.4) | Study | ALL | PK-Cov | IPK | ADAPT (NS) | 2cmt | de Graaf et al. 131 | ||
| NA/0 | NA | NA | PK-Cov, TDM | PPK | NM (PRIOR) | 1cmt | Barrett et al. 81 | ||||
Not specified (NS), Not applicable (NA).
Adult patients present but number of patients was not separately stated..
Children vs. Adults.
Age, median (range), years, for paediatric subjects. If only other measure then median or range were available, these were used.
Study types were retrospective (Retro), pooled meta-analysis of multiple studies or datasets (Meta) or data collected as part of clinical study (Study).
Indications: Acute lymphoblastic leukemia (ALL), Haematopoietic stem cell transplantation (HSCT), Neuroblastoma (NBL), Other (Oth), Medulloblastoma (MED), CNS malignancy (CNS), Acute myeloid leukemia (AML), Soft tissue sarcoma (STS), Philadelphia positive leukemia (PHL), Solid tumor (SLT), Osteosarcoma (OSC).
Study objectives: Characterize PK and/or covariates (PK-Cov), Limited sampling schedule (LSS), Therapeutic drug monitoring (TDM), Event-free survival (EFS), Gastrointestinal toxicitiy (GI-Tox), Mucosits (MCT), Renal toxicity (RT), Vomiting (VOM), Neutropenia (NEUTR).
Analysis types: Population pharmacokinetic/pharmacodynamic analysis (PPK), Individual level pharmacokinetic/pharmacodynamic (IPK) analysis, Physiologically-based pharmacokinetic model (PBPK), Optimal design (OD), Simulation study (SIM).
Software and estimation methods: nonmem (NM), Monolix (MLX), Berkeley Madonna (BM), USC-Pack (USCP), WinNonMix (WNM), First order conditional estimation (FOCE), First order estimation (FO), Simulation (SIM), Nonparametric estimation adaptive grid (NPAG), Stochastic approximation expectation maximization (SAEM), Expectation maximization (EM), Monte Carlo Parameteric Expectation Maximization Algorithm (MCPEM), Iterative two-stage Bayesian (IT2B), Non-parametric Expectation Maximization (NPEM,) Iterative two stage (ITS), Maximum a posteriori Bayesian estimation (MAP).
Model evaluation methods: Visual predictive check (VPC), External data or data-splitting procedure to evaluate model predictions (SPLIT), Posterior predictive check (PPC), Bootstrap analysis (BS).
Model type: For parent drug and metabolite (M). One (1), two (2) and three (3) compartmental (cmt) models, that may have a non-linear (NL) element.
Covariates identified in the analysis: Body surface area (BSA), Pharmacogenetic factors for SNP or enzyme activity xx (PGxx), Total body weight (BWT), Alanine transaminase (ALT), Concomitant or prior drug effect (CMED), Disease related factors (DIS), Height (HT), creatinine clerance (CLCR), Serum creatinine (SCR), Formulation (FRM).