Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation—A 10-Year Single-Center Experience
Abstract
:1. Introduction
2. Methods
2.1. Study Design and Patients
2.2. Busulfan Treatment Regimen
2.3. Co-Medication
2.4. Busulfan Sampling and Dose Adjustments
2.5. Population Pharmacokinetic Analysis
2.6. Non-parametric Estimation of AUC, Cmax, CL, V, t1/2, and MRT
2.7. Covariate Analysis
2.8. Simulations of CL with Time
2.9. Model Evaluation
3. Results
3.1. Patient Characteristics
3.2. Population Pharmacokinetic Analysis
3.3. Model Validation
3.4. Inter-Individual and Inter-Occasion Variability of Busulfan CL
3.5. Dose Adjustments and Busulfan Exposure
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Patients (n = 124) | Demographics |
---|---|
2015 (2010–2020) | Year of transplantation |
4.3 (0.2–27.0) | Age (years) |
23 (18%) | Age <1 (years) |
95 (77%) | Age 1–18 (years) |
6 (5%) | Age >18 (years) |
17.2 (4.3–85.0) | Body weight (kg) |
0.71 (0.25–2.06) | Body surface area (m2) |
Sex | |
89 (72%) | Male |
35 (28%) | Female |
Indication | |
42 (34%) | Malignant disease |
13 (10%) | ALL |
12 (10%) | AML |
6 (5%) | Neuroblastoma |
11 (9%) | Others |
4 (3%) | JMML |
5 (4%) | MDS |
1 (1%) | Ewing sarcoma |
1 (1%) | Lymphoma |
82 (66%) | Non-malignant disease |
32 (26%) | CGD |
14 (11%) | HLH or XLP |
12 (10%) | Hemoglobinopathies |
6 (5%) | β-Thalassemia major |
6 (5%) | Sickle cell anemia |
14 (11%) | Primary immunodeficiencies |
6 (5%) | SCID |
3 (2%) | Wiskott–Aldrich syndrome |
5 (4%) | Others 1 |
8 (6%) | Metabolic diseases |
4 (3%) | MPS |
2 (2%) | X-ALD |
1 (1%) | Other leukodystrophy |
1 (1%) | Alpha-mannosidosis |
2 (2%) | Thrombocytopenia |
Conditioning | |
82 (66%) | Bu/Flu |
13 (10%) | Bu/Flu/TTP |
4 (3%) | Bu/Flu/Mel |
1 (1%) | Bu/Flu/CP |
10 (8%) | Bu/Clo |
7 (6%) | Bu/Mel |
6 (5%) | Bu/CP/Mel |
1 (1%) | Bu/CP |
Serotherapy | |
57 (46%) | Alemtuzumab |
54 (44%) | ATG |
13 (10%) | No |
Stem cell source | |
78 (63%) | Bone marrow |
36 (29%) | Peripheral blood stem cell |
10 (8%) | Umbilical cord blood |
HLA compatibility | |
50 (40%) | MUD |
38 (31%) | MMUD |
24 (19%) | MRD |
5 (4%) | Haplo |
7 (6%) | Auto |
Laboratory parameters | |
0.3 (0.17–0.41) | Hematocrit (L/L) |
4.0 (0.16–20.9) | White blood cells (G/L) |
61 (34–84) | Serum total protein (g/L) |
34 (19–50) | Serum albumin (g/L) |
Step 1: Building the Basic Structural Model (a) | ||||||||
---|---|---|---|---|---|---|---|---|
Model | Number of Compartments | PK Parameters | Random Effects for | df (b) | Δ-2LL (c) | Ref. Model (d) | Comment | Parameters in Table 3 |
1 * | 1 | ln(V), ln(k) | ln(V), ln(k) | 4 | 0 | - | ||
2 | 1 | ln(V), ln(k), dk, ln(κk) | ln(V), ln(k), dk, ln(κk) | 8 | −2245 | 1 * | Excluded, Shrinkage for ln(κk) >40% | |
3 * | 1 | ln(V), ln(k), dk, ln(κk) | ln(V), ln(k), dk | 7 | −2128 | 1 * | Critical Δ-2LL for Δ3 parameters: −7.82(p = 0.05) | θV1, θk1, θdk1, θκk, all Ω2 |
4 | 2 | ln(V), ln(k), ln(V1), ln(k1) | ln(V), ln(k), ln(V1) | 7 | −163 | 1 * | ||
Step 2: Search for covariates by forward inclusion based on model 3 * Inclusion criteria: Δ-2LL (c) ≤−3.84 (p = 0.05) and effect (absolute value, |θ|) ≥ 0.1 (≥ 10% in linear scale) | ||||||||
Model | Step 2a: Testing alternative body size metrics as covariates for ln(V) | df | Δ-2LL | Ref. model | Reason for not including | Parameter in Table 3 | ||
5 | ln(W) on ln(V) | 8 | −294.2 | 3 * | Model 9 * | |||
6 | ln(BSA) on ln(V) | 8 | −304.6 | 3 * | Model 9 * | |||
7 | ln(H) on ln(V) | 8 | −284.5 | 3 * | Model 9 * | |||
8 | ln(FFM) on ln(V) | 8 | −288.3 | 3 * | Model 9 * | |||
9 * | ln(TBW) on ln(V) | 8 | −305.4 | 3 * | θV2 | |||
Step 2b: Including additional covariates | ||||||||
10 | Model 9 * with Tinf on ln(V) | 9 | −31.7 | 9 * | θV3 | |||
11 | Model 10 with Tinf on ln(k) | 10 | −15.2 | 10 | θk6 | |||
12 | Model 11 with ALL on ln(k) | 11 | −14.8 | 11 | θθk5 | |||
13 | Model 12 with HLH/XLP on dk | 12 | −6.94 | 12 | θdk2 | |||
14 | Model 13 with Alb on ln(k) | 13 | −6.09 | 13 | θk4 | |||
15 | Model 14 with ln(TBW) on ln(k) | 14 | −6.54 | 14 | θk2 | |||
16 ** | Model 15 with ln(Fmat) on ln(k) | 15 | −11.4 | 15 | θk3 | |||
17 | Model 16 ** with ln(Leu) on ln(k) | 16 | −5.42 | 16 ** | Step 3 | |||
18 * | Model 17 with ln(Hct) on ln(V) | 16 | −5.25 | 16 ** | Step 3 | |||
Step 3: Evaluation of covariates by backward exclusion Exclusion criterium: Δ-2LL ≥ −6.63 (p = 0.01) | ||||||||
17 | Model 18 *, excluding ln(Hct) on ln(V) | 15 | −5.25 | 18 | Δ-2LL ≥ −6.63 | |||
16 ** | Model 17, excluding ln(Leu) on ln(k) | 15 | −5.42 | 18 | Δ-2LL ≥ −6.63 | |||
Excluding individual covariates from model 16 ** | 14 | ≤−7.40 | 16 ** | |||||
Step 4: Search for the effects of co-medication | ||||||||
19 | NAC on ln(k) | 16 | −0.03 | 16 ** | Δ-2LL > −3.84 | |||
20 | NAC on ln(V) | 16 | −112.8 | 16 ** | |θ| < 0.1 (0.099) (f) | |||
21 | Clofarabine with NAC on ln(k) | 16 | −1.48 | 16 ** | Δ-2LL > −3.84 | |||
22 | Clofarabine with NAC on ln(V) | 16 | +0.62 | 16 ** | Δ-2LL > −3.84 | |||
23 | Paracetamol w/o NAC on ln(k) | 16 | −4.33 | 16 ** | |θ| < 0.1 (0.02) | |||
24 | Paracetamol w/o NAC on ln(V) | 16 | −18.5 | 16 ** | |θ| < 0.1 (−0.05) | |||
25 | Fludarabine on ln(k) | 16 | +0.47 | 16 ** | Δ-2LL > −3.84 | |||
26 | Fludarabine on ln(V) | 16 | +1.57 | 16 ** | Δ-2LL > −3.84 |
Fixed Effects | |||||||
---|---|---|---|---|---|---|---|
Parameter (a) | Reference Value (b) | Fit Value | SE (c) | Range in Population (d) | Untransformed Fit Value (e) | p (f) | CI (95%) from Bootstrapping (g) |
, ln(V, L) at reference values | 2.459 | 0.0189 | 11.70 L | - | 2.432, 2.491 | ||
, effect of Δln(TBW, L) | 10 L | 0.931 | 0.0233 | −1.21; 1.40 | - | <0.001 | 0.872, 0.987 |
, effect of ΔTinf (h) | 3 h | 0.226 | 0.0356 | 0; 0.23 | 1.254 | <0.001 | 0.134, 0.329 |
, ln(k, h−1) at reference values | −1.007 | 0.0329 | 0.365 h−1 | - | −1.065, −0.952 | ||
, effect of Δln(TBW, L) | 10 L | −0.189 | 0.0411 | −0.28; 0.24 | - | < 0.001 | −0.291, −0.106 |
, effect of ln(Fmat) | 0 | 0.697 | 0.2001 | −0.40; 0 | - | < 0.001 | 0.348, 1.061 |
, effect of Δln(Alb, g/L) | 30 g/L | 0.331 | 0.1073 | −0.15; 0.16 | - | 0.001 | 0.090, 0.653 |
, effect of ALL | No ALL | −0.210 | 0.0592 | −0.21; 0 | 0.810 | < 0.001 | −0.398, −0.030 |
, effect of ΔTinf (h) | 3 h | −0.161 | 0.0420 | −0.16; 0 | 0.851 | < 0.001 | −0.264, −0.085 |
, dk (h−1) at no HLH/XLP | - | −0.167 | 0.0191 | −0.167 | - | −0.198, −0.122 | |
, effect of HLH/XLP | No HLH/XLP | −0.145 | 0.0540 | −0.15; 0 | −0.145 | 0.0035 | −0.255, −0.030 |
, ln(κk, h−1) | - | −2.965 | 0.1094 | 0.0516 h−1 | - | −3.204, −2.390 | |
Inter-individual variability: variance Ω2 (standard deviation Ω) of the random effects | |||||||
Parameter | Fit Ω2 (Ω) | SE of Ω2 | Shrinkage | ||||
Ω2 (Ω) of ln(V) | - | 0.029 (0.169) | 0.0039 | 5.5% | |||
Ω2 (Ω) of ln(k) | - | 0.033 (0.182) | 0.0048 | 12.5% | |||
Ω2 (Ω) of dk | - | 0.032 (0.180) | 0.0047 | 12.5% | |||
Residual error | |||||||
Residual error with SE | - | 0.076 | 0.0008 | - | - |
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Schreib, K.M.; Bräm, D.S.; Zeilhofer, U.B.; Müller, D.; Güngör, T.; Krämer, S.D.; Hauri-Hohl, M.M. Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation—A 10-Year Single-Center Experience. Pharmaceutics 2024, 16, 13. https://doi.org/10.3390/pharmaceutics16010013
Schreib KM, Bräm DS, Zeilhofer UB, Müller D, Güngör T, Krämer SD, Hauri-Hohl MM. Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation—A 10-Year Single-Center Experience. Pharmaceutics. 2024; 16(1):13. https://doi.org/10.3390/pharmaceutics16010013
Chicago/Turabian StyleSchreib, Katharina M., Dominic S. Bräm, Ulrike Barbara Zeilhofer, Daniel Müller, Tayfun Güngör, Stefanie D. Krämer, and Mathias M. Hauri-Hohl. 2024. "Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation—A 10-Year Single-Center Experience" Pharmaceutics 16, no. 1: 13. https://doi.org/10.3390/pharmaceutics16010013
APA StyleSchreib, K. M., Bräm, D. S., Zeilhofer, U. B., Müller, D., Güngör, T., Krämer, S. D., & Hauri-Hohl, M. M. (2024). Population Pharmacokinetic Modeling for Twice-Daily Intravenous Busulfan in a Large Cohort of Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation—A 10-Year Single-Center Experience. Pharmaceutics, 16(1), 13. https://doi.org/10.3390/pharmaceutics16010013