Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethics
2.2. Patients
2.3. Fluconazole Administration and Sample Collection
2.4. Measurement of Fluconazole Concentration
2.5. PPK Analysis
2.6. Probability of Target Attainment (PTA) Analysis
2.7. Verification of the Optimal Dose of Fluconazole
3. Results
3.1. Patient Characteristics
3.2. Validation of Fluconazole Measurement
3.3. Pharmacokinetic Model Buiding
3.4. PTA Analysis
3.5. Verification of the Optimal Dose of Fluconazole
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Characteristic | Median or Number | Range |
---|---|---|
Number of patients (male/female) | 31/23 | – |
Body weight (kg) | 57.6 | 39.8–99.1 |
Height (cm) | 162.6 | 143.6–187.7 |
Age (years) | 53 | 20–77 |
BMI (kg/m2) | 21.7 | 15.8–29.1 |
BSA (m2) | 1.62 | 1.31–2.23 |
CG-CLcr (mL/min) | 87.1 | 31.1–193.6 |
eGFRcre (mL/min) | 71.2 | 25.9–148.5 |
eGFRcre (mL/min/1.73 m2) | 69.2 | 31.6–157.5 |
Disease | ||
Acute myeloid leukemia (AML)/Myelodysplastic syndromes (MDS) | 10 | – |
Acute lymphoid leukemia (ALL) | 6 | – |
non-Hodgkin lymphoma (NHL) | 28 | – |
Hodgkin lymphoma (HL) | 2 | – |
Multiple myeloma (MM) | 3 | – |
Others | 5 | – |
Treatment | ||
Chemotherapy | 38 | – |
Autologous peripheral blood stem cell transplantation | 9 | – |
Bone marrow transplantation | 2 | – |
Cord blood transplantation | 2 | – |
Allogeneic peripheral blood stem cell transplantation | 1 | – |
Others | 2 | – |
Parameter | Final Model | Bootstrap Method n = 1000 | ||||
---|---|---|---|---|---|---|
Estimate | SE | CV (%) | 95% CI | Median | 95% CI | |
CL/F (L/h) = θ₁ × (CLcr/5.2)θ₂ × e0.16 | ||||||
θ₁ (L/h) | 1.03 | 0.08 | 7.38 | 0.88–1.18 | 1.03 | 0.86–1.19 |
θ₂ (L/h) | 1.05 | 0.14 | 13.7 | 0.77–1.33 | 1.07 | 0.81–1.37 |
Vd/F (L) = θ₃ × (BW/57.6)θ₄ | ||||||
θ₃ (L) | 62.3 | 8.87 | 14.2 | 44.7–79.9 | 64.3 | 47.5–87.9 |
θ₄ (L) | 1.06 | 0.36 | 34.4 | 0.34–1.78 | 1.08 | 0.08–2.24 |
ka (/h) | 0.34 | 0.12 | 35.1 | 0.10–0.58 | 0.41 | 0.15–0.77 |
PTA by MIC (μg/mL) and f AUC/MIC of 50 | ||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Day 1 (0–24 h) | Day 8 (168–192 h) | Day 15 (336–360 h) | ||||||||||||||||||||||||
Dose (mg/day) | BW (kg) | CLcr (mL/min) | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 |
200 | 40 | |||||||||||||||||||||||||
40 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
60 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
80 | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
100 | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
120 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
140 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
50 | ||||||||||||||||||||||||||
40 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
60 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
80 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
100 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
120 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
140 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
60 | ||||||||||||||||||||||||||
40 | + | + | + | - | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
60 | + | + | + | - | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
80 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
100 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
120 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
140 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
70 | ||||||||||||||||||||||||||
40 | + | + | + | - | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
60 | + | + | + | - | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
80 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
100 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
120 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
140 | + | + | + | - | - | - | - | - | + | + | + | + | - | - | - | - | + | + | + | + | - | - | - | - | ||
400 | 40 | |||||||||||||||||||||||||
40 | + | + | + | + | + | - | - | - | + | + | + | + | + | + | - | - | + | + | + | + | + | + | - | - | ||
60 | + | + | + | + | + | - | - | - | + | + | + | + | + | + | - | - | + | + | + | + | + | + | - | - | ||
80 | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
100 | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
120 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
140 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
50 | ||||||||||||||||||||||||||
40 | + | + | + | + | + | - | - | - | + | + | + | + | + | + | - | - | + | + | + | + | + | + | - | - | ||
60 | + | + | + | + | + | - | - | - | + | + | + | + | + | + | - | - | + | + | + | + | + | + | - | - | ||
80 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
100 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
120 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
140 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
60 | ||||||||||||||||||||||||||
40 | + | + | + | + | - | - | - | - | + | + | + | + | + | + | - | - | + | + | + | + | + | + | - | - | ||
60 | + | + | + | + | - | - | - | - | + | + | + | + | + | + | - | - | + | + | + | + | + | + | - | - | ||
80 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
100 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
120 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
140 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
70 | ||||||||||||||||||||||||||
40 | + | + | + | + | - | - | - | - | + | + | + | + | + | + | - | - | + | + | + | + | + | + | - | - | ||
60 | + | + | + | + | - | - | - | - | + | + | + | + | + | + | - | - | + | + | + | + | + | + | - | - | ||
80 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
100 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
120 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - | ||
140 | + | + | + | + | - | - | - | - | + | + | + | + | + | - | - | - | + | + | + | + | + | - | - | - |
CLcr (Cockcroft-Gault Equation) | ||||||
---|---|---|---|---|---|---|
40–60 mL/min | 60–80 mL/min | 80–100 mL/min | 100–120 mL/min | 120–140 mL/min | ||
Loading dose (Required in the situation neutropenia is predicted within a week) | ||||||
Body | 40–50 kg | 400 mg/day | 500 mg/day | 500 mg/day | 500 mg/day | 600 mg/day |
Weight | 50–60 kg | 500 mg/day | 500 mg/day | 500 mg/day | 600 mg/day | 600 mg/day |
60–70 kg | 500 mg/day | 600 mg/day | 600 mg/day | 600 mg/day | 700 mg/day | |
Maintenance dose | ||||||
Body | 40–50 kg | 200 mg/day | 300 mg/day | 300 mg/day | 400 mg/day | 400 mg/day |
Weight | 50–60 kg | 200 mg/day | 300 mg/day | 300 mg/day | 400 mg/day | 400 mg/day |
60–70 kg | 200 mg/day | 300 mg/day | 300 mg/day | 400 mg/day | 400 mg/day |
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Sakamoto, Y.; Isono, H.; Enoki, Y.; Taguchi, K.; Miyazaki, T.; Kunimoto, H.; Koike, H.; Hagihara, M.; Matsumoto, K.; Nakajima, H.; et al. Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy. J. Fungi 2021, 7, 975. https://doi.org/10.3390/jof7110975
Sakamoto Y, Isono H, Enoki Y, Taguchi K, Miyazaki T, Kunimoto H, Koike H, Hagihara M, Matsumoto K, Nakajima H, et al. Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy. Journal of Fungi. 2021; 7(11):975. https://doi.org/10.3390/jof7110975
Chicago/Turabian StyleSakamoto, Yasutaka, Hikaru Isono, Yuki Enoki, Kazuaki Taguchi, Takuya Miyazaki, Hiroyoshi Kunimoto, Hirofumi Koike, Maki Hagihara, Kenji Matsumoto, Hideaki Nakajima, and et al. 2021. "Population Pharmacokinetic Analysis and Dosing Optimization of Prophylactic Fluconazole in Japanese Patients with Hematological Malignancy" Journal of Fungi 7, no. 11: 975. https://doi.org/10.3390/jof7110975