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Under the Japanese health insurance system, medicines undergoing therapeutic drug monitoring (TDM) can be billed for medical fees if they meet the specified requirements. In Japan, TDM of vancomycin, teicoplanin, aminoglycosides, and voriconazole, which are used for the treatment of infectious diseases, is common practice. This means the levels of antibiotics are measured in-house using chromatography or other methods. In some facilities, the blood and/or tissue concentrations of other non-TDM drugs are measured by HPLC and are applied to treatment, which is necessary for personalized medicine.
Drug | Characteristics | Objective | Renal Function | Dose | Measurement System | Measurement Accuracy | Blood Concentration | CSF Concentration | Ref. |
---|---|---|---|---|---|---|---|---|---|
CTRX | Age: 75 Sex: female | Development of HPLC method for accurate, precise, and selective determination of CTRX and its clinical application | peritoneal dialysis | 2 g/day | HPLC-UV | -Chromatographic peak heights of CTRX: 0.1–100 μg/mL (r = 0.999) -Detection limit of CTRX: 35 ng/mL -Repeatability (n = 6) of the chromatographic peak height for 4.0 μg/mL CTRX: 0.38% RSD.-Recovery rates of CTRX: >95.3%, and these RSDs were <5.8% |
37.35 μg/mL | 2.61 μg/mL | [14] |
Age: 86 Sex: female | Report of encephalopathy associated with high levels of ceftriaxone in plasma and cerebrospinal fluid, investigation of the causal relationship between ceftriaxone administration and the development of encephalopathy | hemodialysis | 2 g/day | HPLC | nd | >100 μg/mL | 10.2 μg/mL | [16] | |
Population: n = 43 patients Sex: male median age: 51.7 years (IQR 33.3–67.1) median BMI: 24.7 kg/m2 (IQR 22.4–27.7 kg/m2) |
Determining the role of transporter genetic variation and blood-brain barrier permeability in predicting ceftriaxone exposure in the central nervous system | estimated creatinine clearance < 30 mL/min |
2 g twice a day | HPLC | -Detection limits: 0.24 mg/L in plasma and 0.5 mg/L in CSF -Accuracy: 5.2% for plasma, 7.2% for CSF -Intra- and inter-day coefficients of variation (CV%): 3.6% and 4.5% for plasma samples, and 7.2%, 7.8%, and 10.3% for CSF samples -Recovery rate: 86% (CV% = 3) for CSF samples and 82% (CV% = 8) for plasma samples. |
Median Cmax: 157,193.00 ng/mL (IQR 105,164.0–184,852.0 ng/mL) |
Median Cmax: 3512.0 ng/mL (IQR 2134.0–6193.0 ng/mL) |
[17] | |
Population: n = 16 patients | Evaluation of tolerability and pharmacokinetic parameters of high-dose ceftriaxone in adult patients treated for central nervous system infections: pharmacological data from two French cohorts | nd | 6.5 g/day (range 4–9 g) 97.5 mg/kg (range 77–131 mg/kg) | HPLC | nd | Median total plasma: 69.3 mg/L (range 21.6–201.3 mg/L; n =14) Median unbound plasma: 7.95 mg/L (range 0.8–43.7 mg/L; n = 8) | Median: 13.3 mg/L (range 0.9–91.2 mg/L) | [18] | |
Population: n = 7 patients | Investigation of the pharmacokinetics ofboth antibiotics in patients with non- inflammatory obstructive hydrocephalus undergoing external ventricular surgery treated with cefotaxime or ceftriaxone for extracerebral infections | Scr < 1.5 mg/dL | 2 g single dose 30 min | HPLC-UV | -Quantification limits of ceftriaxone; 0.8 mg/L in serum and 0.08 mg/L in CSF. -Interday coefficients of variation; 2.0% 249.6; n = 6) at 99.7 and 6.8% at 1.55 mg/L inserum and 3.3% at 16.2 and 6.4% at 0.16 mg/L in CSF (n = 6). |
Cmax: 172.2–271.7 mg/L (median = 249.6; n = 6) | Cmax: 0.18–1.04 mg/L (median = 0.43; n = 5), confirmed 1–16 h after injection (median = 12 h; n = 5). | [19] | |
DAP | Population:16 patients (8 males and 8 females) Age: 70.0 ± 3.4 years weight: 47.6 ± 5.0 kg |
Investigate the optimal dosing regimen for daptomycin and determine the need and appropriateness of a high-dose regimen in terms of PK / PD parameters using Monte Carlo Simulation and TDM in a Japanese clinical setting | CLcr 16.2–173.4 mL/min (n = 11) hemodialysis (n = 5) |
single doses (6 mg/kg, 8 mg/kg, 10 mg/kg, and 12 mg/kg) and dosing intervals (24 h and 48 h) | HPLC-UV | -Lowest limit of quantification: 0.78 μg/mL | Cmin: 0.13–49.4 μg/mL Cpeak: 34.2–130.0 μg/mL |
nd | [20] |
Population: n = 20 patients | Investigate associations between DAP Cmin and creatine phosphokinase elevation via logistic regression analysis (E/R analysis), and to analyze DAP PPK via adaptation of a one-compartment model in Japanese patients to determine optimal DAP doses for minimizing adverse effects and maximizing treatment success by E/R analysis. | CLcr 22.4–213.8 mL/min, | 2.8–8.6 mg/kg | HPLC-UV | -Lowest limit of quantitation: 1.0 μg/mL -within-day and between-day coefficients of variation of <5.0%. |
Cmin: 2.8–92.4 μg/mL Cpeak: 30.4–76.7 μg/mL |
nd | [21] | |
Population: n = 15 patients | Development of an assay method for the determination of total and free daptomycin in human plasma | nd | 4–8 mg/kg once over a 24-hour period. | LC-MS/MS | -Concentration ranges: 1.0–100 μg/mL in total daptomycin and 0.1–10 μg/mL in free daptomycin - Limits of quantitation: 1.0 μg/mL(total daptomycin) and 0.1 μg/mL(free daptomycin) -Recovery rate: total daptomycin measurements ranged from 106.1% and free daptomycin measurements ranged from 98.2% |
The plasma concentration ranges of total and free daptomycin in 15 infected patients were 3.01–34.1 and 0.39–3.64 μg/mL | nd | [22] | |
Population: two patients admitted to intensive care unit (2 males) Weight: 61.1 kg, 59.0 kg |
Development of a new assay for measuring total and free concentrations of daptomycin in plasma with potential clinical applications | CLcr 17.5 mL/min CLcr 140.5 mL/min |
-every 48 h of 350 mg (CLcr < 30 mL/min)-once-daily dose of 350 mg (CLcr ≥ 30 mL/min) |
UPLC-MS / MS | -Concentration ranges: 0.5–200 μg/mL in total daptomycin and 0.04–40 μg/mL in free daptomycin-Recovery rate: approximately 100% of free daptomycin from ultrafiltration -Limits of quantitation: 0.5 μg/mL (total daptomycin) and 0.04 μg/mL (free daptomycin) -Recovery rate: total daptomycin measurements ranged from 57.1 to 67.4% and free daptomycin measurements ranged from 54.6 to 62.3% |
-Patient with low renal function: Cmax of free drug: 2.85 µg/mL (Day 3), 4.2 µg/mL (Day 5) Ctrough of free drug: 0.29 µg/mL (Day 3), 0.86 µg/mL (Day 5) -Patient with normal renal function: Median unbound plasma: Cmax of free drug: 2.69 µg/mL (Day 3), 2.77 µg/mL (Day 5) Ctrough of free drug: 0.77 µg/mL (Day 3), 0.34 µg/mL (Day 5) |
nd | [23] | |
Population: n = 53 patients Sex: Male (n = 33), female (n = 19) |
Examine serum daptomycin levels, creatinine phosphokinase levels, and the incidence of other adverse effects | CLcr ≥ 80 mL/min: n = 15 30 ≤ CLcr < 80 mL/min: n = 23 CLcr < 30 mL/min: n = 14 haemodialysis: n = 8 |
4.0 < dose ≤5.0 mg/kg: n = 7 5.0 < dose ≤6.0 mg/kg: n = 19 6.0 < dose ≤7.0 mg/kg: n = 17 ≤7.0 mg/kg: n = 4 |
HPLC-PDA | -Response at the lowest concentration (3.5 μg/mL) was significantly more than 5 times higher than that of the blank serum -Interday coefficient of variation for the lowest and highest concentration (200 μg/mL) samples was within 15%. |
Cmax: 172.2–271.7 mg/L (median = 249.6; n = 6) | nd | [24] | |
LZD | Age: 78 Sex: male weight: 48.2 kg |
Treatment of mediastinitis with TDM of serum and wound exudate concentrations of linezolid in renal function impaired patients. | Scr: 5.6 mg/dL glomerular filtration rate: 8.6 mL/min/1.73 m2 |
600 mg every 24 h After that, 300 mg every 24 h |
HPLC | -Lower limit: 0.1 μg/mL -Intra/interday precision below 5.0% |
Cmin: 11.5 μg/mL (Day 21) Cmin: 5.5 μg/mL (Day 55) |
nd | [25] |
Age: 77 Sex: female weight: 55 kg |
TDM was effective in preventing thrombocytopenia with linezolid: a case report | CLcr 29.9 mL/min | 600 mg twice a day After that, 600 mg every 24 h |
HPLC | -Lower limit: 0.25 μg/mL -Intra/interday precision below 5.0% |
39.4 µg/mL (Day 9) | nd | [26] | |
Age: 79 Sex: female weight: 58.5 kg |
Successful combination therapy with linezolid and rifampicin with appropriate management of linezolid TDM in MRSA osteomyelitis: a case report | Scr 0.4 mg/dL | 600 mg twice a day Thereafter, 300 mg twice a day At the time rifampicin is combined, 600 mg twice a day |
HPLC | -Lower limit: 0.1 μg/mL -Intra/interday precision below 5.0% |
Cmin: 15.1 µg/mL (Day 5) Cmin: 13.9 µg/mL (Day 8) As a result of combination therapy, Cmin was in the optimal range of 3.7 to 7.2 mg/mL. |
nd | [27] | |
TZD | Population: n = 3 patients | Development of an assay system for simultaneous quantification of plasma concentrations of LZD, DAP, and TZD and its clinical application | CLcr 48.3–64.5 mL/min | 200 mg once daily | UPLC-MS/MS | -TZD showed good linearity over wide ranges of 5–5000 ng/mL. -The lower limited of quantification and three quality controls (QCs: low, medium and high) were less than 15% for both accu-racy and precision. -Recovery rate of TZD: more than 84.8% |
Cpeak and Cmin of TZD ranged from 1.87 to 4.92 μg/mL and from 0.09 to 0.78 μg/mL | nd | [28] |
Population: n = 3 patients | Development of an assay for simultaneous quantification of 12 antimicrobial agents commonly used in ICU and its clinical application | CLcr 51.7–60.4 mL/min | 200 mg once daily | UHPLC-MS/MS | -The concentration ranges of calibration curves for TZD was 0.01–5 μg/mL. -The measured concentrations in blanks were less than 20% of the peak response of the lower limited of quantification and less than 5% for internal standard |
The ranges of Cmin and Cpeak in patients with CLcr of 51.7–60.4 mL/min were 0.06–0.12 and 2.67–4.01 μg/mL | nd | [29] | |
LZD | Age: 78 Sex: male weight: 48.2 kg |
Treatment of mediastinitis with TDM of serum and wound exudate concentrations of linezolid in renal function impaired patients. | Scr: 5.6 mg/dL glomerular filtration rate: 8.6 mL/min/1.73 m2 |
600 mg every 24 h After that, 300 mg every 24 h |
HPLC | -Lower limit: 0.1 μg/mL -Intra/interday precision below 5.0% |
Cmin: 11.5 μg/mL (Day 21) Cmin: 5.5 μg/mL (Day 55) |
nd | [25] |
Age: 77 Sex: female weight: 55 kg |
TDM was effective in preventing thrombocytopenia with linezolid: a case report | CLcr 29.9 mL/min | 600 mg twice a day After that, 600 mg every 24 h |
HPLC | -Lower limit: 0.25 μg/mL -Intra/interday precision below 5.0% |
39.4 µg/mL (Day 9) | nd | [26] | |
Age: 79 Sex: female weight: 58.5 kg |
Successful combination therapy with linezolid and rifampicin with appropriate management of linezolid TDM in MRSA osteomyelitis: a case report | Scr 0.4 mg/dL | 600 mg twice a day Thereafter, 300 mg twice a day At the time rifampicin is combined, 600 mg twice a day |
HPLC | -Lower limit: 0.1 μg/mL -Intra/interday precision below 5.0% |
Cmin: 15.1 µg/mL (Day 5) Cmin: 13.9 µg/mL (Day 8) As a result of combination therapy, Cmin was in the optimal range of 3.7 to 7.2 mg/mL. |
nd | [27] | |
TZD | Population: n = 3 patients | Development of an assay system for simultaneous quantification of plasma concentrations of LZD, DAP, and TZD and its clinical application | CLcr 48.3–64.5 mL/min | 200 mg once daily | UPLC-MS/MS | -TZD showed good linearity over wide ranges of 5–5000 ng/mL. -The lower limited of quantification and three quality controls (QCs: low, medium and high) were less than 15% for both accu-racy and precision. -Recovery rate of TZD: more than 84.8% |
Cpeak and Cmin of TZD ranged from 1.87 to 4.92 μg/mL and from 0.09 to 0.78 μg/mL | nd | [28] |
Population: n = 3 patients | Development of an assay for simultaneous quantification of 12 antimicrobial agents commonly used in ICU and its clinical application | CLcr 51.7–60.4 mL/min | 200 mg once daily | UHPLC-MS/MS | -The concentration ranges of calibration curves for TZD was 0.01–5 μg/mL. -The measured concentrations in blanks were less than 20% of the peak response of the lower limited of quantification and less than 5% for internal standard |
The ranges of Cmin and Cpeak in patients with CLcr of 51.7–60.4 mL/min were 0.06–0.12 and 2.67–4.01 μg/mL | nd | [29] |