Introduction
Patients and methods
Patients
Sampling and analyses
Number | Median (range) | |
---|---|---|
Patient characteristics | ||
Female/male | 161/79 | |
Age (years) | 47 (16–75) | |
BSA (m2) | 1.81 (1.49–2.94) | |
BMI (kg/m2) | 24 (16–46) | |
Weight (kg) | 70 (46–170) | |
Height (cm) | 171 (153–210) | |
Protocol | ||
Non-small cell lung cancer [10] | 21 (21 courses) | |
2–6 × PCa (dose carboplatin AUC 6 mg min/mL administered in 30 min) | Four plasma samples per patient per course | |
t = 0.5, 4.5, 8.5, 23.5 h | ||
58 (95 courses) | ||
PC (dose carboplatin 300–400 mg/m2 per 30 min) | Six to ten plasma samples per patient per course | |
t = 0.5, 0.75, 1, 1.5, 2.5, 4.5, 8.5, 12.5, 24.5, 48.5 h | ||
25 (25 courses) | ||
PC (dose carboplatin 300–600 mg/m2 per 30 min) | 8–12 plasma samples per patient per course | |
t = 0.5, 0.75, 1, 1.5, 2.5, 4.5, 8.5, 12.5, 18.5, 24.5, 48.5 h | ||
High-risk primary breast cancer [11] | 44 (44 courses) | |
CTCb (dose carboplatin 400 mg/m2 per day or AUC 20 mg min/mL administered in 1 h for 4 days) | 15–20 plasma samples per patient per course | |
t = 0.5, 0.75, 1, 1.5, 2.5, 4.5, 8.5, 12.5, 18.5, 24.5, 48.5 h. Days 1 and 3 | ||
Metastatic breast cancer [11] (and additional pat’s) | 47 (113 courses) | |
tCTC (dose carboplatin 267 mg/m2 per day or AUC 13.3 mg min per mL administered in 1 h for 4 days) | 15–20 plasma samples per patient per course | |
t = 0.5, 1, 1.5, 1.75, 2, 2.5, 3.75, 5.5, 10, 24 h. Days 1 and 3 | ||
Refractory germ cell cancer [11] (and additional pat’s) | 19 (35 courses) | |
CTC (dose carboplatin 400 mg/m2/day or AUC 20 mg min/mL administered in 1 h for 4 days) | 15–20 plasma samples per patient per course | |
t = 0.5, 1, 1.5, 1.75, 2, 2.5, 3.75, 5.5, 10, 24 h days 1 and 3 | ||
Refractory germ cell cancer [11] (and additional pat’s) | Five (14 courses) | |
tCTC (dose carboplatin 267 mg/m2 per day or AUC 13.3 mg min/mL administered in 1 h for 4 days) | 15–20 plasma samples per patient per course | |
t = 0.5, 1, 1.5, 1.75, 2, 2.5, 3.75, 5.5, 10, 24 h days 1 and 3 | ||
Metastatic ovarian cancer [11] | 5 (6 courses) | |
tCTC (dose carboplatin 267 mg/m2 per day or AUC 13.3 mg min/mL administered in 1 h for 4 days) | 15–20 plasma samples per patient per course | |
t = 0.5, 1, 1.5, 1.75, 2, 2.5, 3.75, 5.5, 10, 24 h. Days 1 and 3 | ||
Epithelial breast cancer | 16 (27 courses) | |
miniCTCc (dose carboplatin 400 mg/m2 per day or AUC 10 mg min/mL administered in 1 h for 2 days) | 12–16 plasma samples per patient per course | |
t = 0.5, 1, 1.5, 2, 2.5, 3.75, 5.5, 10 h days 1 and 2 | ||
Biochemical parameters | ||
Serum creatinine (μM) | 57 (18–124) | |
Creatinine clearance (calculated with the Cockcroft–Gault formula (mL/min) [4] | 126 (55–451) | |
Albumin (g/L) | 42 (18–52) |
Pharmacokinetics and data analysis
Results
Patients
Subpopulation | Female/male | Age | Serum creatinine (μM) |
---|---|---|---|
Median (range) | Median (range) | ||
Underweight BMI < 18.5 kg/m2
| 4/3 | 38 (16–58) | 46 (32–62) |
Normal weight BMI ≥ 18.5 to <25 kg/m2
| 97/49 | 46 (17–75) | 57 (18–124) |
Overweight BMI ≥ 25 to <30 kg/m2
| 49/23 | 49 (18–74) | 62 (31–118) |
Obese BMI ≥ 30 kg/m2
| 11/4 | 52 (28–68) | 55 (38–87) |
Pharmacokinetics and data analysis
Weight descriptor | |
---|---|
ABW | |
IBW | 49.9 + 0.89 × (height (cm) − 152.4) for men |
45.4 + 0.89 × (height (cm) − 152.4) for women | |
AIBW | IBW + 0.4 × (ABW − IBW) |
Benezet [30] | (IBW + ABW)/2 |
FFM | ABW × (1–0.715) + 12.1 × height (m)2 for men |
ABW × (1–0.713) + 9.74 × height (m)2 for women | |
LBM | 1.1 × ABW − 0.0128 × BMI × ABW for men |
1.07 × ABW − 0.0148 × BMI × ABW for women |
Weight descriptor | Underweight (n = 7) | Normal weight (n = 146) | Overweight (n = 72) | Obese (n = 15) | ||||
---|---|---|---|---|---|---|---|---|
MPE % (95%CI) | MAPE % (95%CI) | MPE % (95%CI) | MAPE% (95%CI) | MPE % (95%CI) | MAPE % (95%CI) | MPE % (95%CI) | MAPE % (95%CI) | |
ABW | 13.9 (−7.06–34.8) | 27.5 (18.6–36.4) | 15.4 (9.41–21.3) | 26.6 (21.8–31.4) | 13.9 (6.97–20.7) | 23.7 (18.5–29.0) | 35.4 (15.0–55.8) | 36.8 (17.1–56.5) |
IBW | 40.2 (7.82–72.6) | 45.7 (18.5–73.0) | 12.9 (6.60–19.3) | 26.9 (21.8–31.9) | −5.22 (−10.6–0.21) | 20.1 (17.0–23.1) | −11.4 (−21.9–0.93) | 20.4 (14.8–26.0) |
AIBW | 29.7 (1.92–57.4) | 38.1 (17.9–58.2) | 13.9 (7.76–20.1) | 26.5 (21.6–31.5) | 2.41 (−3.55–8.37) | 20.0 (16.2–23.8) | 7.34 (−6.77–21.4) | 21.0 (11.4–30.6) |
Benezet [30] | 27.0 (0.43–53.6) | 36.3 (18.1–54.5) | 14.2 (8.04–20.3) | 26.5 (21.6–31.4) | 4.32 (−1.78–10.4) | 20.4 (16.4–24.3) | 12.0 (−3.09–27.1) | 22.6 (11.3–33.9) |
FFM | 6.14 (−18.0–30.3) | 30.1 (25.1–35.2) | −7.61 (−12.6–2.63) | 25.2 (22.1–28.3) | −17.3 (−21.9–12.8) | 22.6 (19.5–25.7) | −14.0 (−24.7–3.40) | 22.1 (16.3–27.8) |
LBM | −0.90 (−21.0–19.2) | 24.3 (19.3–29.3) | −7.26 (−12.1–2.41) | 24.6 (21.7–27.6) | −15.4 (−20.0–10.7) | 21.9 (19.0–24.9) | −15.9 (−25.3–6.45) | 21.0 (15.0–27.1) |
Flat dose | −2.06 (−12.3–8.13) | 8.96 (1.52–16.4) | 3.96 (−0.86–8.77) | 18.1 (14.2–22.0) | 0.91 (−3.99–5.81) | 16.4 (13.3–19.5) | −0.59 (−13.1–11.9) | 19.1 (11.6–26.7) |
Parameter | Estimate (RSE %) | % IIV (RSE %) | % IOV (RSE %) |
---|---|---|---|
Clearance (L/h) | 8.38 (1.41) | 19.4 (8.34) | 9.14 (9.15) |
Volume of distribution (L) | 15.4 (1.79) | 14.5 (11.7) | 10.8 (14.9) |
Distribution microconstant k12 (h−1) | 0.135 (7.85) | 48.2 (18.9) | Nd |
Distribution microconstant k21 (h−1) | 0.215 (5.91) | 43.6 (30.8) | Nd |
Proportional residual error (%) | 19.7 (5.69) |
Weight descriptor | Allometric coefficient (RSE %) | % IIV (RSE %) | ∆OFV |
---|---|---|---|
Basic model | 19.4 (8.34) | ||
ABW | 0.175 (46.2) | 18.7 (8.52) | −6.06 |
IBW | 0.136 (72.9) | 18.8 (8.91) | −2.22 |
AIBW | 0.218 (48.6) | 18.5 (8.84) | −5.03 |
Benezet [30] | 0.220 (46.8) | 18.5 (8.79) | −5.49 |
FFM | 0.138 (72.4) | 18.7 (8.73) | −2.57 |
LBM | 0.207 (46.7) | 18.5 (8.71) | −5.71 |