Table 1.
Pharmacokinetic Parameters |
Total sample | Genotype | Unpaired t-test | |
---|---|---|---|---|
305Ile/305Ile (n=10) | 305Ile/305Phe (n=5) | p-values | ||
C0 (µg/mL) | 278 ± 215 | 190 ± 68.4 | 453 ± 305 | 0.018# |
t1/2 (h) | 1.00 ± 0.200 | 1.10 ± 0.200 | 1.00 ± 0.200 | 0.338 |
AUC0–6 hrs (µg*h/mL) | 149 ± 50.3 | 129 ± 31.4 | 188 ± 61.6 | 0.027# |
Vss (mL) | 13400 ± 5620 | 15300 ± 4990 | 9450 ± 5100 | 0.053 |
Total CL (mL/min) | 247 ± 74.9 | 273 ± 68.9 | 193 ± 60.0 | 0.046 |
CLR (mL/min) | 134 ± 53.0 | 158 ± 44.1 | 84.8 ± 32.1 | 0.006# |
CLCR (mL/min) | 96.3 ± 17.5 | 102 ± 17.9 | 85.8 ± 11.8 | 0.101 |
CLsec (mL/min) | 75.8 ± 49.0 | 97.0 ± 42.2 | 33.3 ± 31.8 | 0.011# |
The cefotaxime pharmacokinetic parameters (mean ± SD) were determined using noncompartmental analysis (WinNonLin 4.1, Pharsight Corporation). The pharmacokinetics parameters are consistent with previously reported values.20,22
C0, is the plasma concentration at first collection time point at 15 min; t1/2, elimination half-life; AUC0–6 h, area under the plasma concentration–time curve (AUC) from the initial time to the last time point at 6 h. The plasma concentrations of cefotaxime are negligible (<% of the initial concentrations) after 6 h.
CLCR, measured creatinine clearance; Vss, apparent volume of distribution at steady state. The renal clearance of cefotaxime (CLR) is the sum of the net secretory clearance (CLsec) and filtration clearance of cefotaxime. Filtration clearance of cefotaxime is creatinine clearance (CLCR) fraction of the cefotaxime unbound to plasma proteins (fu), that is, CLR = CLsec + (fuCLCR). We used 0.6 as the cefotaxime fraction unbound (fu) based on published results.20,32 In one individual who is heterozygous for variant allele, the estimated GFR was used as CLCR instead of using the measured CLCR above. This individual had an abnormal measured CLCR (2.6-fold higher than estimated GFR), whereas other individual had similar values for estimated GFR and measured CLCR.
p value is significant (p < 0.05) when the individual who is heterozygous for variant allele, with an abnormal measured CLCR was removed from the analysis. Overall, the C0, CLR, CLsec, and AUC remained significant when the analysis was performed in 14 healthy volunteers, excluding the individual with the extremely high creatinine clearance.