Discussion
To our knowledge, this is the first research to investigate the effect of TPE on CFP and SUL pharmacokinetics in critically ill TTP patients. The TPE specific properties and pharmacokinetic characteristics of the drug are two key factors determining drug elimination during TPE. The time between the drug infusion and TPE initiation are two factors that affect the amount of drug extracted from TPE. Researches have shown that the closer the time between drug infusion and TPE initiation, the greater the amount of drug removed by TPE [10]. In our presented four cases, TPE was initiated 10 min after intravenous infusion, at which point the majority of drugs would be primarily present in the intravascular space, and could therefore be removed by TPE [4,16]. Besides, volume of exchange is another significant TPE specific parameter driving the amounts of drug be removed by TPE. The treatment target for a plasma exchange procedure should be 1 to 1.5 PV, equivalent to a removal of approximately 63% and 78% of plasma contents respectively [17]. An increase in volume of exchange can increase a greater amount of drug extracted. In this study, the average volume of exchange is approximately 1970±36.74 mL, corresponding to nearly one PV.
The pharmacokinetic properties of Vd and Pb are considered to be the most dominant factors determining whether a drug is susceptible to removal by TPE. Low Pb and high Vd always correlate with drug’s distribution in tissues and cells and therefore are unsusceptible to removal by TPE. In contrast, drug with small Vd (<0.2 L kg-1) and high Pb (>80%) are more easier to be removed during TPE due to the greater distribution of the drug in the vascular space [12,17]. In our study, we found that approximately 2000 mL exchange yielded a higher KelTotal than the Kelpatient without TPE , suggesting that TPE lead to increases in the rate of CFP and SUL elimination. QPEand fe % seems to be the most reliable parameters for the determination of the amount of drug removed via TPE. The fraction eliminated by TPE (fe %) was significant for CFP as 11.38±3.18% (range 8.43~16.75%). SUL is eliminated by TPE with only 2.74±1.13% (range 1.35~4.28%) from effluent port of depleted plasma. The fe % of CFP is over 4-fold higher than that of SUL. The calculated smaller Vd (0.14±0.03 L kg-1for CFP vs. 0.48±0.15 L kg-1 for SUL) and higher Pb (70-93% for CFP vs. 38% for SUL, obtained from non-critically ill patients) may contribute to the remarkable increased fraction eliminated by TPE. In addition, it was suggested that a 30% increase in %CLPE could be considered a clinically significant effect [13]. %CLPE of CFP and SUL were about 27% and 6%, respectively. It is suggest that CFP is more likely to be removed than SUL during TPE. However, CFP and SUL removal by TPE may not be clinically significant.
There were only slight differences in parameters between session I and session II in those four patients(Table 3) . Unexpectedly, AUC0-8 and Vd of CFP on session I were slightly increased than those on session II, contrary to our expectations. There are many aspects needed to be considered. First, it seems that TPE did not alter the pharmacokinetic behavior of CFP and SUL significantly. Then, the relatively elevated peak concentration at session I might due to pharmacokinetic instability might increase the AUC0-8. Finally, the number of patients included in our trial is limited and two of four critically ill patients with severe infection or septic shock received aggressive fluid resuscitation. Overhydrating status may lead to pharmacokinetics changes, such as AUC and Vd [18].
Additionally, TTP is considered as a life-threatening critical illness and often associated with severe complications such as hypoalbuminemia and multiple organ dysfunction (MOF). Hypoalbuminemia might cause decreased drugs binding resulting in less distribution of drugs in the vascular space, in favor of tissue distribution, especially for CFP with a larger Pb [19]. Besides, positive correlation was observed between QPE and plasma drug concentration before TPE, however it failed to reach statistical significance. SUL is mainly excreted by kidney (84%) while most of CFP is excreted via bile. Organ dysfunction is an important factor leading to elevated plasma drug concentration. In our cohort, the largest amount of CFP removed (645 mg) was noted in the patient with impaired bile excretion (TBIL 71.9 µmol L-1, DBIL 31.5 µmol L-1). Similarly, the largest amount of SUL (51 mg) removed in the patient with impaired renal function (Ccr 36 mL min-1, serum creatinine 156 μmol L-1). It is suggested that elevated plasma drug concentration and extended half-life due to organ dysfunction allow more drug removal by TPE. It is more remarkable when drug distribution half-life (T1/2a) is longer than 2 hours of the TPE procedure duration [20]. In our cohort, T1/2a of CFP and SUL showed a prolongation compared with previous parameters in noncritically ill patients (~1.7 h for CFP and ~1 h for SUL). T1/2a of CFP is longer than 2 hours, which is one of the reasons why its fe % is higher than that of SUL.
The pharmacokinetics of CFP/SUL vary widely among critically ill patients. Therefore, it would be worthwhile to carry out further studies to confirm these results.