Chronopharmacokinetics of ciclosporin and tacrolimus

The correct use of immunosuppressive drugs has a considerable influence on the prognosis of patients with organ transplants. The appropriate utilisation of the drugs involves the administration of an adequate dosage to reach the blood concentrations that will suppress the alloimmune response, while avoiding secondary toxicities. However, transplanted patients exhibit heterogeneous immunological responses and high inter- and intraindividual pharmacokinetic variabilities. One cause of these variabilities that is rarely considered is circadian rhythms. In vitro and in vivo experiments have clearly demonstrated that all organisms are highly organised according to an internal biological clock that influences various physiological functions. Considering that the absorption, distribution, metabolism and elimination of drugs is influenced by the physiological functions of the body, it is not surprising that the pharmacokinetic, and consequently the pharmacodynamic, profiles of drugs can be influenced by circadian rhythms. Ciclosporin, a mainstay immunosuppressive drug used following organ transplantation, displays minimum blood concentration (C min ), maximum blood concentration (C max ) and area under the blood concentration-time curve (AUC) in the morning that are generally higher than the corresponding parameters in the evening. These observations are supported by the ciclosporin total body clearance and elimination half-life in the morning, which are, on average, higher and shorter, respectively, than those in the evening. In addition, the disposition of tacrolimus is determined by the time of administration. The tacrolimus C max and AUC after the morning dose are significantly higher than those after the evening dose. Finally, the results reported in this review suggest considering more carefully the chronopharmacokinetics of tacrolimus and ciclosporin in order to obtain better results with fewer adverse effects. Significantly, the morning appears to be the best time for therapeutic monitoring using the C min , C max , concentration at 2 hours after dosing and AUC to modify dosages of tacrolimus and ciclosporin. Less certain are any conclusions about whether, in order to obtain better immunosuppressive control, higher doses must be administered when these drugs are given in the evening to compensate for the higher levels of interleukin-2

Antimicrobial therapy in critically ill patients: A review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability

Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients. Selecting the appropriate antimicrobial at the commencement of therapy, both in terms of spectrum of activity and dose and frequency of administration according to concentration or time dependency, is mandatory in this setting. Despite appropriate standard dosage regimens, failure of the antimicrobial treatment may occur because of the inability of the antimicrobial to achieve adequate concentrations at the infection site through alterations in its pharmacokinetics due to underlying pathophysiological conditions. According to the intrinsic chemicophysical properties of antimicrobials, hydrophilic antimicrobials (beta-lactams, aminoglycosides, glycopeptides) have to be considered at much higher risk of inter- and intraindividual pharmacokinetic variations than lipophilic antimicrobials (macrolides, fluoroquinolones, tetracyclines, chloramphenicol, rifampicin [rifampin]) in critically ill patients, with significant frequent fluctuations of plasma concentrations that may require significant dosage adjustments. For example, underexposure may occur because of increased volume of distribution (as a result of oedema in sepsis and trauma, pleural effusion, ascites, mediastinitis, fluid therapy or indwelling post-surgical drainage) and/or enhanced renal clearance (as a result of burns, drug abuse, hyperdynamic conditions during sepsis, acute leukaemia or use of haemodynamically active drugs). On the other hand, overexposure may occur because of a drop in renal clearance caused by renal impairment. Care with all these factors whenever choosing an antimicrobial may substantially improve the outcome of antimicrobial therapy in critically ill patients. However, since these situations may often coexist in the same patient and pharmacokinetic variability may be unpredictable, the antimicrobial policy may further benefit from real-time application of therapeutic drug monitoring, since this practice, by tailoring exposure to the individual patient, may consequently be helpful both in improving the outcome of antimicrobial therapy and in containing the spread of resistance in the hospital setting