B. Kahan
Nov 1, 1985
Citations
8
Influential Citations
258
Citations
Quality indicators
Journal
Transplantation
Abstract
Initial studies utilizing cyclosporine (CsA)1 immunosuppression documented not only therapeutic efficacy (1), but also appreciable interindividual variation, both in clinical responses and in serum drug concentrations, in spite of fixed dosage regimens (2, 3). Optimal CsA schedules are difficult to establish: on the one hand, the therapeutic effect is not easily quantitated, both because of the absence of objective signs, such as blood pressure provides for antihypertensive agents, and because of the delayed time frame in which to detect rejection in the event of inadequate therapy, which results from the lack of suitable intermediate points with proved correlation with immunosuppression. On the other hand, CsA causes toxic side effects capable of increasing morbidity. Assuming that toxic levels of CsA exceed therapeutic levels, many physicians have routinely administered enough CsA to keep the patient nephrotoxic, in order to avert rejection. However, high initial doses of CsA appear to be associated with intractable nephrotoxicity and renal interstitial fibrosis (4). Indeed, as in theophylline, there appears—at least in some patients—to be an overlap of the concentration/response relationship for therapeutic and toxic effects, neither of which are clearly related to the administered dose. In other pharmacologic settings of a narrow therapeutic range, in part because of the lipophilic nature of the agent and its low apparent bioavailability, with toxic side effects upon overdosage and minimal effect upon underdosage, individualization of the drug regimen has achieved the specific goals of treatment. This overview addresses the question of whether therapeutic drug monitoring, pharmacokinetic analyses, and/or pharmacodynamic assessment of renal transplant recipients proffer criteria suitable for individualization of the CsA regimen, in order to afford prophylaxis of rejection episodes and minimize nephrotoxicity, thereby improving the risk: benefit ratio, obviating the variable outcome, and achieving uniform success of immunosuppressive therapy.