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The immunosuppressant basiliximab--a chimeric monoclonal antibody specific to the interleukin-2 receptor on activated T-lymphocytes--significantly reduces the incidence of acute cellular rejection following renal transplantation. Screening for exposure-response relationships was performed within a randomized, blinded, placebo-controlled efficacy trial in which patients received 40 mg basiliximab (20 mg on days 0 and 4) by intravenous infusion in addition to cyclosporine and corticosteroids. In a subset of patients, serum samples were collected pre-transplant and once in weeks 2, 3 and 4 for determination of basiliximab concentrations. A population pharmacostatistical model was used to derive individual empirical Bayes estimates of each patient's pharmacokinetic parameters. Biopsy-confirmed acute rejection episodes were recorded to month 6 post-transplant. Forty basiliximab-treated patients were evaluated, 30 men and 10 women, aged 48 +/- 12 yr (range, 24-73) and weighing 72.4 +/- 12.9 kg (range, 52.5-107.5). The basiliximab distribution volume was 7.5 +/- 1.7 L, the half-life 7.5 +/- 2.5 d and the clearance 33 +/- 12 mL/h. There was no clinically relevant influence of weight, age, or gender on basiliximab disposition. Receptor-saturating serum basiliximab concentrations (> 0.2 microgram/mL) were maintained for 41 +/- 23 d. Twenty-five patients remained rejection-free over the 6-month observation period, while a total of 26 biopsy-confirmed acute rejection episodes occurred in the remaining 14 patients. Of these episodes, 12 occurred during receptor blockade. No apparent relationship to basiliximab concentration on the day of onset was observed range, 0.1-9.0 microgram/mL) nor did the time of suppression offset represent a period of increased risk for rejection episodes. Fourteen rejection episodes occurred after basiliximab had cleared from the serum. The durations of receptor suppression preceding these events did not differ compared with those in patients who remained rejection-free: 32 +/- 11 versus 45 +/- 26 d, respectively (p = 0.1269). Given the durations of receptor saturation achieved with the chosen basiliximab regimen, this screen for exposure-response relationships did not identify the duration of receptor saturation in peripheral blood as a predictive factor for acute rejection episodes. Further exploration for exposure-effect relationships in a larger population is warranted.

No abstract

Cyclosporin is an immunosuppressant used in organ transplantation and selected autoimmune diseases such as rheumatoid arthritis. In both these indications, the elderly represent an important and growing segment of the patient population. Cyclosporin is primarily eliminated via biotransformation by cytochrome P450 (CYP)3A in the gut wall and liver. Additionally, P-glycoprotein (mdr-1) located in the gastrointestinal epithelium can affect affect blood drug concentrations after oral administration of cyclosporin, presumably by counter-transporting the drug from the systemic circulation back into the gastrointestinal lumen. Theoretically, age-related alterations in either of these pathways could affect cyclosporin disposition in the elderly. These general pharmacological considerations together with the narrow therapeutic index of cyclosporin between minimally immunosuppressive concentrations and those associated with adverse events, underscore the need for dedicated pharmacokinetic studies in the elderly. Single dose studies have demonstrated that cyclosporin pharmacokinetics are not different in healthy elderly individuals compared with healthy young adults, nor is the between-subject variability in pharmacokinetic parameters more heterogenous in healthy elderly individuals. Similarly, there were no apparent differences in cyclosporin disposition in elderly patients with rheumatoid arthritis compared with healthy young and elderly individuals. Whether pharmacokinetic variability may be increased in elderly patients has not been rigorously addressed and requires investigation in a larger patient population for a definitive conclusion. A population pharmacokinetic study of cyclosporin in organ transplant patients, including elderly allograft recipients up to 75 years of age, did not identify age as a covariable influencing cyclosporin pharmacokinetics. Hence, the available pharmacokinetic data in the elderly do not reveal any major differences from the disposition characterised in younger individuals. It is generally recognised that the elderly are more prone to drug-related adverse experiences and are at greater risk for drug-drug interactions secondary to polypharmacy. The former factor may underlie, in part, the increased incidence of renal adverse events reported in patients with rheumatoid arthritis over 65 years of age receiving cyclosporin. Clinical experience with cyclosporin in elderly organ transplant recipients has not revealed a tolerability profile remarkably different from those in younger patients. Polypharmacy may have specific relevance for elderly patients treated with cyclosporin since this agent is a substrate of both CYP3A and P-glycoprotein, both of which are important in the elimination of many commonly used drugs. This implies that the clinician prescribing cyclosporin for an elderly patient must exercise a heightened awareness for potential drug-drug interactions which could affect the pharmacokinetics of cyclosporin. Based on the available cyclosporin pharmacokinetic data in adults, no age-r...