Cyclosporin pharmacokinetics in the elderly.

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-related administration adaptations appear necessary for its use in the elderly.

Pharmacokinetics of cyclosporine and multiple-dose diclofenac during coadministration.

Pursuant to anecdotal case reports of a possible drug-drug interaction between cyclosporine and diclofenac, an open, two-period crossover study in 24 healthy male volunteers was undertaken in which a single oral dose of 300 mg cyclosporine was administered alone and on day 8 of multiple oral dosing of 50 mg diclofenac every 8 hours. Serial blood samples were obtained over 48 hours after each cyclosporine dose and over a dosing interval for diclofenac on day 7 (diclofenac alone) and day 8 (coadministration of diclofenac with cyclosporine). The mean pharmacokinetic characteristics of cyclosporine were unchanged during coadministration with diclofenac. Based on area under the curve comparison, lack of a pharmacokinetic interaction was conclusively demonstrated for the extent of cyclosporine absorption. The diclofenac maximum plasma concentration and area under the curve over a dosing interval were significantly increased during coadministration; however, a straightforward interpretation of the statistical results was confounded by pronounced variability in diclofenac pharmacokinetics. The results underscore the need for continued caution when cyclosporine and diclofenac are coadministered.

Determination of the new aromatic retinoic acid Ro 13-7410 in plasma by two-dimensional gas chromatography negative ion chemical ionization mass spectrometry with selected-ion monitoring.

A highly sensitive and specific method for the determination of the aromatic retinoic acid Ro 13-7410 in plasma at the picogram per millilitre level is described. The method involves extraction of plasma using Extrelut-1 columns, purification of the extract with Bond Elut-NH2 cartridges, derivatization with pentafluorobenzyl bromide, and subsequent analysis by two-dimensional capillary gas chromatography using the zone-cutting technique, stable isotope dilution and selective negative ion monitoring chemical ionization mass spectrometry. A tetradeuterated analogue is used as internal standard. Quantification is possible down to 25 pg/ml using 1 ml of plasma. The coefficients of variation of the method as calculated from quality control samples are 8.5 and 4.2% at the 100 and 400 pg/ml levels. The method has been applied to the analysis of plasma of volunteers following an oral dose of 40 micrograms Ro 13-7410 and plasma of dogs following an intravenous and oral dose of 25 and 50 micrograms, respectively.