Large Within-Day Variation in Cyclosporine Absorption

Abstract

and † Novartis Pharmaceuticals, East Hanover, New JerseyWith the recent focus of monitoring cyclosporine (CsA) therapy using measures of CsA absorption, it is important to understand published reports of diurnal variation in CsA exposure. In 10 renal transplant patients, CsA concentrations were measured 0, 1, 2, 3, and 4 h after both the morning and the evening doses and in a repeat session at least 1 wk later. Both area under the curve for the final 4 h after cyclosporine dose and cyclosporine concentrate 2 h after the cyclosporine dose were more than two-fold higher after the morning dose in both sessions. Because the morning levels were collected in a fasted condition and the evening ones in a fed condition, the study was extended to collect evening levels after fasting. The area under the curve for the final 4 h after cyclosporine dose and cyclosporine concentrate 2 h after the cyclosporine dose values observed now were comparable to the morning fasted values. That the large diurnal variation was due to variation in food consumption, as opposed to a biologic circadian rhythm affecting CsA absorption, has significant implications for therapeutic drug monitoring.

Cyclosporine use in Hematopoietic Stem Cell Transplantation: Pharmacokinetic Approach

“…Curtis et al evaluated the effect of food consumption by CsA level monitoring at both morning fasted and evening fed solid organ transplant patients. They found that removing the effect of food significantly reduced within-day variation of CsA PKs [104]. Consistency of drug administration and sampling time regarding meals is obligatory because of observations for decreased C max and AUC of calcineurin inhibitors with food consumption which may lead to increased dosage requirements [12].…”

Inpatient Management of Postrenal Transplant Patients

“…Depending on the method by which a transplant recipient takes his or her medication, there can be wide variations in levels. The effect of food on calcineurin inhibitor absorption has been reported 15,16 and can account for much of the fluctuation in levels seen in the inpatient setting. The authors advocate a strict empty stomach immunosuppression protocol for all transplant recipients to minimize this fluctuation in levels and to ensure adequate drug exposure.…”

The “generic” effect of food on tacrolimus pharmacokinetics

“…All of the above data are from normal volunteers, as the FDA does not require generic immunosuppressive drugs to be studied in transplant recipients (1). However, concomitant food administration has the same effect decreasing TAC and CSA AUC by 30–40% (3, 4).…”

“…The FDA requires that generics be within 80–125% of branded agents with respect to C max and AUC, as these are the standard measures of bioequivalence (1). The concept that AUC determines efficacy for calcineurin inhibitors is widely accepted and has been supported by several clinical studies in CNI’s as summarized by Curtis (4). Contrary to a popular misconception, the reduction in TAC AUC caused by food is not reflected in similar reductions in 12‐h trough levels.…”

“…One study found that, on average, food decreased CSA AUC by over 50% and trough values by only about 15% (4). If food decreased Neoral absorption by even 30%, chronic “fed‐state” dosing reduces the monthly time averaged exposure as much as would missing empty stomach doses 30% of the time (5).…”