On the dose dependency of cyclosporin A absorption and disposition in healthy volunteers.

The pharmacokinetics of Cyclosporin A (CyA, Sandimmune) was studied in 12 healthy male volunteers after oral dosing of 350 mg, 700 mg, and 1400 mg as a drinking solution. Blood samples were collected over 96 hr and analyzed by high pressure liquid chromatography. Concentration data were evaluated with model-independent and model-based linear pharmacokinetic concepts. Individual CyA concentration-time profiles in whole blood were well described by a two-compartment open model with zero-order absorption for all three doses. Comparison of pharmacokinetic parameters across doses indicates that both absorption and disposition are dose-dependent. Nonlinear disposition is suggested by the significant increase of the terminal half-life from 8.9 +/- 4.9 hr to 11.9 +/- 4.9 hr (mean +/- SD) after a 350 mg and a 1400 mg dose, respectively. Changes in the metabolic activity of the liver with concentration might be responsible for this phenomenon. In addition, the modeling approach indicated that bioavailability decreases with increasing dose. Moreover, the dependence of the rate of CyA absorption (zero-order rate constant) versus dose was well described by a hyperbola. The limited solubility of the drug in the gastrointestinal tract might be responsible for this behavior. The lag time (0.2-0.8 hr) was independent of dose. This value is similar to the time of gastric emptying in fasting volunteers. The duration of absorption for 11 of 12 subjects was in the range 2.5-3.5 hr over all doses and agrees well with the small intestine transit time. Some subjects showed a marked secondary peak at one or two doses, which could be adequately fitted by a model with two successive zero-order inputs. This double-peak behavior was ascribed to the influence of the food on gastric emptying. Dose dependency of disposition and absorption counterbalance each other in the usual dose range. This leads to an almost proportional increase of area under the blood CyA concentration-time profile with increasing dose.