Pretransplant test-dose pharmacokinetic profiles

Abstract

The purpose of this study was to compare the accuracy of pretransplant test-dose pharmacokinetic (PK) profiling after administration of the microemulsion (CsA-ME; Neoral) versus the corn oil-based (CsA-GC; Sandimmune) gel capsule formulations of cyclosporin A (CsA) to estimate posttransplant CsA bioavailability and to individualize starting drug doses. The absolute oral bioavailability (F), clearance rate (CL), average blood concentration (C[av]), peak concentration (Cmax), and time to Cmax (tmax) values were calculated from paired intravenous and oral pretransplant PK profiles of renal transplant candidates, using CsA-GC (n = 70) or CsA-ME (n = 70) administration. The initial posttransplant oral CsA dose was estimated by linear extrapolation of the observed pretransplant value to the target concentration. Because higher mean F (P < 0.0001), but not CL, values were observed in end-stage renal disease patients after CsA-ME compared with CsA-GC treatment, the predicted starting doses for each therapy were markedly different (P < 0.01). From posttransplant days 5 to 7, 54% of patients treated with CsA-ME had a mean dose-normalized C(av) (C(av)/dose, D) value within 20% of the target concentration, compared with 42% of patients treated with CsA-GC (P = 0.03). Administration of the predicted oral dose of CsA-ME produced a Cmax > 700 ng/ml in 90% of patients from days 2 to 4, and in 97% from days 5 to 7, whereas administration of the predicted oral dose of CsA-GC produced a Cmax > 700 ng/ml in only 64 and 82% of patients during these same time periods, respectively (both P < 0.05). The mean estimated posttransplant F value of CsA-ME was significantly higher than that of CsA-GC; even at postoperative day 5 the value for CsA-GC was significantly lower than the pretransplant estimate (P < 0.01). Therefore, CsA-ME pretransplant PK profiles yield more accurate predictions for appropriate starting drug doses than those of CsA-GC.

Clinical Pharmacokinetics and Pharmacodynamics of Voclosporin

“…Because the 1000-ng/mL C max and the AUC for 300 mg of voclosporin are similar to the C max and AUC with conventional 300 mg of cyclosporin, the bioavailability after an oral dose must be comparable. For conventional cyclosporin, the bioavailability has been reported to be 57%, while the value is higher at 74% with the new microemulsion [ 6 ]. The similarity to conventional cyclosporin therefore allows us to predict an oral bioavailability of approximately F = 50% for voclosporin (Table 1 ).…”

Update in feline therapeutics

“…As a result, the nuclear factor of activated T cells is inhibited, leading to decreased production of several principal proinflammatory cytokines such as interleukin (IL)-2, IL-4, tumor necrosis factor-α and interferon-γ. Sandimmune (Novartis Pharmaceuticals) was found to have both poor and highly variable oral bioavailability in human studies, 48,49 and is not routinely used in dogs or cats. The microemulsion or modified CsA formulation (Atopica; Novartis Animal Health) enhances the oral absorption of this otherwise poorly soluble drug and is approved by the FDA for the treatment of allergic dermatitis in cats.…”