Cyclosporine pharmacokinetics and blood pressure responses after conversion to once‐daily dosing in maintenance liver transplant patients

Abstract

In this six-month randomized multicenter trial, we characterized cyclosporine pharmacokinetics and blood pressure profiles in maintenance liver transplant patients converting from twice-daily to once-daily cyclosporine dosing. A total of 60 patients were randomized as follows: group A (n = 14) maintained twice-daily dosing; group B (n = 24) converted to once-daily dosing at the same total daily dose as pre-conversion; and group C (n = 22) was treated the same as group B but with a 25% reduction in dose and C2 at two to three wk post-conversion. After conversion to once-daily dosing in groups B and C, trough blood levels (C0) did not change; whereas, C2 nearly doubled. The total daily area under the concentration-time curve AUC(0-24) increased by 29%. After the dose reduction in group C, the AUC(0-24) was similar to the pre-conversion value. Hence, a 25-30% dose reduction can be considered after conversion to once-daily dosing. In the study observation period in weeks 4-15, the median (25-75 percentile) C2 was 568 (469-750) ng/mL for group A; 1055 (840-1224) ng/mL for group B; and 764 (575-959) ng/mL for group C. Conversion to once-daily dosing was associated with a decrease in nighttime mean arterial blood pressure.

Long‐Term Changes in Cyclosporine Pharmacokinetics After Renal Transplantation in Children: Evidence for Saturable Presystemic Metabolism and Effect of NR1I2 Polymorphism

“…Adult studies with the microemulsion formulation of cyclosporine have been consistent with dose‐linear pharmacokinetics but only at single doses exceeding 3 mg/kg 34 . In 1 study in 60 adult liver transplant patients, cyclosporine AUC 0–24 h increased by 30% when the patients were changed from bid dosing (1.1‐mg/kg single doses) to once‐daily dosing (2.2‐mg/kg single dose) 35 . Thus, it can be hypothesized that the inhibitory effects of cyclosporine on CYP3A4 and P‐glycoprotein 13 , 36 – 38 result in auto‐inhibition and dose‐dependent pharmacokinetics at low single doses, such as those used in our patients, whereas complete saturation of CYP3A4 or P‐glycoprotein renders cyclosporine pharmacokinetics dose‐linear after a certain threshold dose is exceeded 39 …”

“…34 In 1 study in 60 adult liver transplant patients, cyclosporine AUC 0-24 h increased by 30% when the patients were changed from bid dosing (1.1-mg/kg single doses) to once-daily dosing (2.2mg/kg single dose). 35 Thus, it can be hypothesized that the inhibitory effects of cyclosporine on CYP3A4 and P-glycoprotein 13,[36][37][38] result in auto-inhibition and dose-dependent pharmacokinetics at low single doses, such as those used in our patients, whereas complete saturation of CYP3A4 or P-glycoprotein renders cyclosporine pharmacokinetics dose-linear after a certain threshold dose is exceeded. 39 As young children have a larger clearance/body weight than older children, 9 their cyclosporine halflife is shorter, leading to greater peak-to-trough ratios.…”

Investigation of gene therapy of adenovirus in immune suppression

“…Past studies mainly concentrated on reducing the immunogenicity of the adenovirus and the host immune status [6,7]. Now, ciclosporin A is widely used against immunologic rejection after organ transplantation for cancer [8,9]. At the same time, it causes a lower immune status of the human body which leads to tumor recurrence and metastasis.…”