Effect of gastrointestinal inflammation and age on the pharmacokinetics of oral microemulsion cyclosporin A in the first month after bone marrow transplantation

Abstract

Cyclosporin A (CsA) absorption is highly variable in BMT patients. Neoral, a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3mg/kg were given 48 h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA. Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (Cmax), time to Cmax (tmax), concentration at 12 h after the dose (C12), the area under the concentration-time curve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than adults, with an AUC of 861+/-805 vs 2629+/-1487 micromg x h/l (P = 0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUC was high at 0.59+/-0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077+/-1551 microg x h/l compared to 1795+/-973 microg x h/l (P = 0.02), and a similar trend was observed in children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUC. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5 h after dosing accurately approximated AUC in adults (r2 = 0.94), while 1.5 and 5 h was superior in children (r2 = 0.98). These data suggest that 12 h postdose trough measurements of CsA may not be the most appropriate way to evaluate CsA blood concentrations in order to establish therapeutic efficacy in BMT patients. Based on this study, the dose of microemulsion CsA should be adjusted based on recipient age, and the presence of GI inflammation secondary to mucositis or GVHD. These data would suggest that sparse sampling at time points earlier than the trough more accurately reflects the AUC and may correlate more closely with therapeutic efficacy early post-BMT.

Assessment of converting from intravenous to oral administration of cyclosporin A in pediatric allogeneic hematopoietic stem cell transplant recipients

“…12,13,15 However, we conducted part of our study at a later point in the post transplant period, when GI inflammation was improved; the pharmacokinetics of CsA in HSCT recipients may correspond more closely to those for solid organ transplant recipients during the period of time studied in our investigation.…”

“…15,17,21 Several pediatric solid organ transplant centers are using a three times daily dosing schedule instead of twice daily. 39,40 It has been reported that the three times daily dosing schedule of CsA in children helped to avoid deleterious peak levels with less fluctuation in blood concentration; these results have been obtained without any significant change of the average concentration of CsA.…”

“…12 Particularly, HSCT recipients have considerable difference in their gastrointestinal (GI) integrity, as compared to solid organ transplant recipients; these differences are in part caused by GI inflammation that develops after conditioning chemotherapy and radiation treatments and/or intestinal GVHD and viral infection. [13][14][15] In addition, a significant factor for the interindividual variability is the patient's intrinsic capacity to metabolize CsA. 12 In general, many drugs administered to children are characterized by a substantially faster elimination than in adults; however, there are limited data on the pharmacokinetics of CsA in pediatric transplant recipients.…”

CsA 2-h concentration correlates best with area under the concentration–time curve after allo-SCT compared with trough CsA

“…GI inflammation may also affect absorption, with higher levels observed in patients with mucositis or GVHD. 2 The availability of an oral microemulsion formulation (Neoral, Novartis, Sydney, Australia) has improved problems with erratic absorption, 3,4 but high inter-patient variability in absorption and metabolism has resulted in monitoring of CsA levels as standard practice. Given orally twice daily, CsA levels in allo-SCT patients have traditionally been performed 12 h after the preceding dose (C0), although the relationship of trough levels to toxicity and the effectiveness of prevention of GVHD is questionable.…”

Population pharmacokinetics of ciclosporin in haematopoietic allogeneic stem cell transplantation with emphasis on limited sampling strategy

“…Therefore, a model that predicts ciclosporin pharmacokinetics and dose requirements to achieve the desired therapeutic target in an individual HSCT patient would be highly useful. CsA pharmacokinetic studies in HSCT recipients are scarce and most have evaluated only small numbers of subjects [9, [23][24][25][26][27][28].…”