New oral formulation of cyclosporin A (Neoral) pharmacokinetics in allogeneic bone marrow transplant recipients

Abstract

Summary:Cyclosporin A (CsA) absorption is variable in bone marrow transplant (BMT) patients compromising the efficacy of graft-versus-host disease prevention. Neoral, a new microemulsion formulation of CsA which has an improved bioavailibility, increases intestinal absorption of the drug with less variable pharmacokinetic parameters in non-BMT patients. In order to predict the best dosage of Neoral when patients are switched from i.v. to oral administration we performed a randomised study comparing two oral doses, either the same or twice the last i.v. dose used after BMT. Fourteen adults were randomised around day 25 after BMT. Whole blood CSA concentrations were measured 2 and 12 h after the oral administration of Neoral on days 0, 7 and 14 to determine residual and maximum concentration, and modified whenever necessary to maintain blood level CsA concentration within therapeutic range (150-250 ng/ml). We found that patients who received twice the last i.v. dose had better concentrations than patients from the other group while toxicity was identical in both groups. We conclude that doubling the last i.v. dose during the switch to oral administration of Neoral gives the best therapeutic range concentration and should be recommended for graft-versus-host prevention. Bone Marrow Transplantation (2000) 25, 965-968. Keywords: bone marrow transplantation; cyclosporin A; pharmacokineticsIn an attempt to improve the bioavailibility of oral cyclosporin A (CsA) and to reduce variability in absorption, a new microemulsion formulation of CsA has been developed (Neoral).Pharmacokinetic studies conducted in healthy volunteers and renal, liver and cardiac transplant recipients have consistently demonstrated that absorption was increased by an average of 30% in the area-under-the-curve and was faster after Neoral than after Sandimmun. This results in an increased bioavailibility, a lower dependency on food, bile or pancreatic enzymes and a markedly reduced variability

Oral self-nanoemulsifying peptide drug delivery systems: impact of lipase on drug release

“…Although the very first oral peptide drug delivery system that reached the market in 1981, namely Sandimmune (Cyclosporin A) was a self-emulsifying drug delivery system (Klyashchitsky and Owen, 1998) and the later on further improved selfemulsifying system (Neoral) for the same therapeutic peptide still shows with 40% (Parquet et al, 2000) of the highest bioavailability of all marketed peptide drug formulations, this formulation strategy for therapeutic peptides was obviously almost ignored at least by academia for several decades. A likely explanation for it might be the hydrophilic character of most therapeutic peptides being in contrast to cyclosporine that did not allow drug incorporation in lipophilic droplets.…”

Pharmacokinetics of CsA during the switch from continuous intravenous infusion to oral administration after allogeneic hematopoietic stem cell transplantation

“…The initial dose of Neoral was twice the last daily dose of continuous infusion, and was given in two equally divided doses based on the reported bioavailability of Neoral of about 0.4 (40%) in allogeneic HSCT recipients. 5 On the last day of the continuous infusion of CsA (day À1), the serum CsA concentration was measured at 9:00, 15:00, and 21:00. After the patient was switched to Neoral, the CsA concentration was measured just before (C 0 ), and 1 (C 1 ), 2 (C 2 ), 3 (C 3 ), 4 (C 4 ), 6 (C 6 ), and 12 (C 12 ) hours after the oral administration of Neoral on the first day (day 0) and between day 3 and day 5.…”

“…4 However, the appropriateness of this conversion rate has been inconsistent among earlier studies. 5,6 Parquet et al reported that doubling the last intravenous dose provided the best therapeutic range concentration, whereas the concentration/dose ratio was similar in intravenous administration and oral administration and thus, 1:1 conversion seemed appropriate in the McGuire's study. In addition, no data are available regarding the detailed pharmacokinetics in allogeneic HSCT recipients.…”

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].…”