Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression

Abstract

The plasma concentrations of pravastatin in pediatric cardiac recipients receiving triple immunosuppressive medication are nearly 10-fold higher than in hypercholesterolemic children after the same pravastatin dose. However, the short-term therapy of pravastatin was well tolerated and effective in lowering serum cholesterol levels in cardiac recipients.

Influence of Non-Steroidal Anti-Inflammatory Drugs on Organic Anion Transporting Polypeptide (OATP) 1B1- and OATP1B3-Mediated Drug Transport

“…Cyclosporine, for instance, inhibited OATP1B1-and OATP1B3-mediated drug uptake in vitro (Treiber et al, 2007). Thus, it has been observed in humans that coadministration of the OATP1B1 and OATP1B3 substrate pravastatin with cyclosporine increased the plasma concentrations of pravastatin (Regazzi et al, 1993;Olbricht et al, 1997;Park et al, 2002;Hedman et al, 2004). Because pravastatin is not metabolized to a significant extent (Jacobsen et al, 1999), inhibition of OATP1B1-and OATP1B3-mediated pravastatin uptake may be one relevant molecular mechanism behind this observed drug-drug interaction.…”

Organic Anion Transporting Polypeptide 1B1: a Genetically Polymorphic Transporter of Major Importance for Hepatic Drug Uptake

“…7). Cyclosporine has raised the AUC of atorvastatin approximately 7-to 15-fold, that of cerivastatin 4-fold, that of fluvastatin 3-to 4-fold, that of lovastatin 20-fold, that of pravastatin 5-to 10-fold, that of pitavastatin 5-fold, that of rosuvastatin 7-fold, and that of simvastatin approximately 3-to 8-fold (Arnadottir et al, 1993;Regazzi et al, 1993;Olbricht et al, 1997;Mü ck et al, 1999;Åsberg et al, 2001;Ichimaru et al, 2001;Park et al, 2001;Hasunuma et al, 2003;Hedman et al, 2004;Hermann et al, 2004;Simonson et al, 2004;Lemahieu et al, 2005). Although inhibition of CYP3A4 may partly explain the effects of cyclosporine on simvastatin, lovastatin, atorvastatin, and cerivastatin, the other statins, rosuvastatin, pravastatin, and pitavastatin, are not significantly metabolized by CYP3A4 (Neuvonen et al, 2006).…”

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

“…For example, Hedman et al (2004) investigated pharmacokinetics and shortterm safety of pravastatin in children undergoing triple-drug (including cyclosporine) immunosuppressive therapy after cardiac transplantation. The authors found that the C max and AUC of pravastatin were 122.2 6 88.2 ng/ml and 264.1 6 192.4 ng  h/ml, respectively, and these values were nearly 10-fold higher than the corresponding values reported in children with hypercholesterolemia who were receiving the same pravastatin dose in the absence of immunosuppressive therapy.…”