Drug interactions in the hematopoietic stem cell transplant (HSCT) recipient: what every transplanter needs to know

Abstract

Summary:Pharmacokinetic drug interactions among hematopoietic stem cell transplant recipients can result in either increases in serum concentrations of medications, which may lead to enhanced toxicity; or reduced serum concentrations, which can lead to treatment failure and the emergence of post transplant complications. The use of drugs that have a narrow therapeutic index, such as cyclosporine/tacrolimus (calcineurin inhibitors), increases the significance of these interactions when they occur. This report will review the clinical data evaluating the drug interactions of relevance to HSCT clinical practice, focusing on the pharmacokinetic interactions, and provides recommendations for managing these interactions to avoid both toxicity and treatment failure. Keywords: drug interactions; cytochrome P450; cyclosporine; tacrolimus; pharmacokinetic; CYP3A4; azoles A drug interaction is best defined as 'the possibility that one drug may alter the intensity of pharmacological effects of another drug that is given concurrently'. This results in either enhanced activity of the affected drug, which may lead to toxicity, or reduced activity of the affected drug, leading to therapeutic failure. It is also possible that there may be the appearance of a new effect that is not seen with either drug alone, for example, caspofungin and cyclosporine coadministration leading to elevated liver function tests. Drug interactions can be categorized as being either pharmacokinetic (PK) or pharmacodynamic in nature, and the remainder of this review will focus on PK interactions. Pharmacokinetic drug interactions -what are they?Pharmacokinetic drug interactions influence the disposition of the drug in the body. When drugs are ingested, they undergo several processes to produce an end effect, including absorption, distribution, metabolism, and excretion. Interactions between two or more drugs may affect any of these phases, including the modulation of hepatic drug biotransformation, renal clearance, altered distribution, or changes in plasma protein binding. The most clinically relevant mechanisms of PK drug interactions relate to metabolism and elimination of drugs from the body, and involve the cytochrome P450 (CYP) enzymes and the transporter P-glycoprotein at the hepatic and intestinal levels, and glomerular filtration and tubular secretion at the renal level. Cytochrome microsomal enzyme systemThe CYP microsomal enzyme system is a family of hemoproteins that is responsible for the oxidative biotransformation of endogenous substrates and xenobiotics. CYPs are expressed in several tissues, with the main drug metabolizing CYPs concentrated in the liver, with lower expression in the lungs, kidneys, intestines, and brain.1 Of the several different CYP isoforms identified, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 have the greatest involvement in drug metabolism. An extensive list of drugs metabolized by the various isoenzymes is outlined in Table 1. 2 The majority of oxidatively biotransformed drugs are metabolized, at least in part, ...

Effect of Co-administration of Tacrolimus on the Pharmacokinetics of Multiple Subcutaneous Administered Interferon-Alpha in Rats

“…Tacrolimus is a substrate of an efflux transporter, Pglycoprotein (P-gp), and is metabolized by cytochrome P450 3A4 (CYP3A4) (22). Thus there is a possibility that tacrolimus causes drug interactions with other drugs that are also substrates of P-gp or CYP3A4 (23). In this study, we confirmed that the rate of absorption and/or clearance of s.c. administered h-IFN were not affected by i.v.…”

Prevalence of potential drug–drug interactions in bone marrow transplant patients

“…Patients in a conditioning regimen with cyclophosphamide and cyclosporine require more frequent monitoring of cyclosporine blood levels in order to avoid the risk of acute GVHD [7,14]. Cyclosporine was the only immunosuppressant prescribed to the patients investigated in this study.…”

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

“…79 The role of genetic polymorphisms in the cytochrome P-450 enzyme system in the liver in transplant toxicity has not been sufficiently explored. 80,81 Larger cohort studies are needed to confirm the associations that have been observed between specific genetic variants and HSCT-related complications and to identify other genes that modify risk. The benefits of these studies to patients are obvious: the potential for improved risk stratification and development of more effective interventions that target high-risk individuals.…”