Drug Interactions in Stem Cell Transplantation
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Drug Interactions in Stem Cell Transplantation Jeannine McCune, PharmD, BCOP University of Washington Fred Hutchinson Cancer Research Center When is a drug interaction in HCT Learning Objectives recipients important? Explain the common metabolic pathways Drug interaction leads to an undesired in the liver outcome, whether it be efficacy or ↑ toxicity Identify approaches to overcome drug interactions seen in HSCT Type of interactions Pharmaceutical Identify those drug interactions of importance Pharmacokinetic Understand how to preemptively prevent drug Pharmacodynamic interactions from occurring The challenges unique to HCT Quick review of patients are ….. pharmacokinetic-based The concentration-effect (i.e., pharmacodynamic) relationships are drug interaction basics rarely defined Degree of an interaction (and thus its significance) rarely described Drug metabolizing enzymes Cytokines influence regulation Drug Transporters Interpatient variability in the interaction When an adverse drug interaction occurs, we often lack the pharmacokinetic data to explain it Relationship between Pharmacokinetics and Pharmacodynamics Rational Use of Drugs in Patients Dose What the body does to the drug – Absorption pharmacokinetics Distribution Metabolism Excretion Total serum concentration Receptor Site What the drug does to the body – pharmacodynamics Unbound serum concentration Pharmacologic Safety and efficacy Response Protein Bound Concentration Therapeutic Outcome Pharmacology is Multifactorial Pharmacokinetic Parameters Can affect both the pharmacokinetics and Absorption pharmacodynamics The rate at which a drug leaves the site of Factors include… administration and the extent to which it occurs. Age Sex Distribution Ethnicity Process of reversible transfer of a drug to and Weight from the site of measurement. Condition being treated Modifying factors: Pharmacogenetics blood flow Idiosyncrasy plasma protein binding Drug interaction diffusion solubility Volume of Distribution Elimination Processes A measure of the apparent space in the Metabolism body available to contain the drug. predominately liver Relates the amount of drug in the body to Other sites: kidney, lung, GI, plasma the concentration of drug in the blood. Excretion Vd = Amt of drug in body = Dose Kidneys and GI Conc. of drug in blood Concentration Other sites: milk, sweat, saliva, tears Biotransformation (Metabolism) Phase I metabolism: Theory: Oxidation, reduction, hydrolysis Drug inactivation Cytochrome P450 family of enzymes Increased elimination from the body 7 primary enzymes responsible for majority of drug metabolism: However: Can predict drug interactions based on Metabolites may have biological activity; knowledge of metabolites similar or different than parent CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, May contribute to toxic and/or beneficial CYP2E1, CYP3A4 effects The Cytochrome P450 (CYP) Enzyme System Examples of important CYP in HCT Phase I enzymes Liver Drug Substrate forReaction several different isozymes located in endoplasmic reticulum e.g., CYP1A2, CYP2A6, CYP2B6, CYP2C, CYP3A Cyclophos- 2C9, 2C19 Activation to 4hydroxyCY (HCY) Extrahepatic: intestine (CYP3A4/5), kidney (CYP3A5), brain phamide (CY)1 2B6, 3A4/5* (CYP2B6), lungs, breast 3A4/5 Detoxification to dechloroCY Large source of drug interactions 2 Differences in enzyme regulation between animals – humans Imatinib 3A4/5 Elimination Variety of in-vitro methods Prednisone 3A4/5 “ Inhibition: cDNA expressed or human microsomes Dexamethasone 3A4/5 “ Induction: human hepatocytes or some constructed cell lines Cyclosporine 3A4/5 “ In-vivo methods healthy volunteer studies with ‘cocktails’ largely used but effects of Tacrolimus 3A4/5 “ cytokines (e.g., IL6) upon PXR function which contributes to Sirolimus 3A4/5 “ regulation of CYP3A/CYP2B6/pgp induction 1Ren Cancer Research 1997; Huang Biochem Pharmacol 2000; Qiu Clin Pharm Ther 2004. 2Package insert. Effect upon CYP Phase II Metabolism Drug Effect Model* Reference CY CYP3A4, CYP2B6 I Lindley Drug Metab Disp Term coined to represent metabolism CYP3A4 I Moore Clin Pharmacol Ther occurring after oxidation, reduction or Imatinib CYP2C9, CYP2D6 I Package insert hydrolysis associated with CYP3A4/5 I, HV “, Obrien Br J Cancer 2003 bioactivation Many drugs don’t require Phase I Prednisone ? CYP3A4/5 metabolism DEX CYP3A4/5 I, HV McCune Clin Pharm Ther Functional group created conjugated to less toxic or inactive compound *Models. I:in vitro; HV:PK study in healthy volunteers; C:PK study in cancer patients CY: cyclophosphamide; DEX: dexamethasone : induces inhibition Phase II: Conjugation reactions ATP-binding cassette (ABC) superfamily Acetylation (Procainamide, sulfonamides) Transporter Substrate Glutathione S-transferase ABCB1 (MDR1)* calcineurin inhibitors, sirolimus Mediate conjugation of electrophilic ABCC1 (MRP1) etoposide, glutathione compounds to glutathione conjugates of corticosteroids Important detoxifying pathway for alkylating ABCC2 (MRP2) CEPM (CY metabolite), agents Mycophenolic acid Glucuronidation ABC C3, C4, C5 Methotrexate Most common conjugation reaction for drugs ABCG2 (BCRP) UGT (UDP-glucuronosyl transferase) *codes for pglycoprotein (pgp) Conjugation of endogenous substances, bilirubin, mycophenolic acid, morphine Sulfation Pauli-Magnus Pharmacogenetics 2003; 13: 189; Sekine Annals of Oncology 2001; 12: 1515; Qiu J Pharmacol Exper Ther 2004; Oleschuk Am J Physiol Gastrointest Liver Physiol 2003 Feb;284(2):G280; Additional Transporters Excretion organic anion transporting polypeptide (OATP) Drugs are eliminated from the body methotrexate, opioids, corticosteroid metabolites unchanged or as metabolites organic anion transporters (OAT) Polar >>>>>>Lipid soluble drugs beta-lactams, metabolites of corticosteroids, NSAIDs equilibrative nucleoside transporter 1 (ENT) Involves fludarabine Glomerular filtration concentrative pyrimidine-preferring nucleoside Active tubular transport transporter 1 (CNT) Passive tubular absorption Pauli-Magnus Pharmacogenetics 2003; 13: 189; Sekine Annals of Oncology 2001; 12: 1515; Slattery AAPS 2002; Oleschuk Am J Physiol Gastrointest Liver Physiol 2003 Feb;284(2):G280; Clearance Elimination Half-Life A measure of the body’s ability to eliminate The time is take for the amount of drug in drugs. the body to be reduced by 50%. May be regarded as the volume from which all the drug would appear to be removed per unit time T1/2 = 0.693•Vd Clearance is the PK parameter most useful for Cl evaluation of an elimination mechanism Described in terms of eliminating organ where Vd = volume of distribution hepatic clearance Cl = total body clearance renal clearance pulmonary clearance Elimination Half-life Example: Plasma Concentrations Drug with T1/2 = 12 hrs Steady State Dose 100 mg 200 mg Css = the concentration at which the rate of drug input is equal to the rate of drug C 20 g/ml 40 g/ml 0 elimination g/ml g/ml C12hr 10 20 Can be defined as area under the curve/dosing interval (busulfan) C24hr 5 g/ml 10 g/ml C 2.5 g/ml 5 g/ml Takes approximately 5 T1/2 to reach 36hr steady state C48hr 1.2 g/ml 2.5 g/ml Take approximately 5 T1/2 to completely C60hr < 1 g/ml 1.2 g/ml eliminate a drug after discontinuation C72hr < 1 g/ml < 1 g/ml Css is dependent on dosage and clearance Learning Objectives Explain the common metabolic pathways in the liver GVHD Medications Identify approaches to overcome drug interactions seen in HSCT Identify those drug interactions of importance Cyclosporine, Tacrolimus, Understand how to preemptively prevent drug Mycophenolate mofetil, interactions from occurring Methotrexate, Sirolimus, Prednisone Less commonly used GVHD medications The interactions discussed Immunomodulating modalities: Pharmacokinetic interactions relevant to GVHD prophylaxis and treatment mTOR-inhibitors, thalidomide, Will discuss herbal preparations, but recall they are unique because of potential pill to pill variability in hydroxychloroquine, vitamin A content, for fungal contamination, immunologic analogs, clofazimine, rituximab, properties….. Omitting others not because they are less alemtuzumab, etanercept important but they may be Cytostatic agents: mycophenolate more easily identified (e.g., the opioids because of close concentration – effect relationship) mofetil, methotrexate, more broad therapeutic index of the medication (e.g., cyclophosphamide, pentostatin most antibiotics) Pidala BBMT 2011, 17(10):1528; 2Ferrara Lancet 2009, 373: 9674; Holler Best Pract Res Clin Haematol. 2007 Jun;20(2):281-94, Wolff BBMT 2011;17(1):1-17 Effect of food/herbs Calcineurin Inhibitors Pharmacodynamic relationships AED Effect CyA/TAC risk of aGVHD Grapefruit juice intestinal CYP3A, pgp CyA/TAC nephrotoxicity Phytoestrogens/flavonoids competitively ABCG21 occurs even with targeting trough CyA or TAC trough concentrations St. John’s wort CYP3A4, pgp Garlic CYP3A4 Substrates for CYP3A4/CYP3A5 and p- glycoprotein Cancer Research 2004; 64: 4346; Leather BMT 2004; 33:137. Yee; N Engl J Med 1988; 319: 65; Ghalie Annals Pharmacother 1994; 28: 379; Wingard BBMT 1998 Pharmacogenomics of renal dysfunction in HCT Calcineurin Inhibitors patients receiving calcineurin inhibitors Personalized through trough concentrations of cyclosporine Various pharmacogenomic associations found in solid organ or tacrolimus, but considerable interpatient variability in transplant patients efficacy and toxicity remain ABCB1 and CYP3A5