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? Drug interaction leads to an undesired Explain the common metabolic pathways outcome, whether it be efficacy or ↑ in the liver toxicity Identify approaches to overcome drug Type of interactions interactions seen in HSCT 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., drug interaction basics pharmacodynamic) relationships are rarely defined Degree of an interaction (and thus its Drug metabolizing enzymes significance) rarely described 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 Rational Use of Drugs in Patients Pharmacodynamics What the body does to the drug – Dose pharmacokinetics Absorption Distribution Metabolism Excretion What the drug does to the body – Total serum concentration Receptor Site pharmacodynamics Unbound serum concentration Pharm acologic Safety and efficacy Response Protein Bound Concentration Therapeutic Outcom e Pharmacology is Multifactorial Pharmacokinetic Parameters Can affect both the pharmacokinetics and Absorption pharmacodynamics The rate at which a drug leaves the site of administration and the extent to which it Factors include… occurs. Age Distribution Sex 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 for Reaction several different isozymes located in endoplasmic reticulum Cyclophos- 2C9, 2C19 Activation to 4hydroxyCY (HCY) e.g., CYP1A2, CYP2A6, CYP2B6, CYP2C, CYP3A phamide (CY) 1 2B6, 3A4/ 5* Extrahepatic: intestine (CYP3A4/ 5), kidney (CYP3A5), brain (CYP2B6), lungs, breast 3A4/ 5 Detoxification to dechloroCY Large source of drug interactions Imatinib 2 3A4/ 5 Elimination Differences in enzyme regulation between animals – humans Prednisone 3A4/ 5 “ Variety of in-vitro methods Inhibition: cDNA expressed or human microsomes Dexamethasone 3A4/ 5 “ Induction: human hepatocytes or some constructed cell lines Cyclosporine 3A4/ 5 “ In-vivo methods Tacrolimus 3A4/ 5 “ healthy volunteer studies with ‘cocktails’ largely used but effects of cytokines (e.g., IL6) upon PXR function which contributes to Sirolimus 3A4/ 5 “ regulation of CYP3A/ CYP2B6/ pgp induction 1 Ren Cancer Research 1997; Huang Biochem Pharmacol 2000; Qiu Clin Pharm Ther 2004. 2 Package insert. Phase II Metabolism Effect upon CYP Drug Effect Model* Reference Term coined to represent metabolism CYP3A4, CYP2B6 I CY Lindley Drug Metab Disp CYP3A4 occurring after oxidation, reduction or I Moore Clin Pharmacol Ther hydrolysis associated with CYP2C9, CYP2D6 I Imatinib Package insert bioactivation CYP3A4/ 5 I, HV “, Obrien Br J Cancer 2003 Many drugs don’t require Phase I ? CYP3A4/ 5 Prednisone metabolism Functional group created conjugated CYP3A4/ 5 DEX I, HV McCune Clin Pharm Ther to less toxic or inactive compound * Models. I: in vitro; HV: PK study in healthy volunteers; C: PK study in cancer patients : cyclophosphamide; DEX: dexamethasone : induces inhibition CY
ATP-binding cassette (ABC) superfamily Phase II: Conjugation reactions 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 Involves equilibrative nucleoside transporter 1 (ENT) Glomerular filtration fludarabine Active tubular transport concentrative pyrimidine-preferring nucleoside 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 T 1/ 2 = 0.693• Vd unit time Cl Clearance is the PK parameter most useful for 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 Steady State Example: Plasma Concentrations Drug with T 1/2 = 12 hrs Css = the concentration at which the rate Dose 100 mg 200 mg of drug input is equal to the rate of drug C 0 20 g/ ml 40 g/ ml elimination C 12hr 10 g/ ml 20 g/ ml Can be defined as area under the curve/ dosing C 24hr 5 g/ ml 10 g/ ml interval (busulfan) Takes approximately 5 T 1/ 2 to reach C 36hr 2.5 g/ ml 5 g/ ml steady state C 48hr 1.2 g/ ml 2.5 g/ ml Take approximately 5 T 1/ 2 to completely C 60hr < 1 g/ ml 1.2 g/ ml eliminate a drug after discontinuation C 72hr < 1 g/ ml < 1 g/ ml Css is dependent on dosage and clearance Learning Objectives Explain the common metabolic pathways GVHD Medications in the liver Identify approaches to overcome drug interactions seen in HSCT Cyclosporine, Tacrolimus, Identify those drug interactions of importance Mycophenolate mofetil, Understand how to preemptively prevent drug interactions from occurring Methotrexate, Sirolimus, Prednisone Less commonly used GVHD medications The interactions discussed Pharmacokinetic interactions relevant to GVHD Immunomodulating modalities: 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., most antibiotics) cyclophosphamide, pentostatin Pidala BBMT 2011, 17(10): 1528; 2 Ferrara Lancet 2009, 373: 9674; Holler Best Pract Res Clin Haematol. 2007 Jun; 20(2): 281-94, Wolff BBMT 2011; 17(1): 1-17
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