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Awareness of drug interactions increasing in patients with cancer Drug Interactions in Stem Prevalence in HSCT patients Cell Transplantation unknown 4.5-58% in cancer patients Numerous electronic databases exist with variable


  1. Awareness of drug interactions increasing in patients with cancer Drug Interactions in Stem  Prevalence in HSCT patients Cell Transplantation unknown  4.5-58% in cancer patients  Numerous electronic databases exist with variable reliability Jeannine McCune, PharmD, BCOP  Electronic systems and alerts are promising, but have challenges University of Washington  alert fatigue Fred Hutchinson Cancer Research Center Lemachatti et al. Anticancer Res. 2009 Nov; 29(11): 4741-4 ; van Leeuwen Ann Oncol. 2011 Oct; 22(10): 2334-41. Epub 2011 Feb 22. Scott et al. J Am Med Inform Assoc. 2011 Nov-Dec; 18(6): 789-98 When is a drug interaction in HSCT Learning objectives recipients important?  Many potential drug interactions  Explain the common metabolic pathways in the liver  Type of interactions  Pharmaceutical  Identify approaches to overcome drug  Incompatibilities at administration site interactions seen in HSCT  Pharmacokinetic  Identify those drug interactions of importance  What the body does to the drug  Understand how to preemptively prevent drug  Pharmacodynamic interactions from occurring  What the drug does to the body  HSCT interaction example: live vaccines  Important if leads to an undesired outcome, whether it be ↓ efficacy or ↑ toxicity The challenges unique to HSCT 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

  2. Relationship between pharmacokinetics and Pharmacology is multifactorial pharmacodynamics  Can affect both the pharmacokinetics and Dose pharmacodynamics Absorption Distribution  Factors include… Metabolism  Age Excretion  Sex Total serum concentration Receptor Site  Ethnicity  Weight Unbound serum concentration Pharm acologic  Condition being treated Response Protein Bound Concentration  Pharmacogenetics Therapeutic  Idiosyncrasy Outcom e  Drug interaction Slide courtesy of Gail Anderson, PhD Pharmacokinetic parameters: Pharmacokinetic parameters elimination  Absorption  Metabolism  The rate at which a drug leaves the site of  Predominately liver administration and the extent to which it  Other sites: kidney, lung, gastrointestinal occurs tract (GI), plasma  HSCT interaction example: proton pump  HSCT interaction example: many inhibitors with mycophenolate mofetil  Distribution  Excretion  Process of reversible transfer of a drug to and  Kidneys and hepatic/ GI tract from the site of measurement  Other sites: milk, sweat, saliva, tears  HSCT interaction example: non-steroidal anti-  HSCT interaction example: cyclosporine with inflammatory drugs (NSAIDs) with mycophenolic acid methotrexate (also interacts at kidney) 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  Reality  Can predict drug interactions based on  Metabolites may have biological activity; knowledge of metabolizing enzymes similar or different than parent  Various family, subfamily, individual genes  May contribute to toxic and/ or beneficial  CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, effects CYP2E1, CYP3A4/ 5  Example: Cyclophosphamide metabolized by  Inhibition  CYP,  concentration,  dose cytochrome P450 (CYP) to  Induction  CYP,  concentration,  dose 4hydroxycyclophospham ide

  3. Cytochrome P450 (CYP) enzyme system Examples of important CYP in HSCT  Large (but not only) source of drug interactions Drug Substrate Reaction Cyclosporine 3A4/ 5 Elimination  Many in vitro methods to identify which “ Tacrolimus 3A4/ 5 CYP metabolizes a drug, and potential drug “ Sirolimus 3A4/ 5 interactions “ Prednisone 3A4/ 5  However, magnitude of drug interaction “ Dexamethasone 3A4/ 5 difficult to predict Cyclophos- 2C9, 2C19 Activation to 4hydroxyCY (HCY)  ‘Cocktail’ studies in healthy volunteers phamide (CY) 2 2B6, 3A4/ 5*  Cytokines (e.g., IL6) affect CYP 3A4/ 5 Detoxification to dechloroCY Hebert. Metabolic Drug Interactions 2000; Shimada Transplant International 2003. Ren Cancer Research 1997; Huang Biochem Pharmacol 2000; Qiu Clin Pharm Ther 2004 Phase II metabolism Phase II: Relevant conjugation reactions  Glutathione S -transferase  Term coined to represent metabolism  Mediate conjugation of electrophilic occurring after oxidation, reduction or compounds to glutathione hydrolysis associated with bioactivation  Important detoxifying pathway for alkylating  Many drugs don’t require Phase I metabolism agents  Functional group created conjugated to less  Glucuronidation toxic or inactive compound  Most common conjugation reaction for drugs  UGT (UDP-glucuronosyl transferase)  Conjugation of endogenous substances, bilirubin, mycophenolic acid, morphine ABC transporters relevant to HSCT Drug transporters patients Transporter Substrate  Of the 400 transporters in the human genome, 30 are relevant to ABCB1 (MDR1)* calcineurin inhibitors, sirolimus pharmacokinetics corticosteroids ABCC1 (MRP1) methotrexate  ATP-binding cassette (ABC) superfamily ABCC2 (MRP2) cyclophosphamide metabolite  Relevant to systemic mycophenolic acid pharmacokinetics and ABCC3 methotrexate intracellular transport ABCG2 (BCRP) etoposide, topotecan * codes for pglycoprotein (pgp) Endres et al. Eur J Pharm Sci. 2006 Apr; 27(5): 501-17

  4. 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)  Complex, for example renal excretion  beta-lactams, metabolites of corticosteroids, NSAIDs involves  Equilibrative nucleoside transporter 1 (ENT)  Glomerular filtration  fludarabine  Active tubular transport  Concentrative pyrimidine-preferring nucleoside  Passive tubular absorption transporter 1 (CNT)  fludarabine  HSCT interaction example: NSAIDs inhibit renal tubular secretion of methotrexate and/ or reduce renal blood flow by inhibiting prostaglandin synthesis Zhang et . Clin Pharmacol Ther. 2011 Apr; 89(4): 481-4; Pauli-Magnus Pharmacogenetics 2003; 13: 189; Sekine Annals of Oncology 2001; 12: 1515; Oleschuk Am J Physiol Gastrointest Liver Physiol 2003 Feb; 284(2): G280; Elimination half-life Pharmacokinetic parameters Example: Plasma Concentrations Drug with T 1/2 = 12 hrs  Clearance measures body ’ s ability to Dose 100 mg 200 mg eliminate drugs C 0 20  g/ ml 40  g/ ml  Elimination half-life is time it takes for the amount of drug in the body to be reduced by C 12hr 10  g/ ml 20  g/ ml 50% C 24hr 5  g/ ml 10  g/ ml  T 1/ 2 = 0.693• Vd Cl C 36hr 2.5  g/ ml 5  g/ ml  where Vd = volume of distribution and C 48hr 1.2  g/ ml 2.5  g/ ml Cl = total body clearance  Impact of CYP interactions on clearance C 60hr < 1  g/ ml 1.2  g/ ml  Inhibition  CYP,  clearance,  concentration,  dose C 72hr < 1  g/ ml < 1  g/ ml  Induction  CYP,  clearance,  concentration,  dose Slide courtesy of Gail Anderson, PhD Approximate half-lives of relevant Steady state immunosuppressants  Calcineurin inhibitors: 11-35 hours (hr)  Css = the concentration at which the rate of drug input is equal to the rate of drug elimination  Sirolimus: 62 hr  Can be defined as area under the curve/ dosing interval (busulfan)  Mycophenolic acid: 0.6-11.9 hr  Takes approximately 5 T 1/ 2 to reach steady state  Methylprednisolone, prednisone: 1.7 to 4.1 hr  Take approximately 5 T 1/ 2 to completely eliminate a drug after discontinuation  Css is dependent on dosage and clearance

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