ACCP-new-Drug-Drug And Drug-Transporter Interactions As Obstacles For .
10/15/2013Drug‐Drug and Drug‐TransporterInteractions as Obstacles forAbsorptionReza Fassihi Ph.D., AAPS FellowProfessor of Biopharmaceutics and Industrial PharmacyTemple University, School of PharmacyPresented at ACCPMonday, September 23, 2013Symposium VIII, ACCP10/15/2013Reza Fassihi Ph.D.1Honoring the Memory of Dr. W.A. Ritschel“All that live must die, passing through nature to eternity”.10/15/2013Reza FassihiPh.D.W.Shakespeare21
10/15/2013Learning Objectives: Comprehend conditions in which the desired outcomes ofpharmacotherapy are not achieved; Identify methods to develop and test effective drugs for oraladministration; Describe the conditions and the mechanisms behind atherapeutic failure; Recognize problems and prevent therapeutic and R&Dfailure.10/15/2013Reza Fassihi Ph.D.3Reasons for compounds failing ket reasons31%41%Lack of efficacy22%6%ToxicityModern Drug Discovery, January/February 199910/15/2013Reza Fassihi Ph.D.42
10/15/2013Why it is important to maximizeoral bioavailability: Five Reasons1. To most effectively control plasma concentration,safety, and pharmacological effect2. Low bioavailability increases variability*3. To avoid side effects due to products of first‐passmetabolism4. To predict the outcome of therapy(e.g., oral vs. iv ; acute vs. chronic treatment)5. Most cost‐efficient use of drug substance* variability in drug concentration and response maycause unexpected toxicities or drug‐drug interactions.10/15/2013Reza Fassihi Ph.D.Physiological Constraints:GI environmentSmall Intestine SolutionVolume 500mlpH 4-7.5HCO3- y and Amino peptidaseFats-Fatty Acids, LecithinBile saltsTransit time 3-4 hrSurface tension lowPermeability high10/15/20135Gastric SolutionVolume 300mlpH 1-3WaterHCl, Na ,K PO4-3 ,SO4-2HCO3- ,MucusPepsin, ProteinResidence time- variable0.25 - 5 hoursSurface tension waterPermeability lowComplex Colonic Micro and MacroEnvironmentPermeability- Drug dependentTransit time 1 to 24 hRedox potential -400mvBacteria(cfu/g), 1x1012pH 7Fluid 187mL(total), 13mL(free)Length 1.66 mSurface area 3 m2Reza Fassihi Ph.D.63
10/15/2013Drug‐Drug and Drug‐Transporter Interactions asObstacles for AbsorptionDrug transporters affecting absorption andbioavailability contribute to variability indrug concentration and response:The Human Genome Project has identifiedmore than 400 transporters that belong toone of two superfamilies: ATP‐bindingcassette “ABC” (most efflux transporters)Intrinsicfactors ?or solute carrier “SLC” (most uptaketransporters).Extrinsicfactors ?1.Efflux (excretion to bile):P‐gp & BCRP2.Excretion to intestinallumen: (P‐gp, MDR1, ABCB1)drug‐phytochemical interactionFocus of introduction: Modified release formulations (sustained releaseor extended release products) and drug combinations.10/15/2013Reza Fassihi Ph.D.7Biopharmaceutical Considerations in development ofDrug Delivery systemsDrugproperties:SolubilityDissolution,MW & ine fumarate andCarbamazepine; Bioavailability of bothdrugs 80%; Quetiapine is highlypermeable while Carbamazepine isslowly and variably absorbed.Formulation:API dose,Excipients,Special additives,Stability,Unit doseType of DeliverySystemBioavailabilityFasted vs. Fed10/15/2013Regional variations:pH, fluid volume,surface area, Gut wallenzymes, transporters,transit time,micro flora etc.AdministrationNumber ofsubjectsReza Fassihi Ph.D.IVIVCIVIVC8Fassihi 2011, AAPS Annual Meeting Washington DC.4
10/15/2013Absorption of drugs via clinically important transporters in the GI tract that shouldbe considered for evaluation during drug development Organic anion transporting polypeptide(OATP) family; peptide transporter 1; solute‐carriers (PEPT1;SLC15A1) Ileal apical sodium/bile acid co‐transporter(ASBT; SLC10A2) Monocarboxylic acid transporter (MCT1;SLC16A1) The apical ATP‐dependent efflux pumpsinclude multidrug resistance protein (MRP2;ABCC2); breast cancer resistance protein(BCRP; ABCG2); and P‐glycoprotein (P‐gp;MDR1, ABCB1) The basolateral membrane of intestinalepithelia contains organic cation transporter1 (OCT1; SLC22A1); heteromeric organicsolute transporter (OSTα–OSTβ); and MRP3(ABCC3).Adapted from: Giacomini et al., (2010) Nat RevDrug Discov. 9(3):215‐23610/15/2013International Transporter Consortium (ITC) wasformed in 2007 to further the understanding ofdrug transporters in therapeutic and adversedrug effects.Reza Fassihi Ph.D.9Immunohistochemical staining of OATP1A2 and P‐gpin human duodenal sections OATP1A2 expression is co‐localized with P‐gp on thebrush border membrane ofhuman enterocytes Glaeser H. et al. (2007) ClinPharmcol Ther. 81(3); 362‐37010/15/2013Reza Fassihi Ph.D.105
10/15/2013Apical sodium‐dependent bile acid transporter(ASBT; SLC10A2) is highly expressed in the ileum Substantial contribution to theenterohepatic circulation of bileacids Expressed in the ileum, cecumand kidney Mutations in ASBT gene result inbile acid mal‐absorption andcongenital diarrhea Inhibition of ASBT results inchanges in cholesterol and bileacid homeostasisImmuno‐reactive ASBT in human ilealslicesAdapted from: Hruzet al., Gut 2006; 55:395‐40210/15/2013Reza Fassihi Ph.D.11Components of fruit juices that may inhibittransporter‐mediated intestinal absorptionNaringinHesperidinFlavonone glycosides (flavonoids) in citrus juices are believed to bethe ingredients responsible for altering the bioavailability of selecteddrugs (with more examples emerging) due to the inhibition of uptakeprocesses in the intestine or metabolizing enzymes.10/15/2013Reza Fassihi Ph.D.126
10/15/2013Effect of grape fruit juice or naringin on the oral bioavailability offexofenadine10/15/2013from Bailey et al. Clin Pharm Ther. 81(4); 495‐502 (2007) 13RezaAdaptedFassihi Ph.D.Individual Cmax, AUC and t½ of Aliskiren in humansHypertension ; F 2.5% 10/15/2013Low permeability, P‐gp substrateLow absorption in humans and animalsVariable exposure in humansDecrease in exposure seen when given with grapefruit juiceDecreased exposure maybe due to the inhibition of an uptake transporterin the intestineReza Fassihi Ph.D.Tapaninen et al., Clin. Pharm Therap.1420107
10/15/2013Oral Bioavialbility: Human vs. AnimalR2 0.340A confidence interval (CI) isideal for quantifying thedegree of uncertaintyaround common parametersof interest such as thecenter of a sampledpopulation, or its spread.PI Prediction Interval(Data From: Simcyp )10/15/2013Reza Fassihi Ph.D.15Methods for Studying Absorption Examples include:–––––Cell/membrane models,Intact organ/in vivo models;Modeling/imaging tools for dynamic studies,Enzyme/transporter interplay andMechanistic Approaches GastroPlus (ACAT) Advanced Compartmental Absorption andTransit Simcyp’s ADAM model(Advanced Dissolution, Absorption &Metabolism)10/15/2013Reza Fassihi Ph.D.168
10/15/2013Advanced Compartmental Absorption and Transit (ACAT) Model (GastroPlus )GastroPlus is a valuable in silico tool for simulation of GI bioavailability and IVIVCstudies directed at developing formulations of some drugs(BCS)Typically: Simulate drug release profiles within For more details on (ACAT) seeReviews 19 (1996) 359‐376”.the range of e.g. 5min up to 10 h for 100%.10/15/2013RezaFassihiPh.D.Use Virtual Trials—Bioequivalence TestingYu et al. “Advanced Drug Delivery17Simplified Process of Drug Absorption After Per-OralAdministration:Dissolution/Absorption and Drug CombinationsDissolutionin StomachCapsuleand Solid Formulationin StomachDissolved Drugin StomachGastricEmptyingof Drug SolutionGastricEmptyingof Solid DrugSolid Drug inSmall IntestineDissolution inSmall Intestineor ColonBrand nameTherapeutic areaDrug combinationsSymbaxBipolar depressionProzac & ZyprexaTruvadaAnti‐HIVViread & EmtriviaAdvairAsthmaFlovent & SereventEpzicomAnti‐HIVEpivir & ZlagenVytorinHigh cholestrolZocor & ZetiaLotrelHypertensionLotensin & NorvascCaduet10/15/2013CardivasculardiseaseLipitor & NorvascDrug Absorption(Drug Bioavailability)Drug EffectMetabolismEliminationDrug CombinationsReza Fassihi Ph.D.189
10/15/2013Individual variability in addition to food effect Coated pellets in capsulesIndicated for urge incontinence(antispasmodic, antimuscarinic agent).Sanctura XR-60mg10/15/2013F 9.6 % (range 4.0 – 16.1%)Administration ofSANCTURA XR capsulesimmediately after a high(50%) fat‐content mealreduced the oralbioavailability oftrospium chloride by 35%for AUC(0‐Tlast) and by 60%for Cmax.Reza Fassihi Ph.D.19Predicting Drug‐Drug Interactions By understanding which enzymes or transportersmay be involved in the ADME process and thepotential for a drug to be a substrate, inhibitor, orinducer of that process, we can predict the potentialfor drug interactions.In Vitro models/Tools in vivo DDIstudiesPredictExplainThe integration of in vitro and in vivo (both animaland human) data can identify the role oftransporters in drug‐drug interactions.Reza Fassihi Ph.D.10/15/2013Leik.zhang@fda.hhs.gov2010
10/15/2013Examples of Transporter‐Mediated Drug‐Drug InteractionsP.O.10/15/2013Reza Fassihi Ph.D.Leik.zhang@fda.hhs.gov21Drug-Induced QT Interval Prolongation andTorsades de Pointes :Drug-Phytochemical Interaction This ECG showing normal sinusrhythm and a classic exampleof torsades de pointes, which isFrench for "twisting of thepoints”, occurring in associationwith terfenadine (Seldane) use. The QRS complexes during thisrhythm tend to show a seriesof "points up" followed by"points down“.Roden, D. 2000;Lazzara R Torsades de pointes(ventricular tachycardia)due to medication10/15/2013Reza Fassihi Ph.D.2211
10/15/2013Drugs Withdrawn for TdP(Drug-Phytochemical Interaction)DrugClassDate Withdrawn*TerfenadineAntihistamineFeb 1998SertindoleAntipsychoticDec 1998AstemizoleAntihistamineJun 1999*Grepafloxacin (Raxar)AntibioticWarning lableCisaprideJuly 2000GI Prokinetic*Grapefruit juice ( contains furanocoumarin derivatives) can increaseplasma concentration of terfenadine.* Contraindicated in patients with history of increase in the QTc10/15/2013Reza Fassihi Ph.D.23Alteration of Gastrointestinal AbsorptionInteractions that involve a change in drug absorption from theGI tract are of variable importance Alteration of pHComplexation and adsorption: Drug‐Drug interactions– Antacids markedly reduce the absorption of fluoroquinolone derivatives (e.g.,ciprofloxacin), probably as a result of the metal ions complexing with the drug.Antacids should not be used simultaneously or 2 h (or preferably, an even longerperiod) after ciprofloxacinAlteration of motility– By increasing GI motility, metoclopramide may hasten the passage of drugsthrough the GI tract, resulting in decreased absorption– By decreasing GI motility, anticholinergics may either reduce absorption byretarding dissolution and slowing gastric emptying, or increase absorption bykeeping a drug for a longer period of time in the area of optimal absorption.Effect of food– Food has been reported to decrease the absorption of many therapeutic agentsincluding astemizole, captopril, and penicillamine and some antibiotics.CYP enzyme inhibition and P‐gp / Selected efflux & uptake transporters in the gut wallcan cause changes in absorption and adverse reactions.10/15/2013Reza Fassihi Ph.D.2412
10/15/2013Summary Nutrient and uptake transporters in thegastrointestinal tract (e.g.OATP1A2andASBT)may participate in the transport of xenobiotics(e.g. fexofenadine, aliskiren etc.) Inhibition of such processes can represent amechanism underlying drug‐drug, or drug‐dietinteractions. A better understanding of uptake transportactivity is needed to evaluate the role played bysuch processes in influencing thepharmacokinetics of new drug candidates10/15/2013Reza Fassihi Ph.D.25ConclusionUnderstanding absorption transporters and their interactions withdrug(s) and Phytochemicals provides a mechanistic approach to:– Explain variability in bioavailability– Provide insight into PK/PD relationship, and safety in clinical trialsand application– Identify patients at risk of developing adverse events associated withthe drug in question or at risk when drug combinations are used– Help in decision making to improve the use of medications (i.e. Rightdrug; Right dose; Right time; for the Right patient).10/15/2013Reza Fassihi Ph.D.2613
10/15/2013Expert members of the International Transporter Consortium (ITC)Clinical Pharmacology & Therapeutics (2010) 87 1, 32–36The key transporters, P‐glycoprotein (P‐gp, ABCB1); breast cancer resistance protein(BCRP); organic anion transporters (OAT1 and OAT3); organic cation transporter (OCT2);and organic anion transporting polypeptides (OATP1B1 and OATP1B3), identified by ITCwere selected based on evidence in the literature demonstrating that the transportersplay a role in governing drug absorption and disposition and in mediating clinical DDIs.10/15/2013Reza Fassihi Ph.D.27What is Man, when you come to think upon him, but a minutelyset, ingenious machine for turning, with infinite artfulness, the redwine of Shiraz into urine? “Isak Dineson”.Reza Fassihi10/15/2013Reza Fassihi Ph.D.2814
potential for a drug to be a substrate, inhibitor, or inducer of that process, we can predict the potential for drug interactions. In Vitro models/Tools Reza Fassihi Ph.D. 20 The integration of in vitro and in vivo (both animal and human) data can identify the role of transporters in drug‐drug interactions.
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Meekings 2 Contents 3 Declaration 4 Abstract 6 A Mist that Rises from the Sea 215 How A Personal History is Constructed: An Annotated Index of the Past 215 A. Aberdeen Bestiary 226 B. Beginnings 233 C. Chronophobia 237 H. Happiness
