Therapeutic Drug Monitoring

Therapeutic Drug MonitoringTherapeutic Drug MonitoringDefinition: analysis, assessment, & evaluation of circulating concentrations of drugs in serum, plasma, or whole bloodPurpose: to ensure that a given drug dosage produces maximal therapeutic benefit & minimal toxic adverse effectsUsed when safe dosage regimens have not been established & a trial & error approach is not appropriateStandard dosage derived from observations in healthy population.Involves quantitative evaluation of circulating drug concentrationKey factors: route of administration, rate of absorption, distribution of drug within body, rate of eliminationIntroductionOverview of factors that influence the circulating concentration of an orally administered drug

Introduction

Intravenous (IV): injected directly into circulationIntramuscular (IM): injected into muscleSubcutaneous (SC): injected just under skinTranscutaneous: inhaled or absorbed through skinSuppository: rectal deliveryOral Administration: by mouth

Routes of AdministrationFor orally administered drugs, efficiency of absorption from GI tract depends on many factors:Formulation of drug: tablets, capsules, liquid solutionsUptake by transport mechanisms intended for dietary constituents vs. passive diffusionChanges in intestinal motility, pH, inflammation, food, other drugsVariation among populationAge, pregnancy, pathologic conditions

AbsorptionFree vs. BoundOnly free (unbound) fraction of drug can interact with site of action & cause biologic response.Percentage free depends on physiologic & biochemical parameters:Inflammation, malignancies, pregnancy, hepatic disease, nephrotic syndrome, malnutrition, acidbase disturbancesConcentration of other substances competing for binding sitesDrug DistributionAbility of drug to diffuse out of circulation Depends on lipid solubility of drug

Free Versus Bound Drugs and Drug DistributionRate of change of drug concentration over time varies continuously in relation to concentration of drug.Elimination equation: C/T = -kCMetabolic ClearanceHepatic mixed function oxidase (MFO) systemConverts hydrophobic substances into water-soluble onesTransports them into bile or circulation, eliminates them by renal filtrationRenal Clearance

Drug EliminationFirst-order drug elimination

Drug Elimination

PharmacokineticsMathematic modeling of drug concentration in circulationAssists in establishing or modifying a dosage regimenTakes into account all factors that determine concentration of a serum drug & its rate of change (absorption, distribution, elimination, etc.)Sample CollectionTiming is critical: trough concentrations, right before next dose; peak concentrations, 1 hour after oral doseSerum or plasma is specimen of choice.

Pharmacokinetics and Sample CollectionResponders: patients benefitting from therapeutic & desired effects of drugNon-responders: patients not benefitting from therapeutic & desired effects of drugTherapeutic effectiveness of drugs has been attributed to inter-individual variation in genetic polymorphisms of drug metabolism pathways.Cytochrome P450: gene group family that affects drug metabolism

PharmacogenomicsCardiac GlycosidesDigoxinPurpose: used in treatment of congestive heart failureFunction: inhibits membrane Na-K-ATPaseAbsorption: variable, influenced by dietary factors, GI motility, formulation of drugElimination: renal filtration of plasma free formHalf-life (plasma): 38 hours in average adultMeasurement: immunoassay to determine total concentration in serum

Cardioactive Drugs Requiring TDMAntiarrhythmicsQuinidineMost common formulations are quinidine sulfate & quinidine gluconate.ProcainamideDisopyramideUsed as a quinidine substitute when quinidines adverse effects are excessive

Cardioactive Drugs Requiring TDMAminoglycosidesA group of chemically related antibiotics used for treatment of infections with gram-negative bacteria that are resistant to less toxic antibioticsMost common: gentamicin, tobramycin, amikacin, kanamycinVancomycinA glycopeptide antibiotic that is effective against gram-positive cocci & bacilli

AntibioticsFirst GenerationPhenobarbitalA slow-acting barbiturate that effectively controls several types of seizuresPhenytoinA commonly used treatment for seizure disordersUsed as a short-term prophylactic agent in brain injury to prevent loss of functional tissueValproic acidUsed as a monotherapy for treatment of petit mal & absence seizures

Antiepileptic DrugsFirst GenerationCarbamazepineAn effective treatment in various seizure disordersBecause of its serious toxic adverse effects, it is less frequently used.EthosuximideUsed for control of petit mal seizureAntiepileptic DrugsSecond GenerationFelbamateAn orally administered drug that is nearly completely absorbed by the GI tractKnown for its toxicity & is primarily indicated in severe epilepsies such as Lennox-Gastaut syndrome (children) & refractory epilepsy (adults)GabapentinMay be indicated as monotherapy or in conjunction with other antiepileptic drugs in patients suffering from complex partial seizures with or without generalized seizuresAntiepileptic DrugsSecond GenerationLamotrigineLevetiracetamIndicated in partial & generalized seizuresOxcarbazepineA pro-drug that is almost immediately metabolized to licarbazepineIndicated for monotherapy of partial seizures & in secondarily generalized tonic-clonic seizuresAntiepileptic DrugsSecond GenerationTiagabineIndicated in partial seizuresTopiramateIndicated in partial & generalized seizuresZonisamideIndicated in partial & generalized seizuresAntiepileptic DrugsLithium: orally administered; used to treat manic depressionTricyclic Antidepressants: a class of drugs used to treat depression, insomnia, extreme apathy, & loss of libidoClozapine: an atypical antipsychotic used to treat otherwise treatment-refractory schizophreniaOlanzapine: a thienobenzodiazepine derivative that effectively treats schizophrenia, acute manic episodes, & recurrence of bipolar disorders

Psychoactive DrugsCyclosporine: Primary clinical use is suppression of host-versus-graft rejection of heterotropic transplanted organs.Tacrolimus: 100 times more potent that cyclosporineSirolimus: an antifungal agent with immunosuppressive activity; FDA approved for patients receiving kidney transplantsMycophenolic Acid: a lymphocyte proliferation inhibitor; used most commonly as supplemental therapy with cyclosporine & tacrolimus in renal transplant patientsImmunosuppressive DrugsMethotrexateOne of few antineoplastic drugs in which TDM offers benefits to a therapeutic regimenHigh-dose methotrexate followed by leucovorin rescue has been shown to be an effective therapy for various neoplastic conditions.Basis of this therapy involves relative rate of mitosis of normal vs. neoplastic cells.Neoplastic cells divide more rapidly than normal cells, have higher requirement for DNA, and are susceptible to deprivation of this essential constituent before normal cells.Efficacy depends on controlled period of inhibition, accomplished by leucovorin.Antineoplastics