Pharmacology of Chemotherapy Pharmacology of Chemotherapy agentsagents

David Samuel PharmD BCOPDavid Samuel PharmD BCOP

HistoryHistory

Paul Ehrlich – coined the term Chemotherapy – during Paul Ehrlich – coined the term Chemotherapy – during work with work with antibacterial agents. Term now applied to anti-antibacterial agents. Term now applied to anti-cancer agentscancer agents

19421942 Louis Goodman MD and Alfred Gilman PhD recruited by Louis Goodman MD and Alfred Gilman PhD recruited by Department of Department of Defense to investigate therapeutic applications of Defense to investigate therapeutic applications of chemical warfare based chemical warfare based on observations that exposure to on observations that exposure to Mustard gas caused lymphoid and Mustard gas caused lymphoid and myeloid suppression.myeloid suppression.

Recruited Gustov Linskog MD, a thoracic surgeon and Recruited Gustov Linskog MD, a thoracic surgeon and injected injected Mechlorethamine into a patient with Non-Mechlorethamine into a patient with Non-Hodgkin’s lymphoma. Hodgkin’s lymphoma. Patient had a dramatic response, but of Patient had a dramatic response, but of short duration.short duration.

19461946 Published their landmark results in the Journal of the Published their landmark results in the Journal of the American American Medical Association. Reprinted in JAMA in 1984.Medical Association. Reprinted in JAMA in 1984.

HistoryHistory

19481948 Sydney Farber MD at Harvard Medical School studied Sydney Farber MD at Harvard Medical School studied effects of effects of Folic Acid on leukemic cells based on the Folic Acid on leukemic cells based on the observation that Folic Acid caused observation that Folic Acid caused proliferation in pediatric proliferation in pediatric ALL patients.ALL patients.

Farber along with Harriett Kilte at Lederle Labs Farber along with Harriett Kilte at Lederle Labs synthesized synthesized Folic Acid Folic Acid analogs Aminopterin and analogs Aminopterin and Amethopterin Amethopterin (Methotrexate, MTX) . This was (Methotrexate, MTX) . This was the the beginning of rational drug design. Began studying effects of MTX beginning of rational drug design. Began studying effects of MTX in in pediatric ALL.pediatric ALL.

1950s1950s Introduction of combination chemotherapyIntroduction of combination chemotherapy

EtiologyEtiology

Environmental factorsEnvironmental factors Food additives (nitrites)Food additives (nitrites) Pollution (asbestos)Pollution (asbestos) Occupational (benzene)Occupational (benzene) Industrial (hydrocarbons – soot)Industrial (hydrocarbons – soot)

Lifestyle and other factorsLifestyle and other factors Tobacco (leading cause of NSCLC)Tobacco (leading cause of NSCLC) Alcohol (beer – rectal cancer)Alcohol (beer – rectal cancer) Diet (obesity)Diet (obesity) Viruses (HPV, HIV)Viruses (HPV, HIV)

EtiologyEtiology

Knudson’s two hit theory (Rb gene) 1971Knudson’s two hit theory (Rb gene) 1971

R. White – clonality – (APC gene) 1987R. White – clonality – (APC gene) 1987

Goals of therapyGoals of therapy

CurativeCurative

Childhood leukemiaChildhood leukemia

Testicular CancerTesticular Cancer

Hodgkin’s diseaseHodgkin’s disease

Stage I through III Breast CancerStage I through III Breast Cancer Palliative (slow down disease progression)Palliative (slow down disease progression)

Prostate CancerProstate Cancer

Multiple Myeloma, indolent lymphomasMultiple Myeloma, indolent lymphomas

Head & NeckHead & Neck

Stage IV Breast CancerStage IV Breast Cancer

NSCLCNSCLC

Treatment ModalitiesTreatment Modalities

Surgery ( localized disease, staging, palliation, endocrine Surgery ( localized disease, staging, palliation, endocrine ablation, debulking)ablation, debulking)

Radiation (localized disease, debulking, palliation)Radiation (localized disease, debulking, palliation) ChemotherapyChemotherapy ImmunotherapyImmunotherapy

Combined Modality (employ 2 or more modalities to increase Combined Modality (employ 2 or more modalities to increase response)response)

Neoadjuvant – prior to definitive local therapy (surgery) – Neoadjuvant – prior to definitive local therapy (surgery) – potentially organ sparingpotentially organ sparing

Adjuvant – following definitive therapyAdjuvant – following definitive therapy

Tumor growth conceptsTumor growth concepts

Growth FractionGrowth Fraction Doubling timeDoubling time

Early stages – high growth fraction, short doubling Early stages – high growth fraction, short doubling timestimes

Late stages – low growth fraction, long doubling timesLate stages – low growth fraction, long doubling times

Chemotherapy – most effective when growth fraction is high.Chemotherapy – most effective when growth fraction is high.

Gompertzian growthGompertzian growth

Chemotherapy considerationsChemotherapy considerations

Tumor cells undergo the same cellular processes (replication, Tumor cells undergo the same cellular processes (replication, division)division)

Tumor cells don’t necessarily grow faster than normal cellsTumor cells don’t necessarily grow faster than normal cells Non-specific agents interfere with these processesNon-specific agents interfere with these processes Ideal chemotherapy is toxic to tumor cells but spares normal cellsIdeal chemotherapy is toxic to tumor cells but spares normal cells Cell cycle specific agents – antimetabolites, Vinca alkaloidsCell cycle specific agents – antimetabolites, Vinca alkaloids Cell cycle non-specific agents – Doxorubicin, CisplatinCell cycle non-specific agents – Doxorubicin, Cisplatin Give the most effective therapy early in disease pricessGive the most effective therapy early in disease pricess

Purposes of ChemotherapyPurposes of Chemotherapy

Primary – shrink or eliminate tumorPrimary – shrink or eliminate tumor Neoadjuvant – make tumor more amenable to other therapiesNeoadjuvant – make tumor more amenable to other therapies Adjuvant – eradicate micro metastasisAdjuvant – eradicate micro metastasis Palliation – symptom controlPalliation – symptom control

Response to ChemotherapyResponse to ChemotherapyCR – complete disappearance for at least 1 monthCR – complete disappearance for at least 1 monthPR – 50% or > reduction in tumor size or markers and no new PR – 50% or > reduction in tumor size or markers and no new

disease for 1 monthdisease for 1 monthSD – no reduction or growthSD – no reduction or growthProgression – 25% increase in tumor sizeProgression – 25% increase in tumor size

Adjuvant chemotherapyAdjuvant chemotherapy

Risk of recurrence despite surgical resectionRisk of recurrence despite surgical resection

Failure of chemotherapy to cure after recurrenceFailure of chemotherapy to cure after recurrence

Cancers most sensitive to chemotherapy in early stagesCancers most sensitive to chemotherapy in early stages

Decreased probability of biochemical resistance Decreased probability of biochemical resistance

Disadvantage – exposure of truly cured patients to chemotherapyDisadvantage – exposure of truly cured patients to chemotherapyLate complications – sterility, risk of secondary malignancyLate complications – sterility, risk of secondary malignancy

Kinetic basis of ChemotherapyKinetic basis of Chemotherapy

Fractional kill hypothesisFractional kill hypothesisTumor accumulates between cyclesTumor accumulates between cycleschemotherapy follows exponential log kill (never reaches zero)chemotherapy follows exponential log kill (never reaches zero)

Phase specific agents – schedule dependentPhase specific agents – schedule dependentmore effective when given in divided doses at repeated intervalsmore effective when given in divided doses at repeated intervalsmore effective in tumors with high growth fractionmore effective in tumors with high growth fraction

Phase non-specific agents Phase non-specific agents exert effects throughout the cell cycleexert effects throughout the cell cycledose or concentration dependent effectsdose or concentration dependent effectsmay have effect in resting phasemay have effect in resting phase

Biochemical heterogeneityBiochemical heterogeneity

Determinants of responseDeterminants of response

In-vitro testingIn-vitro testing

Inherent sensitivity of tumorInherent sensitivity of tumor

Variable expression of metabolizing enzymesVariable expression of metabolizing enzymes

Molecular targetingMolecular targeting

Pharmacokinetic determinants – AUC dosingPharmacokinetic determinants – AUC dosing

Drug interactionsDrug interactions

20-30% of interactions are caused by drugs20-30% of interactions are caused by drugs

Clinically relevant in up to 80% of elderlyClinically relevant in up to 80% of elderly

Complex pharmacological profileComplex pharmacological profile

Narrow therapeutic window, Steep dose-toxicity curveNarrow therapeutic window, Steep dose-toxicity curve

PK and PD inter-patient variabilityPK and PD inter-patient variability

Failure to recognize leads to over dosing or under dosingFailure to recognize leads to over dosing or under dosing

Drug interactionsDrug interactions

PharmaceuticalPharmaceuticalCisplatin + Mesna results in covalent adductCisplatin + Mesna results in covalent adductMitomycin in Dextrose containing fluidsMitomycin in Dextrose containing fluids5FU dilution in low pH 5FU dilution in low pH Precipitation of Taxanes, VP-16Precipitation of Taxanes, VP-16IL-2 adsorptionIL-2 adsorptionPegylation of DOX – AUC is 300 X greater, Clearance Pegylation of DOX – AUC is 300 X greater, Clearance

decreased 250 Xdecreased 250 XPolyoxyethylated Castor oil versus Tween 80 and Polyoxyethylated Castor oil versus Tween 80 and

Paclitaxel (in-vitro)Paclitaxel (in-vitro)Paclitaxel and Doxorubicin (polyoxyethylated castor oil)Paclitaxel and Doxorubicin (polyoxyethylated castor oil)

Drug interactionsDrug interactions

PharmacokineticPharmacokineticAbsorption: Absorption: 6-MP – allopurinol; 6-MP – Azathioprine (25-33% dose 6-MP – allopurinol; 6-MP – Azathioprine (25-33% dose

reduction required)reduction required)

Distribution: Distribution: liposomal preparations – alter toxicity profileliposomal preparations – alter toxicity profile

Metabolism: Metabolism: CyP3A4 – Taxanes, Cyclophosphamide, IFEX, CyP3A4 – Taxanes, Cyclophosphamide, IFEX, antifungals, antifungals, protease inhibitors, Benzodiazepines, protease inhibitors, Benzodiazepines, AnticonvulsantsAnticonvulsants

CyP2B6 – Cyclophosphamide, Thiotepa CyP2B6 – Cyclophosphamide, Thiotepa Cyp2D6 – DOX, Vinca alkaloidsCyp2D6 – DOX, Vinca alkaloids

VCR – ItraconazoleVCR – ItraconazoleSorivudine – Tegafur (Japan) Sorivudine – Tegafur (Japan) Sequence – Cisplatin – Paclitaxel (25% lower clearance)Sequence – Cisplatin – Paclitaxel (25% lower clearance)

EliminationElimination NSAIDs and MTX or CisplatinNSAIDs and MTX or Cisplatin

Drug interactionsDrug interactions

PharmacodynamicPharmacodynamicCisplatin with gemcitabineCisplatin with gemcitabineCisplatin with topotecanCisplatin with topotecan5FU with Leucovorin5FU with LeucovorinPlatelet sparing effect of Carboplatin with TaxolPlatelet sparing effect of Carboplatin with Taxol

OTC medicationsOTC medicationsSt. John’s wart – potent inducer - avoid with CPT-11St. John’s wart – potent inducer - avoid with CPT-11

Prediction of drug responsePrediction of drug response

Selection of drugs based on previous trialsSelection of drugs based on previous trials

Human tumor xenograft studiesHuman tumor xenograft studies

Biochemical tests – asparaginase, DHFRBiochemical tests – asparaginase, DHFR

Molecular targeting – TKIsMolecular targeting – TKIs

EGFR targeted medicationsEGFR targeted medications

Combination therapyCombination therapy

Improved responseImproved response

Decrease resistance (p-glycoprotein, MDR phenotypes)Decrease resistance (p-glycoprotein, MDR phenotypes)

Non-overlapping toxicityNon-overlapping toxicity

Classes of drugsClasses of drugs

Direct DNA interacting agents – covalent adductsDirect DNA interacting agents – covalent adductsNitrogen mustard, Cyclophosphamide, Ifosfamide, Nitrogen mustard, Cyclophosphamide, Ifosfamide,

CisplatinCisplatin Antitumor antibiotics and Topoisomerase inhibitorsAntitumor antibiotics and Topoisomerase inhibitors

Doxorubicin, Bleomycin, DactinomycinDoxorubicin, Bleomycin, Dactinomycin AntimetabolitesAntimetabolites

ARA-C, MTX, 5-FUARA-C, MTX, 5-FU Mitotic spindle poisonsMitotic spindle poisons

Taxanes, Vinca alkaloids, VP-16Taxanes, Vinca alkaloids, VP-16 Hormonal agentsHormonal agents

Tamoxifen, LHRH agonistsTamoxifen, LHRH agonists Molecular targeted therapiesMolecular targeted therapies

TKI – Gleevec, Monoclonal antibodiesTKI – Gleevec, Monoclonal antibodies

Classes of drugsClasses of drugs

CytokinesCytokinesIL-2, InterferonsIL-2, Interferons

Immune modulatorsImmune modulatorsLevamisole, BCGLevamisole, BCG

Differentiation inducersDifferentiation inducersRetinoidsRetinoids

GlucocorticoidsGlucocorticoidsimmunosuppressive, lympholyticimmunosuppressive, lympholytic

L-asparaginaseL-asparaginaseDepletes asparagineDepletes asparagine

Classes of drugsClasses of drugs

Monoclonal antibodies - UnconjugatedMonoclonal antibodies - UnconjugatedRituximab - (Rituxan) - lymphoma (CD20)Rituximab - (Rituxan) - lymphoma (CD20)Trastuzumab (Herceptin) - breast (her2)Trastuzumab (Herceptin) - breast (her2)Alemtuzumab (Campath) – CLL (CD52)Alemtuzumab (Campath) – CLL (CD52)

Monoclonal antibodies – congugatedMonoclonal antibodies – congugatedIbritumomab (Zevalin) – YIbritumomab (Zevalin) – Y9090 labeled labeledTositumomab (Bexxar) – ITositumomab (Bexxar) – I131131 labeled labeled

ImmunotoxinImmunotoxinGemtuzumab (Mylotarg) – AML (CD33)Gemtuzumab (Mylotarg) – AML (CD33)

New targeted therapiesNew targeted therapies

Tyrosine Kinase Inhibitors – Gleevec, IressaTyrosine Kinase Inhibitors – Gleevec, Iressa Cyclin Dependent Kinase inhibitors – FlavoperidolCyclin Dependent Kinase inhibitors – Flavoperidol Farnesyl transferase inhibitors – R115777Farnesyl transferase inhibitors – R115777 Matrix Metalloproteinase inhibitors – NSC683551Matrix Metalloproteinase inhibitors – NSC683551 Proteosome inhibitor – Bortezomib (Velcade)Proteosome inhibitor – Bortezomib (Velcade) DNA demethylating agent – 5-Azacytidine (Vidaza)DNA demethylating agent – 5-Azacytidine (Vidaza)