Pharmacology of Anticancer Agents Objectives of Phase I Trials

William Douglas Figg • Determine MTD for Phase II Dose

Molecular Pharmacology Section and the Clinical Pharmacology Program Medical Oncology Branch • Characterize SE/DLT National Cancer Institute National Institutes of Health Bethesda, MD USA • Pharmacokinetics/Pharmacodynamics

Narrow Therapeutic Window For most Anticancer Agents

Increased risk of Why do we define MTD in toxicity Typical Anticancer Trials of New Agents? Minimum effective concentration Plasma Concentration Plasma

Time

Phase II Trial Phase II Trial • Determine the Efficacy in Different Tumor Types • Two-Stage Design • Refine the Pharmacokinetic Data – Looking for 1 in 12-15 pts, then expand • Single Arm - typically to 30-40 pts • Single Institution - typically • 0 in 12 - There is only a 10% chance • Maximize the chance of Detecting of rejecting a drug that has a true Clinical Response or Biological response rate of 20% Activity

1 Phase III Success Rate • Large (hundreds of patients) • Clinical approval success rate for all anticancer agents 13.4% (1993-2004) • Randomized - Small Molecules 14.3% • Multiinstitutional - Large Molecules 11.5% • Response Intensive • Agents developed for hematologic indications had • Control group usually receives a higher clinical approval success rate (36% vs standard of care plus placebo 9.8%) • Broad Selection of Pts to Represent • Success of second and third indication was Community dependent on approval of the first indication – (only 2.5% and 1.8% if first indication failed)

DiMasi et al. Tufts Center for Study of Drug Development

Clinical Pharmacokinetics Clinical Pharmacodynamics

• Clinical Pharmacokinetics (PK) • Clinical Pharmacodynamics (PD) – The study and characterization of the time course of – Defining the relationship between pharmacokinetic drug absorption (how fast and how much), distribution, parameters and toxicity, efficacy, and/or another metabolism, and excretion biologic effect

Classical PD: Describing Relationships Between Drug Exposure in Blood/Plasma (e.g., concentration, Clinical Pharmacokinetics & AUC) and Drug Effects Absorption Pharmacodynamics • Why Clinical PK and PD studies?

Target Organ/ – Formulate an administration strategy (e.g., select dose Tissue Effect: Input Distribution exposure parameter, schedule) that separates antitumor Toxicity (Drug Dose) Metabolism Efficacy effect from normal tissue toxicity Elimination Biological Effect – To enhance the safe and effective therapeutic management of the individual patient

Pharmacokinetics (PK) Pharmacodynamics (PD) (Drug Disposition) (Drug Effects)

Markers for Intracellular Pharmacology, Drug-Target Interactions

2 Design of PK Sampling Schemes Construct Linear and Log-Linear Concentration-Time Curves

• Blood, Plasma, or Serum – Intensive (frequent) sampling (e.g., 10 - 15 samples): • enough data to describe the disposition (e.g., mono-, bi-, or triexponential behavior) • detection and characterization of unexpected dispositional phenomena (e.g., enterohepatic recirculation, drug interactions) – Extensive (prolonged) sampling (e.g., 48 hours, day 8): • At end of the infusion, need intensive sampling to

accurately characterize the terminal disposition Troxacitabine 0.8 mg/m2 phase of the drug [Canova et al. Proc ASCO 18:197a, 1999]

3 Graphical Presentation of AUC

Graphical Presentation of Cmax Graphical Presentation of Cmax & Tmax

4 Sources of Pharmacokinetic and Drug metabolizing enzymes Pharmacodynamic Variability Drug Specific: Morphometric: Dose & Schedule Body Size Dosage form Body Composition Genetics:

Demographic: Age Race/Ethnicity Variability Sex Environment: Physiologic: Drug-drug interactions Disease Drug-CAM interactions Hepatic Function Drug-formulation interactions Renal Function Drug-food constituent interactions (Evans and Relling, Science 286: 487-91, 1999)

dapsone[29] (in leprosy) benzodiazepines Substrates Tricyclic Compounds alprazolam[29][31] Cytochrome P450 3A4 (abbreviated CYP3A4), amitriptyline[31] midazolam[29][31] clomipramine[31] triazolam[29][31] some immunosuppressants imipramine[31] diazepam[29] cyclosporin[29][31] is an important enzyme in the body, mainly cyclobenzaprine[33] some hypnotics tacrolimus[29][31] SSRIs zopiclone[31] sirolimus[29][31] citalopram[31] zaleplon[29] found in the liver and in the intestine. Its many chemotherapeutic norfluoxetine[31] zolpidem[29] docetaxel[29][31] sertraline[31] donepezil[31] purpose is to oxidize small foreign organic tamoxifen[29][31] some other antidepressants statins paclitaxel[29][31] mirtazapine[31] (NaSSA) atorvastatin[29][31] cyclophosphamide[31] molecules (xenobiotics), such as toxins or nefazodone[31] lovastatin[29][31] doxorubicin[31] reboxetine[31] simvastatin[31] erlotinib[32] venlafaxine[31] (SNRI) cerivastatin[29] drugs, so that they can be removed from the etoposide[31] trazodone[29] (SARI) calcium channel blockers ifosfamide[31] buspirone[29][31] (anxiolytic) diltiazem[29][31] body. teniposide[31] antipsychotics felodipine[29][31] vinblastine[31] haloperidol[29][31] nifedipine[29][31] vincristine[29] aripiprazole[29] verapamil[29][31] vindesine[31] risperidone[29] amlodipine[29] imatinib[29] ziprasidone[29] lercanidipine[29] irinotecan[29] pimozide[31] nitrendipine[29] sorafenib[29] quetiapine[29] nisoldipine[29] sunitinib[29] opioids (mainly analgesics) amiodarone[31] vemurafenib[29] alfentanil[29][31] dronedarone[31] temsirolimus[29] buprenorphine[34] quinidine[29] anastrozole codeine[29] PDE5 inhibitors gefitinib fentanyl[29] sildenafil[29][31] azole antifungals methadone[29] tadalafil[35] ketoconazole[31] levacetylmethadol[29] itraconazole[31] tramadol macrolides clarithromycin[29][31] erythromycin[29] telithromycin[29]

dapsone[29] (in leprosy) benzodiazepines Substrates kinins[31] (vasodilators, smooth dextromethorphan[29] (antitussive) Tricyclic Compounds alprazolam[29][31] muscle contractors) domperidone[29] (antidopaminergic) amitriptyline[31] midazolam[29][31] sex hormones agonists and eplerenone[29] (aldosterone antagonist) clomipramine[31] triazolam[29][31] some immunosuppressants antagonists lidocaine[29] (local anesthetic, antiarrhythmic) imipramine[31] diazepam[29] cyclosporin[29][31] finasteride[29][31] (antiandrogen) ondansetron[29] (5-HT3 antagonist) cyclobenzaprine[33] some hypnotics tacrolimus[29][31] estradiol[29] (estrogen) propranolol[29] (beta blocker) SSRIs zopiclone[31] sirolimus[29][31] progesterone[29] salmeterol[29] (beta agonist) citalopram[31] zaleplon[29] many chemotherapeutic ethinylestradiol[31] (hormonal warfarin[38] (anticoagulant) norfluoxetine[31] zolpidem[29] docetaxel[29][31] contraceptive) clopidogrel, becoming bioactivated[39] (antiplatelet) sertraline[31] donepezil[31] tamoxifen[29][31] testosterone[29] (androgen) omeprazole[31] (proton pump inhibitor) some other antidepressants statins paclitaxel[29][31] toremifene[31] (SERM) nateglinide[29] (antidiabetic) mirtazapine[31] (NaSSA) atorvastatin[29][31] cyclophosphamide[31] bicalutamide[36] nefazodone[31] lovastatin[29][31] doxorubicin[31] H1-receptor antagonists reboxetine[31] simvastatin[31] erlotinib[32] terfenadine[29][31] venlafaxine[31] (SNRI) cerivastatin[29] etoposide[31] astemizole[29][37] trazodone[29] (SARI) calcium channel blockers ifosfamide[31] chlorphenamine[29] buspirone[29][31] (anxiolytic) diltiazem[29][31] teniposide[31] Protease inhibitors antipsychotics felodipine[29][31] vinblastine[31] indinavir[29][31] haloperidol[29][31] nifedipine[29][31] vincristine[29] ritonavir[29][31] aripiprazole[29] verapamil[29][31] vindesine[31] saquinavir[29][31] risperidone[29] amlodipine[29] imatinib[29] nelfinavir[29][31] ziprasidone[29] lercanidipine[29] irinotecan[29] non-nucleoside reverse transcriptase pimozide[31] nitrendipine[29] sorafenib[29] inhibitors quetiapine[29] nisoldipine[29] sunitinib[29] nevirapine[31] opioids (mainly analgesics) amiodarone[31] vemurafenib[29] some glucocorticoids alfentanil[29][31] dronedarone[31] temsirolimus[29] budesonide[31] buprenorphine[34] quinidine[29] anastrozole hydrocortisone[29] codeine[29] PDE5 inhibitors gefitinib dexamethasone[29] fentanyl[29] sildenafil[29][31] azole antifungals cisapride[29][31] (5-HT4 receptor methadone[29] tadalafil[35] ketoconazole[31] agonist) levacetylmethadol[29] itraconazole[31] aprepitant[29] (antiemetic) tramadol macrolides caffeine[29] (stimulant) clarithromycin[29][31] cocaine[29] (stimulant) erythromycin[29] cilostazol[29] (phosphodiesterase telithromycin[29] inhibitor)

5 INHIBITORS unspecified potency: amiodarone[29] (antiarrhythmic) strong: protease inhibitors Induction bicalutamide[36] ritonavir[29][31][40] ciprofloxacin[29] (antibiotic) indinavir[29] dithiocarbamate[29] (functional group) nelfinavir[29] anticonvulsants, mood stabilizers voriconazole[29] (antifungal) saquinavir[29] [29][31][40] imatinib[29] (anticancer) carbamazepine some macrolide antibiotics[40] mifepristone[29] (abortifacient) [29][31] clarithromycin[29][31] phenytoin norfloxacin[29] (antibiotic) telithromycin[29] [29] some non-nucleoside reverse transcriptase inhibitors[45] oxcarbazepine chloramphenicol (antibiotic)[41] delavirdine[29] [40] some azole antifungals barbiturates gestodene[29] (hormonal contraceptive) ketoconazole[29][31] [29][31] mibefradil[29] (in angina pectoris) phenobarbital itraconazole[29][31] fluvoxamine[29] nefazodone[29][31] (antidepressant) Butalbital star fruit[29][46] [29][31] milk thistle[47] St. John's wort moderate ginko biloba[48] aprepitant[29] (antiemetic) some bactericidals Quercetin some calcium channel blockers [29][40] piperine[50] rifampicin verapamil[29] isoniazid[51] rifabutin[29][31] diltiazem[29] [45] some macrolide antibiotics some non-nucleoside reverse transcriptase inhibitors erythromycin[29] efavirenz[29] some azole antifungals[40] [29] [29] fluconazole nevirapine bergamottin (constituent of grapefruit juice)[29] some hypoglycemics Valerian[42] [29] pioglitazone weak: troglitazone[29] fluoxetine/norfluoxetine[29] [29] [29] cimetidine (H2-receptor antagonist) glucocorticoids (blood glucose increase, immunosuppressive) buprenorphine (analgesic)[43] modafinil[29] (stimulant) cafestol (in unfiltered coffee)[44] orphenadrine

Effect of Grapefruit Juice/Products Volume 361:827-828; August 20, 2009 on Drug Metabolism Case report: Codeine, Ultrarapid-Metabolism Genotype, and Postoperative Death

• Erlotinib Healthy 2-yo boy, underwent outpatient elective adenotonsillectomy; • Dasatinib After surgery, instructions to take 10-12.5mg of codeine + 120 mg APAP q 4-6 hr prn; 2 days post surgery, child died • Gefitinib Autopsy results: Codeine (0.70 mg/L) & morphine (32 ng/ml)  toxic levels CYP2D6 genotyping  3 copies of CYP2D6 allele  ultrarapid-metabolizer • Imatinib phenotype • Nilotinib Ultrarapid metabolizers may metabolize • Lapatinib codeine too efficiently leading to • Sorafenib morphine intoxication • Sunitinib

Pharmacogenomics and Oncology Pharmacogenomics and Oncology

Pharmacogenomic Strategies Most Relevant When: Pharmacogenomic Strategies Most Relevant When: • Narrow therapeutic indices • Narrow therapeutic indices • High degree of inter-individual variability in response • High degree of inter-individual variability in response • Little or no available methods to monitor safety or • Little or no available methods to monitor safety or efficacy efficacy • Few alternative treatment options • Few alternative treatment options

Flowers and Veenstra 2004 Flowers and Veenstra 2004

Anticancer agents meet all of these criteria

6 Imatinib Css,min is highly variable in CML Higher Imatinib Concentrations are associated with adverse events* 351 patients receiving 400 mg daily on IRIS study Adverse Event Q1 Q2 & Q3 Q4 (N=87) (N=179) (N=86) Fluid retention 53 (2.3) 62 (3.4) 76 (3.5) Rash 32 (3.4) 39 (2.2) 51 (1.2) 26-fold Myalgia 20 (0) 25 (2.2) 30 (1.2) variation Anemia 8.0 (0) 12 (2.4) 20 (7.0)

*data are % of toxicity in the Q (% of grade 3/4 toxicity in the Q); significant association with adverse events within 3 months and 5 years (shown)

RA Larson et al. Blood 2008 RA Larson et al. Blood 2008

Selection of Appropriate Genes

Cell membrane One ultimate goal of pharmacogenetics ABCC3* is to provide a patient with individualized ABCG2 ABCC4** therapy (“getting the dose right”) Imatinib ABCB1

Imatinib ? CGP71422 (urine only) CYP3A4

CYP3A5

CYP2D6 Using candidate gene approach - It will Bcr-Abl, cKIT, PDGFR be virtually impossible to assign a CYP3A4 CGP74588 Unknown patient to an unequivocal phenotype and CYP1A1 metabolites Out In especially to an unequivocal genotype * identified as one of the genes with expression features unique to imatinib relapsers in CML (Radich et al, PNAS 2006); ** S Hu et al, CCR 2008

DMET Genotyping Platform 1936 variants (actual causative variants) in 235 PK/PD genes. Useful for haplotype determination. Captures the vast majority of SNPs involved in PK/PD.

Phase I Enzymes Phase II Enzymes Transporters Other CYP1A1 CYP4F2 ADH1A COMT MAOB ABCB1 SLC15A2 SLC7A5 ABP1 NR3C1 CYP1A2 CYP4F3 ADH1B DPYD NAT1 ABCB4 SLC16A1 SLC7A7 AHR ORM1 CYP1B1 CYP4F8 ADH1C FMO1 NAT2 ABCB7 SLC19A1 SLC7A8 AKAP9 ORM2 CYP2A6 CYP4F11 ADH4 FMO2 NNMT ABCB11 SLC22A1 SLCO1A2 ALB PNMT CYP2A7 CYP4F12 ADH5 FMO3 NQO1 ABCC1 SLC22A11 SLCO1B1 AOX1 PON1 CYP2A13 CYP4Z1 ADH6 FMO4 TPMT ABCC2 SLC22A12 SLCO1B3 ARNT PON2 CYP2B6 CYP7A1 ADH7 FMO5 UGT1A1 ABCC3 SLC22A14 SLCO2B1 ARSA PON3 CYP2B7 CYP7B1 ALDH1A1 FMO6 UGT1A3 ABCC4 SLC22A2 SLCO3A1 CBR1 POR CYP2B7P1 CYP8B1 ALDH2 GSTA1 UGT1A4 ABCC5 SLC22A3 SLCO4A1 CBR3 PPARD CYP2C8 CYP11A1 ALDH3A1 GSTA2 UGT1A5 ABCC6 SLC22A4 SLCO5A1 CDA PPARG CYP2C9 CYP11B1 ALDH3A2 GSTA3 UGT1A6 ABCC8 SLC22A5 SULT1A1 CES2 PTGIS CYP2C18 CYP11B2 CHST1 GSTA4 UGT1A7 ABCC9 SLC22A6 SULT1A2 CROT RALBP1 CYP2C19 CYP17A1 CHST2 GSTA5 UGT1A8 ABCG1 SLC22A7 SULT1A3 DCK RPL13 CYP2D6 CYP19A1 CHST3 GSTM1 UGT1A9 ABCG2 SLC22A8 SULT1B1 EPHX1 RXRA CYP2E1 CYP20A1 CHST4 GSTM2 UGT1A10 ATP7A SLC28A1 SULT1C1 EPHX2 SEC15L1 CYP2F1 CYP21A2 CHST5 GSTM3 UGT2A1 ATP7B SLC28A2 SULT1C2 FAAH SERPINA7 CYP2J2 CYP24A1 CHST6 GSTM4 UGT2B4 SLCA13 SLC28A3 SULT1E1 G6PD SETD4 CYP2S1 CYP26A1 CHST7 GSTM5 UGT2B7 SLC10A1 SLC29A1 SULT2A1 HMGCR SPG7 CYP3A4 CYP27A1 CHST8 GSTO1 UGT2B11 SLC10A2 SLC29A2 SULT2B1 HNMT TBXAS1 CYP3A5 CYP27B1 CHST9 GSTP1 UGT2B15 SLC13A1 SLC5A6 SULT4A1 MAT1A TPSG1 CYP3A7 CYP39A1 CHST10 GSTT1 UGT2B17 SLC15A1 SLC6A6 METTL1 TYMS CYP3A43 CYP46A1 CHST11 GSTT2 UGT2B28 NR1I2 VKORC1 CYP4A11 CYP51A1 CHST13 GSTZ1 UGT8 NR1I3 XDH CYP4B1 MAOA

Deeken (Figg) et al. (2009) Pharmacogenomics J

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