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Objectives of Phase I Trials Why Do We 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]
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