Background. Methotrexate Pharmacokinetic and Clinical Review. Therapeutic Uses

Transcription

1 Methotrexate Pharmacokinetic and Clinical Review Weak dicarboxylic acid pka 4.8 and Background Joseph Bubalo PharmD, BCPS, BCOP Oncology Clinical Pharmacy Specialist Background MW Analog of aminopterin, a folic acid antagonist, introduced by Sidney Farber in 1948 for the treatment of acute childhood leukemia Therapeutic Uses Oncologic Uses: Breast cancer acute lymphoblastic leukemia, advanced mycosis fungoides (cutaneous T-cell lymphoma), Hodgkin s & non-hodgkin s lymphoma, osteogenic sarcoma Immunosuppressive therapy: Severe rheumatoid arthritis, psoriasis, asthma, SLE, GVHD prophylaxis. p GVHD = Graft Vs Host Disease Mechanism of Action Competitively, reversibly inhibits dihydrofolate reductase (DHFR) i.e. Enzyme block k i mmol/l DHFR is the intracellular enzyme that reduces folic acid idto tetrahydrofolic t acid id( (reduced d folate) Depletion of reduced folates necessary for the metabolic transfer of 1-carbon units in various biochemical rxns Interfere w/dna synthesis, repair, cellular replication

2 Mechanism of Action MTX acts specifically during DNA & RNA synthesis, thus it is highly cell cycle specific (S-phase) Tissues undergoing rapid cellular turnover with a high fraction of cells in cycle are the most susceptible to MTX: tumor cells & normal cells & tissues Blood cells -> pancytopenia Oral mucosa -> stomatitis, mucositis Regimens Low-dose: doses < 100 mg/m 2 Intermediate-dose: dose: mg/m 2 High-dose: doses > 1000 mg/m 2 No benefit to exceeding gm/m 2 Oral Product MTX po 2.5 mg tablets E.g.. Rheumatrex Dose Pack T peak = 1-5 hrs post dose Examples RA: mg po each week; may gradually increase to a max of mg/week Choriocarcinoma or choriocarcinoma destruens: mg po qd x 5 d Oral Product Examples ALL maintenance therapy: 30 mg/m 2 /week po in 2 divided dose Lymphosarcoma: mg/kg/d PO w/other neoplastics Mycosis fungoides: mg PO once weekly Psoriasis: mg/week as a single PO dose Wegener s granulomatosis: mg/week PO Absorption Interpret the graph on the next slide... Absorption Mean MTX bioavailability y( (F) at various dosages

3 Bioavailability l Dose-dependent Doses < 40 mg/m 2 F = 42% Doses > 40 mg/m 2 F = 18% Mean F oral = 33% (13-76%) No clear benefit to subdividing the po dose Mean F IM = 76% (54-112%) IM administration is used as an alternative to IV Absorption MTX is metabolized by intestinal bacteria to 4-amino-4-deoxy-N methylpteroic acid (DAMPA) Inactive metabolite Accounts for < 5% of the po dose 1/200 th (0.5%) the affinity of MTX for DHFR Factors Affecting Absorption Decrease Food Oral nonabsorbable antibiotics (vancomycin, neomycin, bacitracin) Decreased transit time Increase Increased transit time Distribution Lipid Insoluble pka48and and 5.5 Is it ionized or un-ionized at physiologic ph??ionization at Physiologic ph Distribution %Un-ionized pka %Ionized Where do you think MTX would distribute initially? ph - pka pka 4.8 and 5.5

4 Distribution After IV administration (over 4-6 hrs): Initial rapid distribution into extracellular water 18% of body weight Then, distribution into total body water 40-80% of body weight Vd initial = 0.2 L/kg Vd ss 40-80% of Body weight (0.7 L/kg) Vd may increase with increased plasma concentration due to passive diffusion into cells Concentration vs. Time Curves Plasma disappearance is triphasic w/half- lives of: < 1 hr: disappears during infusion period 1535hrs hrs: release from deep compartments, enterohepatic recirculation, & renal tubular reabsorption Correlates with MTX toxicities Protein Binding Approximately 50% bound to plasma proteins, mainly albumin Displacement interactions: Questionable E.g.. Sulfonamides, PAH Need dhigh hconcentrations ti Noncompetitive interactions: Alteration in MTX binding affinity ASA Protein binding interactions are difficult to distinguish from renal tubular secretion interactions Tissue: Plasma Distribution Ratios Kidney & liver > GI tract > muscle Retention of drug Sm. Intestine > liver > kidney> plasma 3 rd Spacing Pleural effusions Ascites Infection or other pathologically related fluid accumulation Interpret the following graph... Methotrexate Clearance? Methotrexate Levels A1 A Hours Micromo olar What would cause the changes between infusion 1 and 2?

5 Pleural l Effusion Pleural l Effusion Patient was given two 6 hour infusions of 400 mg/kg gin the presence & absence of a pleural effusion Initial rapid decline was similar The difference in decline was evident 30 hours after the infusion T 1/2 before effusion 6.7 hours T 1/2 effusion 14.4 hours Pleural l Effusion Acts as a reservoir At 6 hrs post infusion MTX conc. = plasma 24 hrs later may be 100X that of plasma Result: Prolonged excretion phase Increased potential for toxicity Membrane Transport Pharmacologic/therapeutic effects are dependent on intracellular concentrations Intracellular transport (2 processes): Carrier mediated active transport (not present on cancer cells) Primary pathway at < 5 micromolar MTX conc. Saturated at ~100 micromolar MTX conc. Simple transmembrane diffusion Major pathway at > 100 micromolar MTX conc. CNS Transport At Steady State (SS) ~ 2-3 % of serum concentration is in the CNS With High Dose therapy > than linear amounts cross over into the CNS as the doses increase Metabolism Intestinal bacteria - < 5% of dose Hydrolyzed to 7-OH MTX by hepatic aldehyde oxidase Intracellular polyglutamation Requires free methotrexate in the cell to occur Increases drug retention & inhibitory activity in the cell Folylpolyglutamate synthetase (FPGS) adds up to 5 glutamate residues per molecule Retained longer in malignant cells than normal cells Retained longer in lymphocytes than intestinal epithelium

6 Excretion Major route Renal (1.6-2X GFR) Glomerular filtration, tubular secretion, & reabsorption Low plasma conc. ( micromoles/l) MTX clearance > inulin clearance High plasma conc. ( micromoles/l) decreased net clearance w/ saturated secretion Penicillins, PPI s, and cephalosporins decrease secretion Minor Routes biliary excretion (< 10% of IV dose) can increase with charcoal Excretion Biphasic excretion Alpha T 1/2 3 hr ( ) Terminal T 1/2 ~10 hrs (8-15) Urine Solubility 2 mmol/l at ph 5.5 Goal ph > 6.5 with 100 ml/m2/hr hydration Hydrate with IV fluid containing sodium bicarbonate PPIs = proton pump inhibitors Drug Interactions Historical penicillins, NSAIDS, sulfas, nephrotoxins Recently reported proton pump inhibitors Block hydrogen-potassium ATPase pumps, p including those responsible for methotrexate clearance Increases methotrexate half-life ~65% 7-hydroxy metabolite AUC increases up to 70% Glucarbidase (Carboxypeptidase) Recombinant enzyme which rapidly converts methotrexate to glutamate plus 4-deoxy-4-amino- N 10 -methylpteric acid (DAMPA) Currently has orphan drug status DAMPA is X less potent (lower biding affinity) at DHFR inhibition then methotrexate DAMPA and glutamate are hepatically cleared Single dose of 50 units/kg IV over 5 minutes Reduces methotrexate concentrations to approximately 1 micromolar within 1 hour Clinical l Issues DHFR inhibition is competitive > 95% inhibition needed for response Length of exposure vs. concentration High risk features dehydration, acidosis, renal dysfunction, pleural effusion, ascites, GI obstruction, cisplatin cumulative dose > 300 mg/m2 Concurrent nephrotoxins Serum Monitoring Has had significant impact on toxicity management Levels drawn at specific times 24, 48, 72 hrs Normal levels widely variable 24 hrs micromol/l 48 hrs 3-30 micromol/l 72 hrs - < 0.3 micromol/l Assess rate of MTX decline Signals clearance changes, directs leucovorin rescue

7 Serum Monitoring End of infusion target level is 1,000 micromole for 4 hour and 700 micromoles for 6 hour infusions Associated with higher long term and disease free survival AUC of 4,000 micromole/l.hr also associated with higher disease free and long term survival. Lower AUC (>2400) also sufficient as long as cycles are given on time Leucovorin Rescue Starts (generally within 36) hours from beginning of MTX Infusion Competitive rescue so ECF LV concentration must be > MTX conc. L-leucovorin active form and converted dto 5 methyl THF which crosses into CSF Generally mg/m 2 Q4-6 hours ATC for hrs Doses > 50 mg must be given IV Leucovorin Rescue Leucovorin Rescue Categories Rescue continues until less than 1 X 10-7 M or 5 X 10-8 M if patient has fluid collections MTX Level LV level needed micromole/l equimolar 10 micromole/l 1000 micromoles/l 100 micromole/l Hemoperfusion Leucovorin Rescue Levels > 1 X 10-6 at 48 hrs need increased rescue 1 X 10-6 to 1 X 10-7 at 48 hrs continue at 10 mg.m2 q 6h Intrathecal lmethotrexate 12 mg/m2 maximum 15 mg total dose CSF volume stable after 3 Y/O Major adverse effects Meningeal irritation Transient/permanent tparesis Encephalopathy Headache If renal dysfunction may require LV rescue Always use preservative free diluent

8 Toxicities Hepatic Dysfunction Mucositis Pancytopenia GI desquamation Hepatic dysfunction Renal dysfunction Has been demonstrated with low doses over a long period (Increased LFTS, fibrosis, cirrhosis) or high dose exposure for transient periods Intermittent large doses appear less harmful Significant LFT elevations seen after each high dose infusion Need to return to normal prior to next dose Little long term impact on cirrhosis risk Renal ldysfunction Tumor lysis with elevated uric acid Delayed clearance Cumulative toxicity Other agents Signs Oliguria anuria, increased serum creatinine Hydration critical Pharmacogenetics SNP Single nucleotide polymorphisms Code for proteins that: Mediate disposition of drugs Mediate effects of drugs Haplotypes Larger blocks of heritable variation across a gene SNPs involving 4 of the enzymes involved in MTX metabolism have been identified Methylenetetrahydrofolate reductase (MTHFR) Potential Mechanism of Effects The enzyme maps to chromosome 1p36.3 and contains 11 exons that span 13,454 base pairs Polymorphisms C677T and AL1298G have been associated decreased MTHFR activity These may be protective for leukemic risk and may decrease relapse rates but also may cause increased toxicity

9 C677T Polymorphism Located on exon 4 Found in ~40% of Italians, ~35% of Caucasians, and ~15% or African Americans Homozygous cases have 30 % and heterozygous have 60% of the normal MTHFR activity In one study increased toxicity was seen awhile there was no difference in 2 other studies Clinical implications still uncertain! Useful Equations Mtx conc in micromoles = Mtx conc mg/l Cl mtx = 1.6(CrCl) Pharmacokinetic Calculations l Clinical applications Monitor methotrexate clearance rates Correlate outcomes Predict for,,guide avoidance strategies, or correlate with toxicity Allow optimization of supportive care and at a minimum i cost to patient t and provider Remember to review medications for interactions