Tom Frank, Pharm.D., BCPS Discloses that he is on the speaker’s bureau of Pfizer, Novartis and Amgen 1 Dabigatran • Oral anticoagulant indicated to reduce the risk of stroke and systemic embolism • Non-valvular atrial fibrillation • Direct thrombin (factor IIa) inhibitor • Inhibition of thrombin decreases the conversion of fibrinogen to fibrin • Also inhibits free thrombin, fibrin bound thrombin and thrombin induced platelet aggregation 2 Dabigatran Pharmacokinetics • Hydrolyzed to active moiety • Metabolized to four glucuronides, all are active • Bioavailability 3-7% (do not crush or open capsule) • Peak concentration in one hour • Protein binding 35% • Eliminated primarily in urine • Half life 12-17 hours • Adjust dose for diminished renal function Dabigatran Pharmacokinetics • Drug interactions: • Rifampin (reduced dabigatran levels) • No changes other than Cmax or AUC seen when used with ketoconazole, verapamil, amiodarone, quinidine, clarithromycin • No changes in coagulation when given with given clopidogrel or enoxaparin • No change in dabigatran levels when given with digoxin, H2 blockers or PPI’s • Pharmacodynamics: median aPTT 2x control onset of therapeutic effect between 30 min and 2 hours 3 Dabigatran Clinical Trials • Dabigatran 110mg or 150mg twice daily compared to warfarin (INR 2-3) • Patients with atrial fibrillation and risk factors for stroke • Primary end point: rate of stroke or systemic embolism • Primary safety outcome: rate of major hemorrhage • Low dose aspirin or other anti-platelet allowed • Primary end point: dabigatran 110mg 1.53%/yr; 150mg 1.11%/yr and 1.69%/yr for warfarin • Primary safety end point: dabigatran 110mg 0.12%/yr, 150mg 0.10%/yr and 0.38%/yr for warfarin Dabigatran Adverse Effects • Dyspepsia • Intracranial hemorrhage • Life threatening bleed • Major bleeding • Major GI bleeding • Rates of MI from RE-LY: 0.82% for 110mg, 0.81% for 150mg and 0.64% for warfarin 4 Dabigatran Dosing • 150mg p.o. twice daily • 75mg p.o. twice daily if CrCl 15-30ml/min • If switching from warfarin, stop warfarin and start dabigatran when the INR < 2 • If switching from parenteral anticoagulant, start dabigatran less than 2 hours before next injection would have been given OR at the time IV heparin is discontinued • Discontinue 1-2 days prior to elective surgery; check ECT or aPTT if emergent surgery 5 Denosumab • Human monoclonal antibody indicated for the treatment of postmenopausal women with osteoporosis at a high risk for fracture • Denosumab binds to the RANK ligand and inhibits maturation of osteoclasts • Denosumab mimics the effects of osteoprotegerin 6 7 Denosumab Pharmacokinetics • Bioavailability 100% • Levels detectable within one hour • Half life 25 days • Metabolized by RES • Drug interactions: not studied Denosumab Clinical Trials • Placebo controlled trial evaluating denosumab 60mg SQ every 6 months • Female patients with low T-score at hip or spine • End point: new vertebral fracture at 36 months • Secondary end points: time to first non-vertebral fracture and time to hip fracture • End point reached in 7.2% on placebo and 2.3% on denosumab • Non-vertebral fractures: 8% vs 6.5%; hip fracture rate 1.2% vs 0.7% 8 Denosumab Clinical Trials • Randomized, double blind, placebo controlled trial evaluated denosumab 60mg every six months in men on androgen deprivation therapy for prostate cancer • End point: BMD change after 24 months • Denosumab group improved by 5.6%, placebo group decreased by 1% • New vertebral fractures: 1.5% vs 3.9% Denosumab Adverse Effects • Hypocalcemia • Non-fatal serious infections • New malignancies • Dermatologic reaction • Osteonecrosis of the jaw • Pancreatitis 9 Denosumab Dosing • 60mg subcutaneously every 6 months • Inject into upper arm, thigh or abdomen • Should be administered by healthcare professional • Patient should be taking calcium and vitamin D 10 Belimumab • Human monoclonal antibody indicated for patients with active SLE who are receiving standard therapy • B-lymphocyte stimulator (BLyS) protein inhibitor • Blocks binding of BLyS to receptors on B-cells • Inhibited B-cell survival and reduced differentiation of B-cells Belimumab Pharmacokinetics • Half life 19.4 days • No changes based on age, gender race or renal impairment • Drug interactions: steroids and ACEI produce increased clearance but no clinical impact; no impact with used with mycophenolate, azathioprine, methotrexate, antimalarials, NSAID’s, aspirin and HMGCoA reductase inhibitors 11 Belimumab Clinical Trials • Randomized double-blind, placebo-controlled trials in patients with active SLE disease (76 weeks and 52 weeks duration) • Stratified based on SELENA-SLEDAI score, proteinuria and race • >70% were on 2 or more SLE drugs • Patients with severe lupus nephritis or CNS lupus excluded • Assigned to 1mg/kg/day or 10mg/kg/day or placebo • Doses given on day 0, 14, 28 then every 28 days Belimumab Clinical Trials • SLE Responder Index end point reached in 41%, 43% and 43% respectively in 76 week trial • End point reached in 51%, 58% and 44% respectively in 52 week trial • Subgroup analysis: response rate in black/African American patients less than placebo in one study and similar response to other patients in second study 12 Belimumab Adverse Effects • Nausea • Diarrhea • Pyrexia • Death • Serious infections • Malignancy • Hypersensitivity reactions • Infusion reactions • Depression Belimumab Dosing • 10mg/kg at two weeks intervals for first three doses and four week intervals after that • IV infusion given over one hour • Can pre-medicate for infusion reactions 13 Ulipristal • Progesterone agonist/antagonist indicated for emergency contraception • Selective progesterone receptor modulator • Binds to progesterone, glucocorticoid and androgen receptors • Primary mechanism of action is inhibition or delay of ovulation 14 Ulipristal Pharmacokinetics • Highly protein bound • Peak concentration in one hour • Presence of food does not require dose adjustment • Metabolized by CYP 3A4 • Half life 32 hours • Drug interactions: CYP 3A4 inducers (barbiturates, carbamazepine, felbamate, rifampin, St. John’s wort, topiramate) Ulipristal Clinical Trials • Open-label trial; ulipristal 30mg in women who presented for emergency contraception within 48-120 hours after unprotected intercourse; 27 pregnancies (observed rate 2.2%, expected rate 5.5%) • Ulipristal 30mg compared to levonorgestrel 1.5mg in single blind trial • Stratified according to time since unprotected intercourse • Taken with 72 hours: pregnancy rates were ulipristal 1.8% and levonorgestrel 2.6% • Between 72-120 hours: ulipristal no pregnancies, levonorgestrel 3% pregnancy rate 15 Ulipristal Adverse Effects • Headache • Abdominal pain • Nausea • Dysmenorrhea • Fatigue • Dizziness • Rapid return of fertility likely • Cycle length increased by mean of 2.5 days Ulipristal Dosing • Take one tablet orally as soon as possible within 120 hours after unprotected intercourse or a known or suspected contraceptive failure 16 Dienogest/estradiol valerate • Indicated for preventing pregnancy in women with BMI < 30kg/m2 • Estradiol inhibits ovulation • Dienogest potent progestin with anti- androgenic activity- thicken cervical mucus and changes in endometrium • Packaged in four-phase dose configuration 17 Dienogest/ethinyl estradiol Pharmacokinetics • Peak estrogen level in 3 hours, peak progestin levels in 1.5 hours • Estradiol 2-3% circulates free, dienogest 10% circulates free • Metabolism by CYP 3A4 • Half life: estradiol 14 hours, dienogest 11 hours • Drug interactions: drugs that induce CYP 3A4 (decrease efficacy/BTB); do not use with strong CYP 3A4 inducers; strong CYP 3A4 inhibitors increase hormone concentrations; protease inhibitors Dienogest/estradiol valerate Clinical Trials • Open-label, single-arm study • Treated for up to 28 cycles • 3,969 exposure cycles • 5 pregnancies identified in 13 cycle window • Pearl Index of 1.64 • Contraceptive failure rate after a year of 0.016 on Kaplan Meier curve 18 Dienogest/estradiol valerate Clinical Trials • Dienogest/estradiol compared to levonorgestrel/EE over seven cycles to compare withdrawal bleeding patterns • Withdrawal bleeding on schedule: dienogest/estradiol- 77-83% compared to levonorgestrel/EE 89-93% of the time • Duration of withdrawal bleeding: dienogest/estradiol- 4.1-4.7 days; levonorgestrel/EE- 5.0-5.2 days • Breakthrough bleeding rates 14% vs 12% Dienogest/estradiol valerate Adverse Effects • Headache • Metrorrhagia and irregular menstruation • Breast pain • Nausea or vomiting • Acne • Increased weight 19 3.5 3 2.5 2 yellow = 1.5 Estradiol green= 1 Dienogest 0.5 0 Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day 1 3 5 7 9 11 13 15 17 19 21 23 25 27 28 Dienogest/estradiol valerate Dosing • One tablet once a day (note different tablet colors associated with varying content) • Response to missed pills depends on which pill was missed • Start on first day of menses 20 The time to onset of therapeutic effect (aPTT > 2x control) for dabigatran is 1 hour 6 hours 2-3 days One week 21 Ceftaroline • “Next generation” cephalosporin indicated for treatment of acute bacterial skin and skin structure infections and community acquired pneumonia • Unique binding properties among cephalosporins for PBP2a • Good activity for MRSA and streptococci including multi-drug resistant Streptococcus pneumoniae • Lacks enterococcus coverage, limited gram negative spectrum Ceftaroline Pharmacokinetics • Low protein binding • Converted to active form by phosphatase enzyme • Half life 2.6 hours