Therapeutic Drug Monitoring και ΙΦΝΕ το 2018

Transcription

1 Therapeutic Drug Monitoring και ΙΦΝΕ το 2018 TDM: Ναι το χρειαζόμαστε, σε όλους και πάντοτε Κωνσταντίνος Κατσάνος

2 Conflict of interest By means of this, the speaker confirms that he receives honoraria for consulting services (educational services, scientific articles, participation in Advisory Boards, clinical trials, other) from the companies as follows AbbVie, ENORASIS,Ferring, JANNSEN, MSD, Shire and Takeda.

3 Adam S. Cheifetz Director, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center Harvard Medical School Κώστας Παπαμιχαήλ

4 This is NOT a new concept Nomogram for once daily gentamicin dosing 1995! We were all very good at this as interns Nicolau DP, et al. Antimicrob Agents Chemother.1995;39(3):650-5

5 Thiopurines Methotrexate Biologics Drugs we can monitor Anti-TNFs Vedolizumab Ustekinumab

6 Thiopurine Metabolism Osterman M, et al. Gastroenterology 2006

7 Can we (do we) check methotrexate levels? We can - red blood cell methotrexate polyglutamate Systematic review for rheumatoid arthritis studies, 8 showed association between higher levels and lower disease activity At least moderate potential for bias in all 8 of these studies Relatively large increases in concentrations required to produce a meaningful clinical change Potentially useful, may be limited by dose-related adverse events Little work in IBD: inverse relationship between drug level and efficacy but direct correlation with adverse events Mohamed HJ, et al. Eur J Clin Pharmacol 2015 Brooks AJ, et al. Ther Drug Monit 2007

8 Optimizing Treatment of Biologics Induction regimen and maintenance dosing Combination therapy with immunomodulator Earlier use of biologics Therapeutic drug concentration monitoring (TDM) Reactive testing of drug concentration and antibodies Better directs care and more cost-effective Proactive TDM improves outcomes and cost-effective During maintenance During induction When stopping immunomodulator (in combination with anti-tnf) Optimized (biologic) monotherapy

9 BRIDGe (Rand panel): When should drug concentration and antibody testing be performed? Appropriate to perform testing At the end of induction, primary non-response Secondary non-response During maintenance, responding Restarting after drug holiday (before 2 nd infusion) Uncertain to perform testing At the end of induction, in responders Melmed et al, CGH

10 Anti-TNF concentrations correlate with outcome: Cohort studies and post-hoc analysis Disease Drug Concentration Clinical outcome Notes CD (Maser CGH 2006) IFX Detectable Clinical remission, CRP, Trough assessed after 1 year (range after 6-37 Endoscopic remission infusion) CD (Cornillie GUT 2014) IFX > 3.5 Sustained response Post hoc analysis of ACCENTI CD (Bortlik JCC 2013) IFX > 3 Sustained response Week 14 or 24 trough CD (Lamblin JCC 2012) IFX > 5.6 Reduced CRP CD (Drobne Gastro 2011) IFX Undetectable Loss of response UC (Arias JCC 2012) IFX > 7.19 Sustained response UC (Seow GUT 2010) IFX Detectable Higher rates of remission, Undetectable serum IFX associated with Endoscopic improvement colectomy Failed to respond to increase CD/UC (Yanai AJG 2011) IXF > 3.8 in IFX or change to another anti-tnf Population was patients with LOR CD/UC (Roblin CHG 2014) CD/UC (Yanai AJG 2011) CD/UC (Roblin AJG 2014) ADA UC (Velayos CGH 2013) ADA > 4.58 ug/ml Week 12 clinical response CD (Colombel CGH 2014) CTP ADA > 4.9 Mucosal healing Higher trough concentrations associated with clinical remission and mucosal healing Failed to respond to increase ADA > 4.5 in ADA or change to another Population was patients with LOR anti-tnf < 4.9 ug/ml Prospective trial with ADA demonstrating Clinical response toada benefit of dose optimization for low trough dose intensification concentration Week 2-4 concentration predicts week 12 response Higher quartile (mean value for Endoscopic and clinical response and remission highest quartile: 30.1 ug/ml)

11 Factors Affecting the Pharmacokinetics of Monoclonal Antibodies Presence of anti-drug antibodies Concomitant use of immunomodulator High baseline TNF Low albumin High baseline CRP Body size Gender Impact on Pharmacokinetics Decreases serum drug concentration Threefold-increased clearance Worse clinical outcomes Reduces formation of anti-drug Ab Increases serum drug concentration Decreases drug clearance Better clinical outcomes May decrease serum drug concentration by increasing clearance Increases clearance Worse clinicaloutcomes Increasesclearance High BMI may increase clearance Males have higher clearance mab, monoclonal antibody; ADA, antidrug antibody Ordas I et al. Clin Pharmacol Ther. 2012;91:635.

12 When to monitor? PROactive REactive Up for debate Adapted from Silva-Ferreira F. et al. Inflamm Bowel Dis 2016.

13 Reactive TDM (Secondary non-response) Better directs care More cost effective than empiric dose escalation

14 Reactive testing algorithm Secondary loss of response (disease activity confirmed) Therapeutic anti- TNF concentration Sub-therapeutic concentration ADA negative ADA positive Low level High level Change drug class or surgery ADA = anti-drug antibody Dose escalate Consider dose escalation, addition of immunomodulator or change anti-tnf Change to different anti-tnf Adapted from Papamichail and Cheifetz, JCC 2016

15 Reactive testing is cost effective and more appropriately directs care Compared to empiric dose escalation for secondary loss of response 1 Reactive testing yielded similar QALYs Similar rates of remission and response Reactive testing was less expensive Lower use of high-dose biologics Greater time off biologics $38,000 $37,000 $36,000 $35,000 $34,000 $5,000 $33,000 $32,000 $31,000 $30,000 $29,000 Reactive testing Empiric dose escalation 1 Velayos et al. Clin Gastronetol Hepatol 2013;11:

16 Proactive TDM (During maintenance, responding) Improves clinical scores and CRP Decreases need for rescue therapy Prolongs duration of infliximab with less infliximab discontinuation Cost-effective Vande Casteele et al. Gastroenterolgy 2015 Vaughn B et al. Inflamm Bowel Dis 2014 Nov;20(11):

17 Therapeutic drug monitoring Proactive monitoring Commonly performed in other situations Cyclosporine, tacrolimus in solid organ transplantation 1 Cyclosporine and tacrolimus use in UC 2,3 Vancomycin and gentamycin in sepsis 4,5 Therapeutic window High concentrations can result in increased toxicity Low concentrations result in lack of efficacy Biologics low concentrations result in immunogenicity* 1 Monchaud C et al. Clin Pharmacokinet 2009;48: Van Assche G et al. Gastroenterology 2003;125: Ziring DA et al. J Pediatr Gastroenterol Nutr 2007;45: Zelenitsky S et al. Int J Antimicrob Agents 2013;41: Hansen M et al. Acta Anaesthesiologica Scandinavica 2001;45:

18 Proactive testing in IBD: TAXIT Trough level Adapted infliximab Treatment (TAXIT) trial. Patients: Infliximab maintenance therapy with stable clinical response All patients underwent infliximab dose optimization to trough level of 3-7ug/ml Randomized to: Infliximab dosing based on clinical symptoms and CRP Infliximab dosing based on trough concentration Primary outcome: Clinical remission at 1 year Vande Casteele et al. Gastroenterolgy 2015

19 Dose escalation for Crohn s improved disease control (symptoms and CRP) Most patients with UC were in remission with normal CRP Vande Casteele et al. Gastroenterolgy 2015

20 Primary endpoint - 1 year after optimization: No difference in remission rates between concentration and clinically dosed groups Vande Casteele et al. Gastroenterolgy 2015

21 TAXIT results: Secondary endpoints favor dosing to infliximab concentration Concentration-dosed group Less patients needed rescue therapy (7% vs. 17.3%; p=0.004) More patients maintained trough 3-7 (74% vs. 57%; p<0.001) Less patients had undetectable trough concentrations (OR 3.7; p<0.001) Non-significant trend towards fewer acute infusion reactions Similar cost between both groups Vande Casteele et al. Gastroenterolgy 2015

22 Probability on Infliximab Proactive therapeutic concentration monitoring and dose optimization results in a longer duration of infliximab and less discontinuation than standard of care TCM No TCM P = * Number at risk Weeks TCM No TCM Vaughn B et al. Inflamm Bowel Dis 2014 Nov;20(11):

23 Patients who achieved a trough concentration > 5 ug/ml had a longer duration on infliximab P < * P = 0.6 Similar results seen with cut off of 3ug/ml Vaughn B et al. Inflamm Bowel Dis 2014 Nov;20(11):

24 Standard dosing of infliximab is insufficient in the majority of pediatric CD Monte Carlo model REACH & ACCENT I 10 y.o. with CD Wt., alb, IMM,ATI Aim = trough > 3ug/ml Frymoyer et al, JPGN 2016;62:723

25 Proactive testing algorithm: Dose optimize to infliximab trough > 5 (-10) Patient in remission on maintenance IFX therapy ATI Positive ATI Negative High level ATI Low level ATI Change to different anti-tnf If failed multiple anti-tnfs change class Consider surgery Increase dose Add on IMM High IFX concentration* Therapeutic IFX concentration* Low IFX concentration* Reduce dose If at 5mg/kg, extend interval Continue IFX dose and interval Consider re-check in 6-12 months Undetectable level: increase dose to 7.5mg/kg and consider next dose at 4 or 6 weeks Low concentration: increase IFX by mg

26 Early infliximab trough concentrations correlate with short term mucosal healing in UC Papamicheal K et al. Clinc Gastroenterol Hepatol 2016Apr;14:543-9

27 Early IFX trough concentrations are associated with persistent remission in pediatric IBD patients Wk 14 IFX > 7 = PPV 100% of Persistent Remission Singh (Dubinsky) Inflamm Bowel Dis 2014

28 Proactive TDM (Optimized monotherapy with anti-tnf) Combination therapy with immunomodulator increases anti-tnf concentration and decreases anti-drug antibodies Combination therapy has been associated with increased adverse events (opportunistic infection and HSTCL) Optimized monotherapy with anti-tnf may be an alternative to combination therapy

29 Optimal drug concentrations (?) Infliximab Adalimumb Outcome Clinical remission Deeper remission Week 14 Clinical remission Deeper remission Week 4 Concentration >5 >8 >7 >5 >8 >7

30 Vedolizumab response and remission higher with higher trough concentrations Sandborn WJ et al. NEJM 2013

31 Issues with drug concentration monitoring Optimal trough concentration window Timing of testing Test that is accurate, accessible, and inexpensive Prospective data on implementation of TDM

32 In practice Know your test Drug tolerant assay? Cost (to patient)? Know what to do with your results BRIDGe If nothing else, test reactively Proactive testing likely best Check after induction Follow during maintenance

33 What to do with theresults? ANTI-TNF OPTIMIZER Found at: Accessible on all devices (smart phones, tablets and computers) Melmed et al, CGH 2016

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