Folie 1 - Amazon S3

Folie 1 - Amazon S3

Der Qualittsmanager Antifungal Dosing and Therapeutic Drug Monitoring Andrew J. Ullmann, MD, FIDSA Julius-Maximilians-Universitt Department of Internal Medicine II Division of Infectious Diseases Wrzburg, Germany [email protected] Disclosure of Potential Conflicts of Interest: 1. Employment or Leadership Position None 2. Advisory Role Basilea, Pfizer, MSD, Astellas, Gilead, Aicuris 3. Stock Ownership

None 4. Honoraria Astellas, Gilead, MSD, Astellas, and Pfizer 5. Financing of Scientific Research Astellas, Gilead, MSD, Astellas, Pfizer, and BioCryst 6. Expert Testimony None 7. Other Financial Relationships none TDM = therapeutic drug monitoring Important to adjust dosage for toxicity and/or Adjust dosage for efficacy

or just for academic purposes? Topics What do we know about TDM and Flucytosine Itraconazole ... and what about the newer ones? Voriconazole Posaconazole What is the story about the old antifungal agents? Reviewed in Smith et al. Ther Drug Monit 2008 Flucytosine: Pyrimidine analog Limited to combination therapy (e.g. AmB)

Oral absorption reliable Wide inter- and intrapatient PK variation Relatively rapid half-linfe: 3-6h Weight based dosing: 150mg/kg (divided in 4 doses) Target levels (mg/L): non-neonates (trough 3040, peak 7080); neonates (trough 2040, peak 5080) All levels >100 mg/L are considered potentially toxic What is the story about the old antifungal agents? Flucytosine: only 20.5% of flucytosine levels were in the expected therapeutic range Levels were low in 40.5% (i.e. trough <20 mg/L or peak <50 mg/L for neonates; trough <30 mg/L or peak <70 mg/L for non-neonates) High levels were observed in 38.9% (i.e. any trough level >40 mg/L or peak >80 mg/L), of which 9.9% were potentially toxic levels (.100 mg/L). Pasqualotto et al. AAC 2007

60.8% versus 37.3%; P < 0.001 What is the story about the old antifungal agents? Itraconazole: Broad spectrum antifungal triazole Three formulations (suspension, capsule, and iv) Suspension: w/o a meal (NPO) Capsule: with a meal, Dosage 200mg twice daily Reviewed in Smith et al. Ther Drug Monit 2008 Large variation in PK

Long half-life: 24h Mean conc. (oral) 741 ng/L In bioassay Coccidioidomycosis: 6.5 +4.2 mg/L w/ success, 4.0 +3.2 mg/L w/o response; Crypto: >1mg/L Animal data IA: 6.5mg/L vs 4.5mg/L Prophylaxis in N/F: >.25 - .5mg/L less infections ... and what about the younger kids on the block? Voriconazole Due to saturation of metabolism (MichaelisMenten kinetics) Greater than proportional increase in exposure with increasing

dose On average, 1.5-fold oral dose escalation from 200 mg q 12 h to 300 mg q 12 h will lead to a 2.5-fold increase in exposure Average Steady State Plasma Concentration (g/ml) Voriconazole Non-linear Pharmacokinetics 8 7 6 5 4

3 2 1 0 0 100 200 300 Twice Daily Dose (mg) 400 Voriconazole

Two formulations: oral and iv Oral bioavailability of 96% Volume of distribution of 4.6 L/kg Plasma protein binding 58% Voriconazole Factors Influencing Pharmacokinetic Variability CYP2C19 genotype Race Gender and age in adults

Children (2 - < 12 years) Body weight Hepatic impairment Renal impairment Concomitant medications Incidence of treatment failure and visual or auditory hallucinations below and above voriconazole concentration limits Dolton et al. AAC 2012 Retrospective multicenter study: N=201, 783 samples Comparison of recommended lower and upper target voriconazole concentration limits from voriconazole TDM studies Dolton et al. AAC 2012

Factors associated with a significant change in voriconazole concentration identified from multiple linear regression analysis Dolton et al. AAC 2012 Voriconazole Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Trifilioet al AAC 2009 Voriconazole Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Approx 40% had 6-1865% variation between initial and follow-up sample Trifilio et al AAC 2009

There is a lack of correlation if the initial level is <2 g/ml and significant correlation if the initial level is >2 g/ml. N=64, pair samples Voriconazole trough plasma concentrations and probabilities predicted by the logistic regression models for response of infection to therapy and grade 3 associated neurotoxicity N=55 505 samples Pascual et al. CID 2012 Population-based simulation: Probability of Achieving Different Voriconazole Trough Plasma Concentrations Targets With 200, 300, and 400 mg Twice-Daily Oral and Intravenous Dosing Regimens Pascual et al. CID 2012

The doses were adjusted (50% increase/decrease) in case of nonresponse of IFI and toxicity with trough plasma concentrations 1 and 5.5 mg/L, respectively Voriconazole Dose Adjustment Park et al. CID 2012 Adjusted 2448 hours after blood sampling based on the results of TDM. Target trough concentration range (1.05.5 mg/L) Determined to be the fourth day after the initiation of therapy Dosage increased by 100% if the trough level was <1.0 mg/L Dosage was lowered by 50% if the trough level was >5.5 mg/L and there was no drugrelated adverse event. Trough level was >10.0 mg/L or if an adverse event

was suspected in a patient with a level >5.5 mg/L, one dose was skipped and subsequent doses were reduced by 50% Initial or final voriconazole trough level solid circle or square denotes a severe adverse event Park et al. CID 2012 Randomized, assessor-blinded, controlled, single center trial, n=110 solid circle or square denotes a complete response x indicates treatment failure ...and there is another azole out there

Posaconazole Exposure After Single-Dose Administration AUC(I) (ngh/mL), thousands Courtney RD et al. Antimicrob Agents Chemother. 2003;47:2788-2795. 70 60 50 40 30 R2 = 0.99 (50800 mg) 20 10 0

0 200 Dose (mg) 400 600 800 1000 1200 Absorption With Solid Food 600 Courtney R et al. Br J Clin Pharmacol. 2004;57:218-222.

Posaconazole (ng/mL) 500 Fasted Nonfat meal High-fat meal 400 300 200 100 0 0 12 24

36 Time (h) 48 60 72 Dividing the Dose of Posaconazole Increases Absorption Fasted Healthy Volunteers Ezzet F et al. Clin Pharmacokinet. 2005;44:211-220. Posaconazole Plasma Concentration (ng/mL) 450

200 mg four times daily 400 mg twice daily 800 mg once daily 400 350 300 250 200 150 100 50 0 0 4 8

12 16 20 24 28 Time (h) 32 36 40 44 48 Mean posaconazole plasma concentration-time profile on

day 10 in patients receiving 400 mg b.i.d., 600 mg b.i.d., or 800 mg q.d. posaconazole oral suspension. Ullmann AJ et al. AAC 2006 Response Pharmacokinetic Walsh et al. CID 2007 Posaconazole Serum Levels and Clinical Outcomes Comparison of posaconazole and fluconazole / itraconazole as prophylaxis for IFI in patients with neutropenia1 Comparison of posaconazole and fluconazole as prophylaxis for IFI in

patients with GVHD *Cavg: 583 381 ng/ml *Cavg: 1,103 744 ng/ml MIC90 for most Aspergillus spp. is ~500ng/ml 1.Cornely et al. NEJM 2007;356:348-359 2. Ullmann et al. NEJM 2007;356:335-347 3. Jang et al. Clin Pharm & Ther 2010;88:115-119 4. Sabatelli et al. Antimicrob Agents Chemother 2006;50:2009-2015 Some data from the real world Predicted probability of breakthrough fungal infection

determined from logistic regression N=72, with >1 sample 17% developed breakthrough IFI median 289 mg/mL (range: 50 471 ng/mL) versus median 485 ng/mL (0 - 2035 ng/mL) Dolton et al AAC 2012 Posaconazole serum concentration - response relationship for patients receiving prophylaxis Jang HS et al. Clinical pharmacology & Therapeutics 2010 So i d

y h w h p o r dp x a l y Cornely OA; Ullmann AJ Clinical Pharmacology & Therapeutics 2011 i

? k r o w s Pharmacokinetics and Intracellular p u : C Concentrations I M C/ n i U

r A e h e l g i o h z d a d l e n r o

o f a p 0 acPosaconazole 0 s m 1 o o Voriconazole l c P a r n

e a r v b e s Plasma 2.08 g/ml 2.2 g/ml m e to m m u ll r e

e c s e to h t Alveolar cells 87.7 g/ml 14.4 g/ml *1 * 2 Posaconazole: 14 doses of 400mg (bd) over 8 days Voriconazole: IV loading dose of 6mg/kg bd on day 1; maintenance dose of 4mg/kg bd on day 2; single dose of 4mg/kg on day 3

Plasma Cmax of voriconazole is greater than for posaconazole BUT posaconazole concentrates highly inside alveolar cells 1. Conte et al, Antimicrob Agents Chemother 2008;53(2):703-707 2. Crandon et al. Antimicrob Agents Chemother 2009;53:5102-5107 Posaconazole TDM Issues Higher plasma concentration of posaconazole is associated with improved clinical response in patients with established invasive fungal disease Predictors of low plasma posaconazole exposure is well established TDM in prophylaxis seems to be different due to higher exposure posaconazole in host cell members. TDM at day +3 may predict steady-state concentrations Adjusting dosage above a cumulative daily dose of 800mg

does not provide higher exposure => making TDM a challenge Summary Agent 5-FC Assay HPLC/BIO/ Enz Itraconazole HPLC/Bio Voriconazole HPLC/Bio Reviewed in Smith et al. Ther Drug Monit 2008 Posaconazole HPLC/Bio AmB HPLC/Bio

Echinocandins HPLC/Bio Fluconazole HPLC/Bio Concentration outcome Toxicity Efficacy PK Variability Yes Yes Yes (renal) Yes No Yes (absorption) Yes Yes Yes (metabolism) Yes

No Yes (absorption) No No No Yes(animal) Yes Yes (animal) No No No ww w. TIM

rg M2 01 3.o Save the date! 11-14 October 2013

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