Anti-fungal therapeutic drug monitoring and azole dose modification Tim Felton

Contents Triazoles – an overview Therapeutic drug monitoring (TDM) Specific drugs

Triazoles Bind cytochrome P450-enzyme lanosterol 14- demethylase Inhibits the conversion of lanosterol to ergosterol Fluconazole Itraconazole Voriconazole Posaconazole (Isavuconazole) membrane

Emergence of resistance Therapeutic window

Exposure Peak Concentration AUC MIC Time>threshold

Indications for TDM Variable pharmacokinetics

PK-PD: the black arts Survival Resolution of clinical syndrome DOSE OUTCOME OF CLINICAL INTEREST/IMPORTANCE BIOMARKER Quantifiable Linked to pathogenesis Linked to an outcome of clinical interest Survival Resolution of clinical syndrome Conc Dose PHARMACOKINETICS PHARMACODYNAMICS

Pharmacokinetic variability Voriconazole Concentration (mg/L) Toxic 20 patients given IV voriconazole 4mg/kg Sub-therapeutic Time (hours)

Pharmacokinetic variability Monte Carlo simulations from the population pharmacokinetic model for oral (A) and i.v. (B) therapy. Intravenous (i.v.) therapy results in higher measures of drug exposure compared with oral therapy. Hope WW. AAC. 2012. In press

Pharmacokinetic variability FIGURE 1 . A Monte Carlo simulation from the population pharmacokinetic model of AbuTarif 17 showing the median along with the 5th and 95th percentiles for concentration-time profiles of 5000 simulated patients throughout the first week of therapy for patients receiving posaconazole 200 mg every 8 hours. A 2-compartment model with the following parameters was used: Ka 0.0396 h-1, elimination rate constant 0.0198 h-1 (between-subject variability 0.221), and V/F 3290 L (between-subject variability 0.156). The simulations were performed using the pharmacokinetic program ADAPT 5. Howard S. TDM. 2012. 34:72-76

Pharmacokinetic variability Absorption Vomiting Diet Genetic differences in drug-transport/gut-metabolism Concomitant medications Distribution Amount of body fat Presence of extravascular fluid collections Hypoalbuminaemia Metabolism Hepatic dysfunction Genetic differences in drug-metabolism Concomitant medications Excretion Renal insufficiency Genetic differences in drug-elimination pathways Genetic variabilty P-glycoprotein Concomitant medications - PPI

Pharmacogenomics CYP2C19 status makes a big difference to voriconazole levels, but only accounts for a small portion of observed variance

Absorption Suspension (fasted) Suspension (non-fat meal) Suspension (high-fat meal) Postprandial posaconazole exposure was greater when administered as a suspension than as a tablet formulation. Compared with the tablet formulation, the oral suspension increased mean posaconazole AUC (0,72 h) by 37% (p = 0.001) and Cmax values by 23% (p = 0.004). All but two of the 20 subjects had increased systemic exposure to posaconazole with the suspension vs the tablet formulation. [Courtney p220] Mean AUC(0.72 h) and Cmax values of posaconazole suspension were four-fold greater when administered with a high-fat meal than when administered while fasted (p < 0.001). Administration of posaconazole suspension with a non-fat meal also enhanced exposure, with mean AUC(0,72 h) and Cmax values 2.6-fold and three-fold greater than the fasted state, respectively (both P < 0.001). [Courtney p220]   Courtney R et al. Br J Clin Pharmacol 2004;57(2):218–222. Time (hours) Courtney R . Br J Clin Pharmacol 2004:218–222. 13

Saturation of metabolism 6 mg/kg i.v 2 dosages 4 mg/kg b.d. i.v 200 mg bd oral And, the PK are nonlinear

Saturation of metabolism Dosage escalation from 200 mg bd to 300 mg bd

Indications for TDM Variable pharmacokinetics Clinically relevant exposure–response relationships

Exposure-response relationship Rabbit Neonatal HCME with anidulafungin Warn PA. AAC. 2012. In press

Indications for TDM Variable pharmacokinetics Clinically relevant exposure–response relationships

Experimental IPA in rabbits Berenguar et al, AAC 1994;38:1303-8

Exposure-trough conc. Relationship between the AUC0-12 and the trough concentration at the end of the first week of voriconazole for 43 patients receiving voriconazole (6 mg/kg i.v. for 2 doses followed by 4 mg/kg i.v.). The values are highly positively correlated (Spearman coefficient, 0.977; 43 observations; P < 0.01). Only 7/43 patients had trough concentrations of <1 mg/liter. Hope WW AAC. 2012. 56:526-31.

In-vitro alveolus model of IPA Jeans. A. JID. 2012. In press

Clinical IPA 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability effect Effect 1 2 3 4 5 6 7 8 9 10 Voriconazole trough concentrations (mg/L) 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A Pascual et al. CID. 2008. 46:201-11

Indications for TDM Variable pharmacokinetics Clinically relevant exposure–response relationships Clinically relevant exposure–toxicity relationships

Concentration-toxicity —Predicted probability of an adverse event vs. concentrations of itraconazole, from the logistic regression model. Data are mean values (95% confidence intervals) for the study population within 5 quintiles (determined by plasma itraconazole concentration level). The highest quintile includes values ⩾25.6 mg/L. The solid line represents a logistic regression model fitted to the measurements from each patient. The parameters for logistic regression are as follows: intercept, −0.111; coefficient, 0.151; odds ratio, 1.163 (95% confidence interval, 1.114-1.213; P<.001 Lestner J M. CID. 2009. 49:928-930

Clinical IPA 1 2 3 4 5 6 7 8 9 10 Voriconazole trough concentrations (mg/L) 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability effect or toxicity Effect Toxicity 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A Pascual et al. CID. 2008. 46:201-11

Indications for TDM Variable pharmacokinetics Clinically relevant exposure–response relationships Clinically relevant exposure–toxicity relationships Narrow therapeutic window

Clinical IPA Therapeutic window 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 Voriconazole trough concentrations (mg/L) 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability effect or toxicity Effect Toxicity 181 measurements with high-pressure liquid chromatography were performed during 2388 treatment days in 52 patients. A Pascual et al. CID. 2008. 46:201-11

Indications for TDM Variable pharmacokinetics Clinically relevant exposure–response relationships Clinically relevant exposure–toxicity relationships Narrow therapeutic window Unable to rapidly assess response Serious/poor prognostic disease Drug–drug interactions Compliance Dosage adjustment PD of hyper/hypotension

Specific dugs Fluconazole Itraconazole Voriconazole Posaconazole Indication Pharmacology/pharmacokinetics Exposure–response relationship Exposure–toxicity relationship TDM target membrane

Fluconazole Indication Pharmacology/pharmacokinetics Prophylaxis Empirical therapy Treatment of superficial and invasive candidiasis Pharmacology/pharmacokinetics Linear PK High bioavailability Exposure–response relationship Well defined Patients with mucosal candidiasis Rodríguez-Tudela J L. AAC. 2007. 51:3599-3604

Fluconazole Exposure–toxicity relationship TDM target High LFTs, nausea, vomiting, seizures at high dosages TDM target Wide therapeutic index Treatment of isolates with reduced susceptibility Poor absorption Paediatric patients

Itraconazole Indication Prophylaxis of IFI Treatment of IPA Treatment of CPA Treatment of ABPA Hydroxyitraconazole produced in a 1:1 ratio

Itraconazole Pharmacology/pharmacokinetics Highly lipophilic and protein bound  capsule solubility in acidic environment Different manufactures' capsules behave differently  absorption with PPI and H2-antagonists Suspension (cyclodextrin) 20-50% higher bioavailability Non-linear (probably) Extensive variability Active metabolite (OH-itraconazole) (bioassay/HPLC) CYP3A4 Poorly soluble Hydroxyitraconazole produced in a 1:1 ratio

Itraconazole Exposure–response relationship Peak itraconazole levels and successful outcome of mucosal candidiasis in patients with AIDS In vivo data Exposure–toxicity relationship Gastrointestinal intolerance, hypokalaemia, fatigue, ankle oedema, cardiac failure and deranged LFTs Nausea more common with suspension (cyclodextrin)

Itraconazole TDM target 200mg b.i.d. Trough concentration Lower level Prophylaxis in neutropenia & treatment of oesophageal candidasis in HIV 0.5mg/L HPLC or 5mg/L bioassay Upper level 17mg/L (bioassay)due to high probability of toxicity

Itraconazole Tips to improve low levels Usually poor absorption Capsule with food or acid drink? Stop PPI or H2-antagonist (if possible) Compliance Consistently prescribe the same preparation Check for drug interactions Increase to capsule 300mg twice daily or change to suspension 200mg twice daily Check serum levels again! (enzyme inducers - rifampicin, phenytoin, carbamazepine)

Itraconazole Tips to reduce high levels +/- toxicity Usually saturated clearance Stop drug for 1-2 weeks Re-start at a lower dose Check serum levels again!

Voriconazole Indication Pharmacology/pharmacokinetics Disseminated candidasis IPA and CPA Pharmacology/pharmacokinetics Excellent bioavailabilty (96%) IV preparation – cyclodextrin (potentially nephrotoxic) Marked PK variability (100-fold) Sex, age and CYP2C19 genotype only partially explain Weight important in paediatric patients CYP2C19, 3A4 and 2C9 substrate (polymorphisms present in  4% whites,  20% Asian patients) High levels in poor hepatic function, critical ill- ness, poor metabolizer CYP2C19 genotype and the elderly. Herbrecht R. NEJM. 2002. 347:408-15

Voriconazole Exposure–response relationship In-vivo, in-vitro and clinical data Exposure–toxicity relationship Gradual increase in probability with increasing concentration Abnormal LFTs, visual disturbance, photosensitivity, confusion etc Pascual et al. CID. 2008:46;201-11

Voriconazole TDM target 200mg b.i.d. (i.v. loading dose) Trough concentration Lower level Trough 1mg/L associated with 70% probability of success Upper level Less well established >6mg/L associated with high probability of CNS toxicity and hepatitis

Voriconazole Tips on use Tips to improve low levels Loading dose Switch IV to oral Tips to improve low levels Dosage escalation carefully by 50mg daily Check levels every 1-2/52 Tips to reduce high levels +/- toxicity Stop for 1 week or by TDM then reduce dosage Stop omeprazole Check levels

Posaconazole Indication Pharmacology/pharmacokinetics Salvage therapy IPA Prophylaxis neutropenia and HSCT Pharmacology/pharmacokinetics Only oral suspension Linear PK to 800mg/day Absorption saturated above 800mg/day Better absorption with fatty food and low stomach pH Long t½ with comparable average and trough levels Variability 1 week to reach steady state Felton TW. CID. 2010;51:1383-1391

Posaconazole Exposure–response relationship In-vivo (mouse IC and rabbit IPA) Increased clinical response with increasing average and trough concentration Exposure–toxicity relationship GI intolerance, abnormal LFT No dose dependent Walsh T. CID. 2007. 44. 2-12

Posaconazole TDM target 400mg b.i.d Trough concentration (but long t½ life) Lower level >0.7mg/L Higher might be better if formulation/cost allowed! Upper level Not known/defined

Posaconazole Tips to improve low levels Fatty foods, milk or fatty food supplements Stop enzyme inducers Stop PPIs Can try fractionating the regimen Dosage escalation unhelpful above 800mg/day Serum level changes are unpredictable Rifampacin, carbamazepine, phenytonin etc

Indications for TDM Variable pharmacokinetics Clinically relevant exposure–response relationships Clinically relevant exposure–toxicity relationships Narrow therapeutic window Unable to rapidly assess response Serious/poor prognostic disease Drug–drug interactions Compliance Dosage adjustment PD of hyper/hypotension

Emergence of resistance Therapeutic window

Conclusions TDM required for itraconazole and voriconazole Probably for posaconazole TDM should Improve outcomes Reduce emergence of resistance BUT there is an associated cost (especially in more severe disease with less therapeutic options

Fungal infection and allergy Invasive fungal infection High mortality and morbidy Chronic fungal infection Fungal allergy High morbidy Could do 2 slides with graphs

Fungal infection and allergy Triazole are the most commonly used treatment Increasing levels of triazole resistance Could do 2 slides with graphs

Saturation of metabolism Voriconazole i.v. switching to 300 mg po bd

Saturation of metabolism Voriconazole i.v. switching to 400 mg po bd