Pharmacokinetics and safety of Moxifloxacin: Preliminary results of a dose escalation study

Transcription

1 Pharmacokinetics and safety of Moxifloxacin: Preliminary results of a dose escalation study A.D. Pranger 1, W.C.M. de Lange 2, R. van Altena 2, P. van der Harst 3, M.P. van den Berg 3, D.R.A. Uges 1, J.G.W. Kosterink 1, T.S. van der Werf 4, J.W.C. Alffenaar 1 University of Groningen,, Groningen, The Netherlands. 1. Dept of Hospital and Clinical Pharmacy. 2. Tuberculosis Center Beatrixoord, Haren, The Netherlands. 3. Dept of Cardiology 4. Dept. of Internal Medicine and Pulmonary Disease and Tuberculosis

2 Moxifloxacin (MFX) High in vivo and in vitro activity MIC mg/l mg once daily, not FDA approved Practicing clinicians cornerstone MDR- and XDR-TB 1-3 Intolerance to first-line anti-tb agents 1 Future first line cornerstone Shorten first line TB treatment 4-7 Reduction of time to culture conversion compared with INH van den Boogaard; AAC 2009, 2 Poissy; AAC 2010, 3 Pranger; CPD 2011; 4 Conde; Lancet 2009, 5 Dorman; AJRCCM 2009, 6 Rustomjee; IJTLD 2008, 7 Burman; AJRCCM 2006, 8 Nuermberger; AJRCCM 2004, 9 Nuermberger; AJRCCM 2004

3 PK / PD of MFX Too low MFX exposure Patients at risk (rifampicin; MIC 0.25 mg/l) fold PK variability 4 Advice: measurement of plasma concentration PK/PD: AUC/MIC > 100, fauc/mic > AUC/MPC, dose > mg once daily 3 optimal kill suppression of resistance 1 Nijland; CID 2007, 2 Drusano; MBio 2010, 3 Gumbo; JID 2004, 4 Pranger; ERJ 2011, 5 Shandil; AAC 2007, 6 Wright; JAC 2000, 7 Peloquin; AAC 2008, 8 Nuermberger; EJCMID 2004

4 Adverse events: Safety of MFX Vomiting and diarrhoea 1 Aggrevation of QT prolongation 2-3 Healthy volunteers: ± 24 ms (placebo); 394 ± 33 ms (400); 396 ± 28 ms (800) Mean max. increase 4.5% ± 3.8% TB patients: lower MFX exposure 2,4 Standard dose (400 mg ) well tolerated 4-8 Limited safety data of switching to high dose (600; 800 mg) 4, Bal; CT 2004, 2 Demolis; CPT 2000, 3 Sherazi; CJ 2008, 4 Pranger; ERJ 2011, 5 Valerio; JC 2003, 6 Codecasa; RM 2006, 7 Conde; Lancet 2009, 8 Rustomjee; IJTLD 2008, 9 Alffenaar; CID 2009, 10 Noel; CPT 2003

5 Study design Design Prospective clinical trial Approved by local ethical committee Primairy objective To compare a standard (400 mg) with an escalated dose (600 mg; 800 mg) of MFX PK / PD parameters safety / tolerability

6 Design: assessment & inclusion Inclusion TB patients Starting 400 mg MFX as part of TB care Informed consent Exclusion Baseline QT c interval > 450 msec (Holter) Cardiac risk factors Abnormal elektrolyts History of adverse events to fluoroquinolones HIV infection RIF treatment during last 3 weeks (wash-out)

7 Design: dose steps Inclusion & assessment End of study 7 th, 14 th, 21 th day: AUC 0-24h, Holter ECG T=0, 2, 3, 4 and 8 MFX 400 mg MFX 600 mg MFX 800 mg ECG & vital signs (once daily), lab (thrice weekly), SAE monitoring Day 22

8 Design: evaluation & clinical decision Evaluation of safety before dose-escalation AUC value 60 (400mg); 70 (600 mg) mg*h/l QT c prolongation (Holter) QT c interval: < 500 msec, <10% increase Vital signs Cardiac repolarisation (12-lead ECG) Laboratory test (clinical chemistry, urinalysis) SAE with clear-time relationship to MFX Personalized dose for clinical practice AUC/MIC and safety

9 Tuberculosis Results: patients 3/4 patients extra pulmonary, 1 patient pulmonary TB Resistance pattern: all MDR-TB Characteristics Median age: 23 (range, 19 30) years Median BMI: 23 (range, 18 28) kg/m 2

10 Results: safety No serious clinical AEs Diarrhoea, vomiting, renal or hepatic injury 2 CTC No abnormalities on Holter registration ie. QT c > 500 msec, > 10% increase compared to baseline Vital signs, ECG monitoring, laboratory tests undeviating

11 Results: PK / PD 400 mg 600 mg 800 mg Pt MIC AUC ratio AUC ratio AUC ratio * * * * Disproportional AUC increase

12 Discussion: optimal dose? AUC / MIC > 100, fauc / MIC > 60, safe 3/4 patients: 400 mg once daily 1 patient, MIC = 1 mg/l: > 800 mg once daily? AUC / MIC target -> optimal individualized dose? Multiple drug treatment 1 PO -> IV 1 Balasubramanian et al; AAC 2012

13 Conclusions High dose MFX (600 mg; 800 mg) seems to be a safe option in patients at risk for inadequate exposure TDM is recommended to prevent too low MFX exposure More patient data should be collected to underline these statements