High-dose rifampin: potential for treatment shortening

Transcription

1 High-dose rifampin: potential for treatment shortening Martin Boeree, MD, PhD Associate Professor Radboud University Nijmegen Medical Centre Rob Aarnoutse, Georgette Plemper van Balen, Andreas Diacon, Rod Dawson San Francisco, September 8th, 2012

2 1959 rifampicin (US rifampin) was discovered; a hydrazone of rifamycine B; in 1967 orally available, FDA registration 1971

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4 Reasons dosage RIF 600 mg Pharmacokinetic reasons Toxicity reasons Cost

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6 Higher dose rifampicin (13 mg/kg) in Indonesia rifampicin plasma concentration (mg/l) standard dose group (rifampicin 10 mg/kg) high dose group (rifampicin 13 mg/kg) Ruslami et al. Antimicrob Agents Chemother time after dose (h)

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8 What is the right dosage of rifampin?

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10 The trial plan All trials will be performed at registration standard, GCP/GCLP compliant 1) Maximum Tolerated Dose (MTD) study (Cape Town and Stellenbosch) 2) Phase II trial 3 x 50 in Moshi and Bagamoyo, Tanzania; 10 mg/kg (600), 15 mg/kg (900), 20 mg/kg (1200) 3) Higher dosages in phase II according to the MAMS design in 7 sites in Tanzania and RSA

11 MTD study in mice (De Steenwinkel et. al.) MTD in mice was 160 mg/kg

12 HR1 study Title Design A Phase IIA Dose Ranging Trial to Evaluate the Safety, Tolerability, Extended Early Bactericidal Activity and Pharmacokinetics of Higher Doses of Rifampicin in Adult Subjects with Newly Diagnosed, Uncomplicated, Smear- Positive, Pulmonary Tuberculosis. Phase IIA, multiple dose rising study Treatment pre-treatment period 7 days monotherapy RIF 7 days combination (+HZE) therapy Control group 10 mg RIF/kg (n=8) Study groups 20, 25, 30 up to 35 mg RIF/kg (n=15, per RIF dose) Parameters Safety and tolerability (biochemistry, haematology, AEs) Pharmacokinetics (PK) EBA # Patients 68 Question What is the highest tolerated dose?

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14 Grading according to CTCAE version 4.0

15 Arm Total Grade 1 AE Grade 2 AE Grade 3 AE Grade 4 AE Grade 5 AE Control mg RIF/kg mg RIF/kg mg RIF/kg mg RIF/kg

16 Grade 1 Adverse Events Arm Total Unrelated Possibly related Related Control mg RIF/kg mg RIF/kg mg RIF/kg mg RIF/kg

17 Grade 2 Adverse Events Arm Total Unrelated Possibly related Related Control mg RIF/kg mg RIF/kg mg RIF/kg mg RIF/kg

18 Grade 3 Adverse Events Arm Total Unrelated Possibly related Related Control mg RIF/kg mg RIF/kg mg RIF/kg mg RIF/kg

19 Pharmacokinetics Intensive PK sampling at day 7 (rifampicin) and at day 14 (RHZE) Intake of drugs with a standardized light breakfast sampling at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours measurement of total plasma concentrations with validated HPLC methods calculation of PK parameters using non-compartmental analysis

20 Results PK of rifampicin at day 14 Group AUC 0-24 (h* mg/l) Geometric mean Min - max 10 mg/kg (control) mg/kg mg/kg mg/kg Group Cmax (mg/l), normal range circa 8-12 mg/l Geometric mean Min - max 10 mg/kg (control) mg/kg mg/kg mg/kg

21 No ceiling in AUC/C max upon repeated dose increases Disproportional increase in AUC and C max (nonlinear PK): more than 7-fold increase in average AUC from 10 to 30 mg/kg Interindividual variability in PK: be aware of higher exposure in individual patients

22 Results PK of rifampicin at day AUC 0-24 (mg*h/l) Cmax (mg/l) AUC 0-24 (mg*h/l) C max (mg/l) Dose in mg/kg 0 Exposure at day 7 may be higher in view of auto-induction of rifampicin

23 Preliminary results TTP n Median baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 control arm 8 0,0 0,0 0,0 7,6 5,8 7,6 5,8 8,1 20 mg RIF/arm 15 0,0 5,6 6,4 7,5 7,5 8,6 9,0 8,2 25 mg RIF/arm 15 0,0 5,2 5,8 7,3 7,2 8,0 7,9 8,5 30 mg RIF/arm 15 0,0 5,6 7,1 7,8 9,0 9,1 9,3 10,1 35 mg RIF/arm (n=14) 14 3,8 5,2 6,2 7,0 8,1 8,2 9,0 9,5

24 HR2 Moshi and Bagamoyo, Tanzania, study design

25 HR2 End of enrolment June 2012, end of follow-up december 2012, expected results march 2013

26 MAMS Multiple arm, multiple stage design Several combinations in phase II Several interim analyses Poor arms discontinue, better arms continue Phase III selection design

27 Start Recruitment of 1 st Interim Analysis 2 nd Interim Analysis End of Recruitment Control Regimen Novel regimen 1 Stop Novel regimen 2 Novel regimen 3 Stop Novel regimen 4 Stop Stage 1 Stage 2 Stage 3

28 MAMS in PanACEA Control: HRZE isoniazid (H), rifampicin Std (R), pyrazinamide (Z), ethambutol (E) (anticipated start Jan 2013) Experimental Arm 1: HRZQ isoniazid (H), rifampicin 10 mg (R), pyrazinamide (Z), SQ mg(Q) Experimental Arm 2: HR 20 ZQ isoniazid (H), rifampicin 20 mg (R 20 ), pyrazinamide (Z), SQ mg (Q) Experimental Arm 3: HR 20 ZM isoniazid (H), rifampicin 20 mg (R 20 ), pyrazinamide (Z), moxifloxacin (M) Experimental Arm 4: HR 35 ZE isoniazid (H), rifampicin 35 mg (R 35 ), pyrazinamide (Z), ethambutol (E)

29 Acknowledgements All PanACEA site collaborators Rob Aarnoutse, Georgette Plemper van Balen, Marloes Weijers, Jakko van Ingen, Dick van Soolingen, Melanie Wattenberg, Johan Mouton, RUNMC Andreas Diacon, Jeanine Du Bois, Armour Venter, University of Stellenbosch, RSA Rod Dawson, Kim Narunsky, UCT, Cape Town, RSA Patrick Phillips, Andrew Nunn, MRC, London, UK Stephen Gillespie, St Andrews, UK Michael Hoelscher, LMU, Munich, Germany Gibson Kibiki, Hadija Semvua, Charles Mthabo, KCRI, Moshi, Tanzania Cecil Magis, Wouter Hoefsloot, Dekkerswald and RUNMC

30 Thank you