Effects of Moxifloxacin PK-PD and drug interactions on its use in the Treatment of Tuberculosis(TB) Session: Fanning the Flames of HIV and TB Cointeraction SA AIDS Conference-Durban ICC 13-15 June 2017 Anushka Naidoo CAPRISA is the UNAIDS Collaborating Centre for HIV Research and Policy CAPRISA hosts a DST- NRF Centre of Excellence in HIV Prevention CAPRISA hosts a MRC HIV-TB Pathogenesis and Treatment Research Unit
TB incidence rates/ HIV prevalence in new and relapse TB cases in 2015 >300 cases per 100000 population >50% HIV prevalence in new TB cases
Globally Background ~ 10.4 million cases of tuberculosis in 2015 ~ 1.1 million of whom were co-infected with HIV The African Region had 26% of the world s tuberculosis cases in 2015. South Africa is one of the highest tuberculosis-hiv burden countries in the world Early detection, diagnosis and effective treatment of tuberculosis is critical
Role of Moxifloxacin in treatment of TB Moxifloxacin~8-methoxy fluoroquinolone with potent activity against MTB Recommended by the World Health Organisation for treatment of MDR-TB May be used in drug susceptible TB when toxicity develops to first line drugs or for INH mono-resistance Investigated in several clinical trials to determine ability to shorten the duration of TB treatment for both drugsusceptible and MDR-TB Current evidence does not support the use of moxifloxacin in treatment shortening drug regimens in drug susceptible tuberculosis
STREAM MDR TB TRIAL- Stage 1-Moxifloxacin, clofazimine, ethambutol and pyrazinamide, + kanamycin, isoniazid and prothionamide
Conclusions The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, non-inferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. Gillespie et al 2014 CONCLUSIONS The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not non-inferior to the control regimen. Jindani et al 2014
Reasons for failure? Mouse model of TB and MTB cultured in the laboratory does not fully represent the human model of infection? Eight week sputum culture conversion endpoint used in earlier studies is not as predictive of relapse as was thought previously? Moxifloxacin distribution in caseum? Reinfection vs Relapse? Is the 400mg Dose of Moxifloxacin Adequate in all patients? Other?
? Is a 400mg daily dose of Moxifloxacin adequate in all patients Rifampicin may decrease Moxifloxacin AUC by 30% Including drug exposure as a covariate in ReMOX analysis may have contributed to explaining unfavourable outcome Limited data show 800mg dose may be safe Alffenaar et al NEJM 2015 Feb
Rifampicin/Moxifloxacin interaction Moxifloxacin is metabolized by UDPglucuronosyltransferase (UGT) and sulphotransferase and is a substrate of the drug transporter P-glycoprotein Several studies found that rifampicin co-administration decreased moxifloxacin plasma concentrations by up to 31%, due to rifampicin induction of UGT and P- glycoprotein.
Rifampicin Moxifloxacin by 27-30% in healthy individuals in India and USA and TB patients in Indonesia,
Knowledge gaps Lack of data on the effect of rifampicin co-administration on moxifloxacin pharmacokinetics in African patients with tuberculosis. Impact of HIV co-infection and ART co-treatment on moxifloxacin pharmacokinetics in high HIV burden settings. Clinically validated targets of moxifloxacin efficacy for treatment of tuberculosis
Improving Retreatment Success- IMPRESS IMPRESS RCT designed to determine if a moxifloxacin-containing regimen, substituting moxifloxacin for ethambutol, of 24 weeks duration is superior to a standard control regimen of 24 weeks duration in improving recurrent tuberculosis treatment outcomes. We conducted a pharmacokinetic sub-study within the IMPRESS trial conducted at CAPRISA
Objective We compared the pharmacokinetics of moxifloxacin in the presence of rifampicin co-treatment or when dosed alone in African patients, with drug susceptible, recurrent tuberculosis, the majority of whom were HIV co-infected and on efavirenz-based antiretroviral therapy (ART)
Naidoo et al 2017
Results Fifty-eight patients studied; 41(70.7%) were male, 42(72.4%) HIV co-infected and 40(95%) on efavirenz-based ART. Oral clearance (CL/F) with rifampicin-based TB treatment was 24.3 L/h for a typical patient and AUC of 16.5 h mg/l. In keeping with previous studies 29% increase in moxifloxacin intrinsic clearance was observed during rifampicin based tuberculosis treatment. Unexpectedly, in HIV co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4% resulting in a 30% reduction in moxifloxacin AUC both during TB treatment with rifampicin or after
Scenario Steady-State Moxifloxacin on RIF-based TB treatment NO EFV Steady-State Moxifloxacin on RIF-based TB treatment + EFV Intrinsic CL (L/h) Hepatic Extraction (E H ) (%) 48.5 33% Pre-hepatic bioavailabilit y (F pre-h ) (%) 100% - Reference Oral CL (CL/F) (L/h) Change in CL/F (%) AUC (h mg/l) b 24.3 REFERENCE 16.5 69.1 41% 100% 34.5 +42.4% 11.6 Single Dose Moxifloxacin without RIF-based TB treatment 34.4 26% 77% 22.4-7.8% 17.9 NO EFV a Single Dose Moxifloxacin without RIF-based TB treatment 49.0 33% 77% 31.8 +31.3% 12.6 + EFV a
Clinical relevance? Moxifloxacin exhibits dose dependent activity- factors affecting in drug exposure are likely to impact clinical efficacy AUC:MIC ratio shown to be a predictor of moxifloxacin clinical efficacy Although the moxifloxacin/efavirenz interaction needs validation in other studies, it is concerning, given the high HIV-TB co-infection rates in many TB endemic settings where the ART backbone remains efavirenz. The effects of efavirenz may have direct implications for studies evaluating novel drug regimens containing moxifloxacin and for current national and international guidelines that advocate moxifloxacin use in treatment regimens for both drug-susceptible and drug resistant tuberculosis.
Future studies Clinically validated targets for treatment efficacy need to be defined for moxifloxacin and other TB drugs New clinical trials in TB treatment should include PK-PD studies to determine effect of drug exposure (such as AUC:MIC ratio) on treatment outcomes New technologies such as use of dry blood spots to measure drug concentrations and sensititre plates for MIC testing may make these studies more feasible in RLS
Acknowledgements The IMPRESS trial was funded by the European & Developing Countries Clinical Trials Partnership (EDCTP) (TA.2011.40200.044) South African Medical Research Council CAPRISA HIV-TB Pathogenesis and Treatment Research Unit South African Medical Research Council Self-Initiated Research Grant CAPRISA was established as part of the Comprehensive International Program of Research on AIDS (CIPRA) of the National Institutes of Health (NIH) (grant# AI51794) Co-investigators/Collaborators: Nesri Padayatachi, Paolo Denti, Maxwell Chirhewa, Helen McIlleron, Kogieleum Naidoo, Sabiha Essack, Nonhlanhla Yende-Zuma, Eddy K. Phongi, John Adamson, Katya Govender The IMPRESS Study Participants CAPRISA is the UNAIDS Collaborating Centre for HIV Research and Policy CAPRISA hosts a DST- NRF Centre of Excellence in HIV Prevention CAPRISA hosts a MRC HIV-TB Pathogenesis and Treatment Research Unit CAPRISA Partner Institutions:
(a) MALDI mass spectrometry imaging of small molecules in TB-infected lung tissue. The relative ion abundance of specific analytes in regions of interest delineated on the basis of histology staining can be measured to provide semiquantitative data. (b) Ion maps of PZA and MXF in representative (selected from more than 200 lesions) lung lesions sampled throughout the dosing interval; signal intensity is fixed for each drug. Hematoxylin and eosin (H&E) staining of adjacent sections is also shown (bottom). Outlines highlight the necrotic center of each lesion. Scale bars, 5 mm.(c) Left, diffusion of MXF in caseum as a function of caseum cellularity. **P < 0.05, two-tailed unpaired t-test. Error bars, mean ± s.d. (n = 3). Right, a typical H&E example representative of each cellularity score. Prideaux et al 2015