Linking rifampicin exposure to treatment response over 6 months in patients with pulmonary tuberculosis
Elin M Svensson (1,2), Robin Svensson (2), Lindsey te Brake (2), Martin Boeree (1), Norbert Heinrich (3), Gavin Churchyard (4), Rodney Dawson (5), Andreas H Diacon (6) , Gibson S Kibiki (7), Lilian T Minja (8), Nyanda E Ntingiya (9), Ian Sanne (10), Stephen H Gillespie (11), Michael Hoelscher (6), Patrick PJ Phillips (12), Ulrika Simonsson (2), Rob Aarnoutse (1)
(1) Radboud University Medical Center, Nijmegen, The Netherlands (2) Uppsala University, Uppsala, Sweden (3) Medical Centre of the University of Munich, Munich, Germany (4) The Aurum Institute, Johannesburg, South Africa (5) University of Cape Town, Cape Town, South Africa (6) University of Stellenbosch, Cape Town, South Africa (7) Kilimanjaro Clinical Research Institute, Moshi, Tanzania (8) Ifakara Health Institute, Bagamoyo, Tanzania (9) NIMR-Mbeya Medical Research Centre, Mbeya, Tanzania (10) University of the Witswatersrand, Johannesburg, South Africa (11) University of St Andrews, St Andrews, United Kingdom (12) MRC Clinical Trials Unit, University College of London, London, United Kingdom
Objectives: Rifampicin (RIF) is the most important component of first-line anti-tuberculosis (TB) therapy, but the optimal dosing of this pivotal drug is uncertain. The potential for TB treatment shortening with higher doses of RIF has been studied recently[1]. Our aim was to characterize the relationship between RIF plasma exposure and treatment response measured over 6 months as time to stable culture conversion (TSCC, i.e. 2 sequential negative cultures) in this trial.
Methods: The trial included 4 experimental arms with 4 months of treatment and one control arm with standard 6 months of treatment using RIF 10 mg/kg combined with standard TB drugs. The experimental arms used RIF 20 or 35 mg/kg, and/or substitution of ethambutol with moxifloxacin or SQ109. Response was monitored with liquid cultures from sequential sputum samples and TSCC was derived. The dataset included 336 patients (97 with full plasma PK curves, day 28). A sequential PK-PD analysis using multiple imputation (MI) methodology for patients lacking PK data was performed in NONMEM 7.3 [2]. Parameter values from the MI procedure were averaged to final estimates.
Results: RIF PK was described with a simplified version of a previously presented model [3]. The model’s prediction of AUC was evaluated [4] and found adequate (median observed values within predicted 95%CI for each dose group). TSCC was modeled with a time-to-event model; a three-parameter surge function defined the hazard. In the MI procedure 100 sets of AUCs were simulated for each patient missing PK observations, and each tested in the PD model. A linear effect of RIF AUC was significant (α=0.05) in 99/100 cases, and a (sigmoid) Emax-model did not improve the fit. Lower bacterial load at baseline, lower proportion of missing sputum samples and substitution with moxifloxacin were found to significantly shorten TSCC, while substitution with SQ109 increased TSCC. Simulations assuming standard regimen components, median baseline bacterial load and no missing sputum samples showed that the proportion of patients with TSCC<8 weeks is expected to increase from 39% to 54% when RIF dose is increased from 10 to 35 mg/kg.
Conclusions: Higher RIF exposure generally leads to faster treatment response. No target exposure indicating maximal effect could be derived, probably due to limited range of exposures. RIF doses of 35 mg/kg, and higher if safe and tolerable, should be further studied for its potential to shorten TB treatment duration.
References:
[1] M Boeree et al, Lancet infectious diseases, 2016, High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomized controlled trial
[2] Å Johansson et al, The AAPS Journal, 2013, Multiple Imputation of Missing Covariates in NONMEM and Evaluation of the Method’s Sensitivity to η-Shrinkage
[3] R Svensson et al, PAGE 2016, Population pharmacokinetic modeling to assess the non-linear increase in exposure following increasing doses of rifampicin
[4] C Acharya et al, Computer Methods and Programs in Biomedicine, 2016, A diagnostic tool for population models using non-compartmental analysis: The ncappc package for R
