Elin M Svensson (1,2), Sofiati Dian (3), Lindsey te Brake (1), Ahmad Rizal Ganiem (3), Vycke Yunivita (4), Reinout van Crevel (5), Rob Aarnoutse (1), Rovina Ruslami (4)
(1) Department of Pharmacy, Radboud Institute of Health Sciences, Radboudumc, Nijmegen, The Netherlands, (2) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (3) Department of Neurology, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia, (4) Department of Biomedical Science, Pharmacology and Therapy Division, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia, (5) Department of Medicine, Institute of Health Sciences, Radboudumc, Nijmegen, The Netherlands
Objectives: Tuberculosis meningitis (TBM) is the most severe form of tuberculosis, with up to 50% mortality mostly within the first 2 weeks after presentation of disease [1]. The currently recommended antimicrobial treatment for TBM is the same as for pulmonary tuberculosis and consists of a 4-drug combination: rifampicin (RIF), isonizid, ethambutol and pyrazinamide. Recent studies suggest that an intensified regimen with higher rifampicin doses during the first critical days of treatment may improve the outcome of TBM. The objective of this work was to characterize the population pharmacokinetics (PK) of high-dose RIF in plasma and cerebrospinal fluid (CSF), investigate predictors of PK variability and evaluate a link between individual RIF exposures and mortality during the first 6 month of treatment in an individual patient data meta-analysis.
Methods: Data originated from three randomized controlled phase II trials preformed in the same center in Bandung, Indonesia [2-4]. The studies compared the standard RIF oral dose of 450mg to intensified 14 or 30-days regimens including 750, 900 or 1350mg oral RIF, or an intravenous RIF infusion (1.5h) of 600mg. Rich plasma PK sampling were performed at day 2±1 and for two of the studies also at day 12±3. A single lumbar puncture was performed at PK days for quantification of RIF and metabolites in CSF as described in the original publications [2-4]. The 6-month survival was captured and described with time-to-event models. The exposure-response analysis was preformed sequentially using NONMEM 7.3.
Results: The PK dataset included 133 individuals and 1266 RIF observations of which 1150 (170 from CSF) were above the limit of quantification and included in the fit. The final model included absorption through a chain of transit compartments, a well-stirred liver model [5], and two disposition compartments. Intrinsic clearance (CLint) was saturable following Michaelis-Menten kinetics [5, 6]. RIF’s autoinduction was accounted for by a separate CLint estimated for late samples (after day 7) and found to be 49% (95% confidence interval 27-71) higher compared to during the first days. The bioavailability of a 450mg dose was estimated to be 72% (62-82), and increased nonlinearly with dose as previously described [6]. The volume of distribution was found to be 19% (12-27) lower at late time points, potentially reflecting an improvement in disease status. Allometric scaling with fat-free mass and fixed coefficients was included on all disposition parameters.
RIF CSF concentrations were modeled with a partition coefficient and a half-life for the distribution between plasma and CSF [7], estimated to be 5.5% (4.5-6.5) and 2.1 (1.3-2.9) hours, respectively. Addition of inter-individual variability in the partition coefficient was statistically significant and estimated to be 37%CV. Measured protein concentration in CSF was a significant covariate on the partition coefficient, with higher protein concentration correlated to higher CSF RIF concentrations.
The survival dataset included 148 individuals of which 58 died and 15 dropped out before 6 months. The hazard model that best described the survival was a exponentially declining function (deltaOFV -91.2 and -24.3, compared to constant and Weibull functions, respectively).
The effect of individual RIF exposure (plasma and CSF AUC0-24h and plasma Cmax) on the hazard was evaluated with linear, power and Emax-relationships. Plasma AUC0-24h was the best performing exposure metric and the effect on the hazard was coded as follows:
hi = hb* (1 – AUCi/(AUC50 + AUCi))
An estimated maximal effect did not improve the model, nor did a different effect for 14 or 30 days of intensified treatment. The AUC50 was estimated to be 161 mg/L*h, the observed range of RIF AUC0-24h was 1-486 mg/L*h. Simulations predicted the mortality to decrease from 49.6% as expected with the 450mg dose (median exposure 48 mg/L*h), to 30.5% expected with the 1350 mg dose (233 mg/L*h).
Conclusions: This individual patient data meta-analysis showed that higher RIF exposure during the first 14 days of treatment substantially decreased the risk of death in Indonesian TBM patients. Maximal effect was not reached within the studied range of exposures, indicating that doses even higher than 1350 mg could bring additional benefits if they can be safely administered. The optimal dose of RIF in treatment of TBM should be further investigated in phase III type trials.
References:
[1] Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol. 2013;12(10):999-1010.
[2] Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis. 2013;13(1):27-35.
[3] Yunivita V, Dian S, Ganiem AR, Hayati E, Hanggono Achmad T, Purnama Dewi A, et al. Pharmacokinetics and safety/tolerability of higher oral and intravenous doses of rifampicin in adult tuberculous meningitis patients. Int J Antimicrob Agents. 2016;48(4):415-21.
[4] Dian S, Yunivita V, Ganiem AR, Achmad TH, Colbers A, Van Crevel R, et al., editors. High dose rifampicin for the treatment of TB meningitis: a dose finding study. 10th International Workshop on Pharmacology of Tuberculosis Drugs; 2017 15 October; Atlanta, USA.
[5] Chirehwa MT, Rustomjee R, Mthiyane T, Onyebujoh P, Smith P, McIlleron H, et al. Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction. Antimicrob Agents Chemother. 2015;60(1):487-94.
[6] Svensson RJ, Aarnoutse RE, Diacon AH, Dawson R, Gillespie SH, Boeree MJ, et al. A population pharmacokinetic model incorporating saturable pharmacokinetics and auto-induction for high rifampicin doses. Clin Pharmacol Ther. 2017. [E-pub ahead of print]
[7] Savic RM, Ruslami R, Hibma JE, Hesseling A, Ramachandran G, Ganiem AR, et al. Pediatric tuberculous meningitis: Model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children, Clin Pharmacol Ther. 2015;98(6):622-9.
Reference: PAGE 27 (2018) Abstr 8579 [www.page-meeting.org/?abstract=8579]
Poster: Drug/Disease Modelling - Infection