Navarat Panjasawatwong (1), Nguyen Duc Bang (2,3), Maxine Caws (2,4,5), Thai Thanh Truc (2), Tran Ngoc Duong (3), Nguyen Huy Dung (3), Dang Thi Minh Ha (2,3), Guy E. Thwaites (2,5), Doortje Heemskerk (2,5), Laura Merson (2,5), Pham Van Toi (2,5), Jeremy J. Farrar (2,5), Marcel Wolbers (2,5), Thomas Pouplin (2,5,6), Jeremy N. Day (2,5) and Joel Tarning (5,6)
(1) Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; (2) Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam; (3) Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam; (4) Department of Clinical Sciences, Liverpool School of Tropical Medicine, UK; (5) Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine Research Building, University of Oxford, Oxford, UK; (6) Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Bangkok, Thailand
Introduction/Objective: Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis (TB), characterized by the presence of tuberculosis bacteria in the brain parenchyma. Due to the relatively weak immune system in children, they more commonly contract TBM compared to adults. The drug regimens used today to treat TBM in children have been extrapolated from the current treatment of pulmonary TB in adults. The usefulness of this approach has been challenged by several studies showing that the drug exposure to the four first-line anti-TB drugs (i.e. isoniazid, rifampicin, pyrazinamide and ethambutol) after a standard treatment were lower in children compared to adults.
Rifampicin is the backbone of the first-line anti-TB combination treatment today. However, the penetration of rifampicin into cerebrospinal fluid (CSF) is poor. There is limited information on the pharmacokinetics of rifampicin in children with TB, especially in children with TBM. The objective of the study was to investigate the population PK of rifampicin in Vietnamese children with TBM.
Methods: One-hundred Vietnamese children with TBM were treated with an 8-month pediatric anti-TB treatment regimen which was based on the 2006 World Health Organization guidelines. The treatment consisted of isoniazid (5 mg/kg), rifampicin (10 mg/kg) and ethambutol (15 mg/kg) for 8 months, with the addition of pyrazinamide (25 mg/kg) for the first 3 months and streptomycin (15 mg/kg) for the first 2 months. The drugs were given once daily.
For each child, two plasma samples were collected on days 1 and 14 after the first dose. One plasma and one CSF samples were drawn less than 15 minutes apart on days 30 and 90. The concentrations of the four drugs were quantified using a fully validated liquid chromatography-tandem mass spectrometry method.
Pharmacokinetic properties of rifampicin in plasma and CSF were evaluated using nonlinear mixed-effects modelling in NONMEM version 7.4. First-order conditional estimation method with interaction (FOCE-I) was used throughout the model-building process. Different structural, variability and covariate models were evaluated. Enzyme maturation and enzyme turnover models were also evaluated.
Results: Fifty-six percent (56%) of the patients were male and the median age was 3 years (IQR: 1-7). A total of 492 plasma and 154 CSF concentrations from 100 participants were included in the model. Rifampicin concentration-time data were best described by a one compartment disposition model with transit absorption (one fixed transit compartment). Inter-occasion variability was added on elimination clearance, volume of distribution and mean transit time. An enzyme turnover model was retained in the final model to describe the autoinduction of rifampicin, resulting in an enzyme induction half-life similar to what have been seen previously. A CSF compartment was integrated into the final structural model to describe the distribution of rifampicin into the brain. The distribution of rifampicin into CSF was assumed to be passive and governed by a first-order rate constant.
Body weight and age were significant covariates in the final model. Body weights were implemented as a fixed allometric function on elimination clearance and volume of distribution. Ages were included as a maturation factor on elimination clearance to describe the maturation of enzymes during the early years of life.
Conclusions: The population pharmacokinetics of rifampicin were well explained by a one-compartment distribution model with one-fixed transit compartment in the absorption phase. The exposure to rifampicin was higher on day 1 compared to day 14 and was described in the model by an enzyme autoinduction. The developed model can be used to optimize the dosing of rifampicin to achieve adequate exposure in CSF.
References:
[1] Pouplin T, Bang ND, Toi PV, Phuong PN, Dung NH, Duong TN, et al. Naive-pooled pharmacokinetic analysis of pyrazinamide, isoniazid and rifampicin in plasma and cerebrospinal fluid of Vietnamese children with tuberculous meningitis. BMC Infect Dis 2016;16:144.
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[3] Svensson RJ, Aarnoutse RE, Diacon AH, Dawson R, Gillespie SH, Boeree MJ, et al. A population pharmacokinetic model incorporating saturable pharmacokinetics and autoinduction for high rifampicin doses. Clin Pharmacol Ther 2017. doi:10.1002/cpt.778. [E-pub ahead of print].
[4] 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 rifampicin and levofloxacin for children. Clin Pharmacol Ther 2015;98(6):622-9.
[5] Kumpulainen E, Valitalo P, Kokki M, Lehtonen M, Hooker A, Ranta VP, et al. Plasma and cerebrospinal fluid pharmacokinetics of flubiprofen in children. Br J Clin Pharmacol 2010;70(4):557-66.
Reference: PAGE 27 (2018) Abstr 8548 [www.page-meeting.org/?abstract=8548]
Poster: Drug/Disease Modelling - Infection