New dosing recommendations for anti-tuberculosis therapy in Indian children
Benjamin Guiastrennec (1), Geetha Ramachandran (2), Mats O. Karlsson (1), A.K. Hemanth Kumar (2), Perumal Kannabiran Bhavani (2), N. Poorana Gangadevi (2), Soumya Swaminathan (2), Amita Gupta (3), Kelly E. Dooley (3) and Radojka M. Savic (4)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden; (2) National Institute for Research in Tuberculosis, Indian Council of Medical Research, Chetpet, Chennai, India; (3) Johns Hopkins University School of Medicine, Baltimore, MD, USA; (4) University of California San Francisco, San Francisco, CA, USA.
Objectives: Pediatric dosing recommendations of first line anti-tuberculosis (TB) treatment are based on pharmacokinetic (PK) studies in adults. Yet new evidence revealed that small children are often underexposed and could lead to poor clinical outcomes. India has the highest TB burden in the world, accounting for 27% of total incident cases. In November 2017, India officially switched from a thrice-weekly to a daily dosing, although still relying on a constant mg/kg dosing across the different pediatric weight bands.
The present work aimed 1) to characterize the PK of the first line anti-TB drugs isoniazid (INH), rifampin (RIF) and pyrazinamide (PZA) in underweight Indian children undergoing thrice weekly dosing as per previous Indian pediatric dosing recommendations, 2) to establish the relationship between the plasma exposures of these drugs and the anti-TB treatment outcome, 3) to evaluate the previous and new Indian pediatric dosing recommendations and finally 4) to propose optimized dosing recommendations via a model-based approach.
Methods: The clinical data were pooled from two studies in 161 Indian children (1–15 yr, 6–44 kg) diagnosed with drug sensitive TB , 84 of whom had human immunodeficiency virus (HIV) coinfection  and also received anti-retroviral therapy. After at least two weeks of thrice-weekly anti-TB treatment, the plasma concentrations of INH, RIF and PZA were measured at 0, 2, 4, 6 and 8 h following dose intake.
Published population PK models in South-African children featuring maturation functions and delayed absorption, were used as starting point. All clearances and volumes were allometrically scaled to the total body weight using exponents of ¾ and 1 respectively. Non-linearity in absorption and elimination were evaluated using a Michaelis-Menten type parametrization. A stepwise covariate modeling (SCM) approach with forward inclusion (p<0.05) and backward deletion (p≥0.01) steps was used to explore additional effects of total body weight, nutritional status (z-scores) and HIV-related covariates on the clearance, volumes, relative bioavailability and absorption delay.
The treatment outcome at 6 months – reported as favorable (cure/treatment completion) or unfavorable (death/treatment failure) – was modeled using a logistic regression model. The covariates and individual model-predicted weekly exposures (i.e. area under the concentration time curve) of each drug were evaluated as predictors of the treatment outcome through a second SCM.
The selected PK-PD model was used to evaluate through simulations (n = 1000) the probability of unfavorable treatment outcome (Punfavorable) under the previous thrice-weekly and new daily pediatric Indian dosing recommendations. Optimized doses were proposed based on a Punfavorable of 5% or less.
Parameter estimation was conducted in NONMEM v.7.3, using the FOCE-I estimation method for continuous data and the Laplacian method for categorical data.
Results: In total, 805 plasma concentrations were collected for INH, 794 for RIF, and 720 for PZA. Samples below the detection limit (INH: 148, RIF: 174, PZA: 75) were mostly represented by trough concentrations and were excluded from the analysis.
Drug distribution was biphasic for INH and monophasic for RIF and PZA. The PK of all three drugs was linear over the studied doses ranges and all also displayed significant delays in absorption (i.e. ≥0.98 h). The estimation of the absorption rate constants was supported by the use of frequentist priors. The estimated clearances for INH and RIF were significantly lower (-24% and -46% respectively) than reported values for similar studies in South-African children, while PZA clearance was similar in both populations. For all three drugs, the predictions were significantly improved when the relative bioavailability was scaled to total body weight through a power relationship, indicating lower exposure in smaller children. In addition, HIV coinfection influenced the relative bioavailability of INH (-20%) and RIF (-42%) as well as the clearance of RIF (+32%). Finally, the fast INH metabolizer status was associated with a decreased relative bioavailability (-21%) and an increased clearance (+94%) compared to the normal metabolizers. For all three drugs, the between subject variability (BSV) in clearances and volumes was substantial (>34% coefficient of variation (CV)) and for RIF, BSV was also increased with HIV coinfection (clearance: +74%, volume: +106%) as compared to subjects with TB monoinfection.
The treatment outcome was favorable in 109 children (68%), unfavorable in 33 (20%) and unknown in 19 (12%); the latter were excluded from the PD analysis. Weekly RIF exposure (range, 9.81–231 μg.h/mL) was the only statistically significant independent predictor of treatment outcome. No statistically significant effect of INH (p=0.74) or PZA (p=0.81) exposures could be detected on Punfavorable within the observed exposure ranges (INH: 3.89– 346 μg.h/mL and PZA: 351–2780 μg.h/mL).
Under the previous thrice-weekly dosing regimen, the highest incidence of poor treatment outcome (mean Punfavorable up to 35%) was linked to low RIF exposure in HIV coinfected and small (<10 kg) children. Overall, the situation has improved under the new Indian daily dosing regimen, however the mean Punfavorable remained high in small and especially in HIV coinfected children (mean Punfavorable up to 25%).
The weekly RIF target exposure (i.e. Punfavorable≤5%) was defined to 185 μg.h/mL. Optimized daily RIF pediatric doses were computed using this target exposure and given different weight bands and HIV coinfection status. In comparison to the Indian guidelines, the predicted optimized doses were mostly increased for children with low body weight (<10 kg) and especially for children with TB-HIV coinfection, with doses up to 43.4 mg/kg. For heavier children (>25 kg), the model predicted that the target exposure could be achieved with daily doses as low as 5.2 mg/kg.
Conclusions: The previous thrice-weekly and new once daily Indian pediatric dosing recommendations were evaluated through a population PK-PD approach linking the anti-TB exposure to Punfavorable. Under the previous thrice weekly dosing regimen, an increased risk of poor treatment outcome was seen in children with low total body weight and with TB-HIV coinfection. Under the new once-daily dosing regimen the predicted treatment outcome showed an overall improvement, although children with low body weight (<10 kg) and TB-HIV coinfection are still expected to display high rates of poor outcome due to the use of constant mg/kg doses across the different weight bands. Optimized RIF doses were computed based on a weekly target exposure. The clinical practice in India is evolving and this work has the potential to support the design of new clinical trials exploring the safety and efficacy of higher RIF pediatric doses as it is currently the case in adults.
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