Nuo Xu1#, Weijian Liu2, Wei Li3, Wenyao Mak1, Tian He3, Hongjuan Qin2, Shuihua Lu2, Xiaoqiang Xiang1, Peize Zhang2, Xiao Zhu1*
1 Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China 2 Department of Pulmonary Medicine & Tuberculosis, The Third People’s Hospital of Shenzhen, National Clinical Research Center for Infectious Disease, Southern University of Science and Technology, Shenzhen, China 3 Department of Pharmacy, The Third People’s Hospital of Shenzhen, National Clinical Research Center for Infectious Disease, Southern University of Science and Technology, Shenzhen, China
Introduction
Current treatment of latent tuberculosis infection (LTBI) include combined rifapentine (RFT) and isoniazid daily treatment for one month (1HP) that is suitable for children and adolescent[1,2]. Dosing in pediatrics is typically performed based on body size, but this may be unsuitable for rifapentine. A recent meta-analysis [3] advised a flat-dosing RFT for non-Chinese adults, cautioning against underexposure with weight-based dosing. Nonetheless, the finding could not be extrapolated into pediatrics and non-Caucasian population. In addition, the safety of RFT particularly on liver functions, warranted further investigation given its structural similarity to hepatotoxic rifampicin.
Objective
- To develop a population pharmacokinetic-toxicity (PopPK-TX) model of RFT in Chinese children to explore the safety and efficacy of 1HP regimen
- To propose an optimal dose algorithm for Chinese pediatric patients with LTBI
Method
An open-label clinical trial was conducted on LTBI subjects below 13 years old. A conservative weight-based approach was used, prescribing 15mg/kg RFT for 28 days, capped at 600mg daily (all subjects >40kg received a fixed 600mg dose). At this stage, total bilirubin (TBIL) was a biomarker under investigation and was not considered in dose-calculation. Regular weekly clinic follow-ups were performed. Statistically significant biomarkers will be concurrently considered for inclusion in the PopPK-TX model with RFT concentrations.
Non-linear mixed-effects modeling was performed with FOCE-i algorithm for parameter estimation. Considering pediatric physiological features, allometric scaling of clearance (CL) and volume of distribution (V) was tested a priori[4,5]. The final model was graphically evaluated by GoF, VPC plots and bootstrap. Monte Carlo simulation of weight-based (10, 15, 20mg/kg QD) and flat doses (100, 150, 300mg QD) were performed to investigate possible changes in concentrations within the predetermined efficacy and safety window, as well as changes in liver biomarkers.
Results
The study enrolled 36 subjects, median (range) age 4.6 years (0.89-9), weight 16.8kg (8-35). No 1HP-related AEs occurred, and no significant AST/ALT changes (p=0.25/0.33). Total bilirubin (TBIL) showed a statistically significant but not clinically meaningful increase (pre- vs post-treatment, median: 7.9 vs 14.1μmol/L, p<0.05).
Due to limited absorption phase data, the absorption model was adopted from the literature[6]. As 93.5% of RFT concentrations (median 16.7 mg/L) in the study significantly exceeded the reported EC90 (5.32mg/L) for autoinduction[3], we assumed complete autoinduction had occurred. This allowed us to simplify the full autoinduction model into the following formula as time-varying CL:
CL = CL0 *[1+ Emax*(1-e-kenz*time)]
Allometric scaling increased AIC by 8.8. Hence, it was not considered for further model development. Both GoF and VPC showed that one-compartment model with transit absorption and time-varying CL could sufficiently describe RFT data and parameters were precisely estimated. Results indicate a maximum 70.4% CL increase due to autoinduction, reaching a plateau by Day 21, aligning with reported 73% increase after 21 days in Hibma et al.[3]. An indirect response model with inhibitory effect of RFT on TBIL elimination could capture the observed kinetic profile of TBIL. The estimated IC50 and Imax for inhibitory effect was 10.8mg/L and 68.8%.
Simulation suggested weight-based dosing had led to underexposure in children below 14kg, as body weight did not significantly influence CL. Specifically, plasma RFT in 73% (n=8/11) did not reach the 350 h·mg/L efficacy target[7]. TBIL remained under the laboratory alert level (44μmol/L, defined as twice the upper limit of reference value[8]) in all tested dosing algorithms. Alternatively, a flat dose of 300mg QD produced sufficient exposure in all subjects aged 1-10 years. Sensitivity analysis of the allometric scaling model also supported the use of 300mg QD in this age group. Our model-based approach extended the flat-dosing algorithm of adults into pediatric, which concurrently ensure adequate drug exposure while simplifying RFT treatment.
Conclusions
Our study suggested a flat dose of 300mg QD RFT was both safe and effective for LTBI treatment in Chinese children. This work demonstrated the utility of pharmacometrics to help integrate data, optimize dosing algorithms and prevent unnecessary empirical individualization of medication.
References:
[1] Villarino, M. E., Scott, N. A., Weis, S. E., Weiner, M., Conde, M. B., Jones, B., Nachman, S., Oliveira, R., Moro, R. N., Shang, N., Goldberg, S. V., Sterling, T. R., International Maternal Pediatric and Adolescents AIDS Clinical Trials Group, & Tuberculosis Trials Consortium (2015). Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid. JAMA pediatrics, 169(3), 247–255
[2] Malik, A. A., Farooq, S., Jaswal, M., Khan, H., Nasir, K., Fareed, U., Shahbaz, S., Amanullah, F., Safdar, N., Khan, A. J., Keshavjee, S., Becerra, M. C., & Hussain, H. (2021). Safety and feasibility of 1 month of daily rifapentine plus isoniazid to prevent tuberculosis in children and adolescents: a prospective cohort study. The Lancet. Child & adolescent health, 5(5), 350–356.
[3] Hibma, J. E., Radtke, K. K., Dorman, S. E., Jindani, A., Dooley, K. E., Weiner, M., McIlleron, H. M., & Savic, R. M. (2020). Rifapentine Population Pharmacokinetics and Dosing Recommendations for Latent Tuberculosis Infection. American journal of respiratory and critical care medicine, 202(6), 866–877.
[4] Anderson BJ, Holford NH. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child. 2013;98(9):737-744
[5] Sinha J, Al-Sallami HS, Duffull SB. Choosing the Allometric Exponent in Covariate Model Building. Clin Pharmacokinet. 2019;58(1):89-100.
[6] Pham, M. M., Podany, A. T., Mwelase, N., Supparatpinyo, K., Mohapi, L., Gupta, A., Samaneka, W., Omoz-Oarhe, A., Langat, D., Benson, C. A., Chaisson, R. E., Swindells, S., & Fletcher, C. V. (2022). Population Pharmacokinetic Modeling and Simulation of Rifapentine Supports Concomitant Antiretroviral Therapy with Efavirenz and Non-Weight Based Dosing. Antimicrobial agents and chemotherapy, 66(9), e0238521.
[7] Savic RM, Weiner M, MacKenzie WR, et al. Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials. Clin Pharmacol Ther. 2017;102(2):321-331
[8] Witek, K., Scislowska, J., Turowski, D., Lerczak, K., Lewandowska-Pachecka, S., & Pokrywka, A. (2017). Total bilirubin in athletes, determination of reference range. Biology of sport, 34(1), 45–48
Reference: PAGE 32 (2024) Abstr 11160 [www.page-meeting.org/?abstract=11160]
Poster: Clinical Applications