Optimizing dosing of the cycloserine pro-drug terizidone in children with rifampicin-resistant tuberculosis

Abstract

There are no pharmacokinetic data in children on terizidone, a pro-drug of cycloserine and a World Health Organization (WHO)-recommended group B drug for rifampicin-resistant tuberculosis (RR-TB) treatment. We collected pharmacokinetic data in children <15 years routinely receiving 15-20 mg/kg of daily terizidone for RR-TB treatment. We developed a population pharmacokinetic model of cycloserine assuming a 2-to-1 molecular ratio between terizidone and cycloserine. We included 107 children with median (interquartile range) age and weight of 3.33 (1.55, 5.07) years and 13.0 (10.1, 17.0) kg, respectively. The pharmacokinetics of cycloserine was described with a one-compartment model with first-order elimination and parallel transit compartment absorption. Allometric scaling using fat-free mass best accounted for the effect of body size, and clearance displayed maturation with age. The clearance in a typical 13 kg child was estimated at 0.474 L/h. The mean absorption transit time when capsules were opened and administered as powder was significantly faster compared to when capsules were swallowed whole (10.1 vs 72.6 min) but with no effect on bioavailability. Lower bioavailability (-16%) was observed in children with weight-for-age z-score below -2. Compared to adults given 500 mg daily terizidone, 2022 WHO-recommended pediatric doses result in lower exposures in weight bands 3-10 kg and 36-46 kg. We developed a population pharmacokinetic model in children for cycloserine dosed as terizidone and characterized the effects of body size, age, formulation manipulation, and underweight-for-age. With current terizidone dosing, pediatric cycloserine exposures are lower than adult values for several weight groups. New optimized dosing is suggested for prospective evaluation.

Keywords: Mycobacterium tuberculosis; antibiotic resistance; pediatric drug therapy; pharmacokinetics.

Fig 1

Visual predictive check for cycloserine in children with rifampicin-resistant tuberculosis, using 1,000 simulations. The solid and dashed lines represent the 5th, 50th, and 95th percentiles of the observed data, while the shaded areas (pink and blue) are the model-predicted 95% confidence intervals for the same percentiles. Observed data are displayed as blue circles.

Fig 2

Simulated steady-state area under the curve (AUC_0–24) of cycloserine vs body weight in children receiving the pro-drug terizidone, first at the current (2022) WHO-recommended weight band dosing (1st graph) and then at the proposed optimized weight band dosing (2nd graph). Additionally, the maximum concentrations (C_max) of cycloserine vs body weight at the proposed optimized weight-band dosing (3rd graph) are displayed. The black dashed lines represent the median AUC_0–24 of 419 mg∙H/L and 615 mg∙H/L, observed with dosing at 500 mg (adults <46 kg) (bottom line) and 750 mg (adults ≥46 kg) daily (top line), respectively, i.e., current WHO recommended adult doses. The red line represents the median C_max (40 mg/L) observed with dosing at 750 mg daily.