In silico children and the glass mouse model: clinical trial simulations to identify and individualize optimal isoniazid doses in children with tuberculosis

Abstract

Children with tuberculosis present with high rates of disseminated disease and tuberculous (TB) meningitis due to poor cell-mediated immunity. Recommended isoniazid doses vary from 5 mg/kg/day to 15 mg/kg/day. Antimicrobial pharmacokinetic/pharmacodynamic studies have demonstrated that the ratio of the 0- to 24-h area under the concentration-time curve (AUC(0-24)) to the MIC best explains isoniazid microbial kill. The AUC(0-24)/MIC ratio associated with 80% of maximal kill (80% effective concentration [EC(80)]), considered the optimal effect, is 287.2. Given the pharmacokinetics of isoniazid encountered in children 10 years old or younger, with infants as a special group, and given the differences in penetration of isoniazid into phagocytic cells, epithelial lining fluid, and subarachnoid space during TB meningitis, we performed 10,000 patient Monte Carlo simulations to determine how well isoniazid doses of between 2.5 and 40 mg/kg/day would achieve or exceed the EC(80). None of the doses examined achieved the EC(80) in ≥90% of children. Doses of 5 mg/kg were universally inferior; doses of 10 to 15 mg/kg/day were adequate only under the very limited circumstances of children who were slow acetylators and had disease limited to pneumonia. Each of the three disease syndromes, acetylation phenotype, and being an infant required different doses to achieve adequate AUC(0-24)/MIC exposures in an acceptable proportion of children. We conclude that current recommended doses for children are likely suboptimal and that isoniazid doses in children are best individualized based on disease process, age, and acetylation status.

FIG. 1.

Relationship between pharmacokinetic parameter and age. The correlations with age as a continuous variable were r = 0.04 and a slope of 0.0003 ± 0.0014 for clearance and r = 0.24 and a slope of −0.0049 ± 0.0039 for V.

FIG. 2.

Plasma and cerebrospinal fluid pharmacokinetics of isoniazid, showing the concentrations observed by Donald et al. (8) as well as our modeled concentration-time profiles, including standard deviations.

FIG. 3.

Performance of different isoniazid doses in children who are fast acetylators. The probabilities of achieving an isoniazid AUC_0-24/MIC of 287.2 in children with disseminated TB with no meningitis (A), TB meningitis (B), and pneumonia (C) are shown.

FIG. 4.

Performance of different isoniazid doses in children 1 to 10 years old who are slow acetylators. The probabilities of achieving an isoniazid AUC_0-24/MIC of 287.2 in children with disseminated TB with no meningitis (A), TB meningitis (B), and pneumonia (C) are shown.

FIG. 5.

Performance of different isoniazid doses in infants who are slow acetylators. The probabilities of achieving an isoniazid AUC_0-24/MIC of 287.2 in children with disseminated TB with no meningitis (A), TB meningitis (B), and pneumonia (C) are shown.

FIG. 6.

Relationship between dose and target attainment probability. The results are for 10,000 children who are fast acetylators (A), slow acetylators and between 1 and 10 years old (B), slow acetylator infants (C), or fast acetylators with M. tuberculosis highly susceptible to isoniazid (D).