This study provides original pharmacokinetic data for pyrazinamide and ethambutol in children. Recommended dosages for TB in children are from pharmacokinetic studies of adults, yet there are likely to be important age-related differences in drug absorption, metabolism, and clearance. We have found that serum drug levels achieved using intermittent pyrazinamide or ethambutol therapy at recommended doses are very low in Malawian children. Only 2 of 27 children in our study recorded a maximum serum pyrazinamide concentration above the median of 66 mg/liter recorded using intermittent dosing for North American adults and children (37
). Both these children were 5 years old or older, not HIV infected, and not severely malnourished. For ethambutol, none of the children in our study recorded a maximum concentration in serum above what is considered the low cutoff point of 4 mg/liter for intermittent dosing from earlier studies of adults (36
Studies have found lower concentrations and delayed absorption of anti-TB drugs in children compared to adults receiving the same dose (29
). An important recent study of 64 South African children under the age of 13 years (median age, 3.8 years) found that younger children eliminate isoniazid faster than older children and that children require a higher mg/kg dose to achieve concentrations comparable to those for adults (29
). An earlier study compared mean Cmax
values among 28 European children of different age ranges who received 35 mg/kg ethambutol. That study found lower levels for the younger children—1.5 mg/liter for 2- to 5-year-olds compared to 2.3 mg/liter for 6- to 9-year-olds and 3.0 mg/liter for 10- to 14-year-olds (14
). We did not find a similar trend with ethambutol.
We did find that younger children reached significantly lower serum pyrazinamide concentrations than older children. There may be confounders. Younger children in the pyrazinamide arm of the study had a significantly higher HIV prevalence and received lower mean drug dosages than older children. The sample size was not large enough to allow multivariate analysis. There is some evidence that adults with HIV/AIDS do not absorb some anti-TB drugs, especially rifampin, as well as non-HIV-infected patients (10
). Absorption might be especially reduced in HIV-infected individuals with severe immunosuppression and HIV-related enteropathy, but we did not perform CD4 cell counts. Pyrazinamide and ethambutol levels were not significantly lower in HIV-infected or severely malnourished children in our study. A recent study of 48 HIV-infected adults with TB in the United States, 75% with a CD4 cell count of <200/mm3
, found that adequate concentrations were achieved with intermittent dosing of pyrazinamide (27
We compared pharmacokinetic parameters in relation to malnutrition. Levels of pyrazinamide but not ethambutol were lower for more malnourished children, but these differences did not reach the level of significance. Severe malnutrition was as common in older children as in younger children, and HIV prevalence was not significantly higher in children with marasmus. Previous studies of isoniazid and rifampin in children have been carried out to examine the impact of malnutrition and did not find a major effect (30
It is known that reduced absorption occurs if the drugs are taken with a meal, especially a high-fat meal (24
). We are not sure what impact the taking of a low-fat meal around 30 min after the drugs had on absorption in our study group. The practice in this study was consistent with the usual practice in Malawian hospitals when anti-TB treatment is administered.
Important reasons for undertaking this study were the worsening outcomes for child TB in Malawi and elsewhere in the region and the relatively recent recommendation for ethambutol usage for all childhood age groups. The death rate for 2,739 Malawians treated for TB in 1998 was 17%, and the outcome was unknown for an additional 21% (13
). Evidence from the region including Malawi suggests that coinfection with HIV is a major reason for the high death rate (15
). Malabsorption of anti-TB drugs may be one reason for poor outcomes for HIV-infected children, but there are likely to be others, such as wrong diagnosis (17
), coinfection with other pathogens (4
), inadequate dosages received (12
), and poorer compliance (9
). Another factor contributing to poor outcome may be that ethambutol is not as effective as rifampin in the continuation phase of therapy (16
). Ethambutol replaced thiacetazone in regions of HIV endemicity because thiacetazone caused severe and often fatal adverse reactions in HIV-infected adults and children (3
). There were concerns about the use of ethambutol for young children because of their inability to report the early symptoms of optic neuritis, the most important side effect, that can lead to blindness. This is a dose-related side effect, so this risk is considered negligible if recommended doses are used (7
). Ethambutol is now recommended and commonly used for children of all ages in standard regimens (21
). This study suggests an important potential problem with ethambutol in that currently recommended doses result in inadequate therapeutic drug levels rather than any risk of toxicity.
In the majority of developing countries, where most childhood TB occurs, anti-TB therapy is available only in tablet form. This means that the same portions of tablets are given to all children within a particular age range (21
). This is a potential problem, especially for children with low weights. For example, children weighing 5.0 kg and 8.9 kg receive the same dose. Figure shows that all five patients between 7.9 and 8.2 kg (who received a recommended dose of 200 mg, or 25 mg/kg [21
]) recorded maximum serum drug concentrations of <30 mg/liter. These recommendations may need to be revised.
We examined the relationship between a reactive TST and drug levels. This is because a reactive TST is likely to be a readily available surrogate marker for immunocompetence in regions where CD4 counts are not available. Although numbers were small, the maximum pyrazinamide concentration was significantly higher in children with reactive TSTs, but there was no difference for ethambutol. A nonreactive TST can be due to immunosuppression due to advanced HIV disease or severe malnutrition, but it may also indicate a wrong diagnosis. Therefore, the potential use of the TST result in determining drug dosage would be limited to those with a positive result.
In conclusion, this pharmacokinetic study has found poor absorption of pyrazinamide and ethambutol in Malawian children. It has also found that low serum drug levels are common using intermittent therapy at recommended doses and that young age is an important risk factor for low levels. Studies areneeded that compare pharmacokinetic parameters using higher doses and that measure the impact of higher doses on outcome, as well as the incidence of adverse reactions.