Plasma concentrations of rifampicin may be too low in children using currently recommended doses

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The currently recommended dosage of rifampicin for children may be too low according to a fairly large pharmacokinetic study presented at the 39th Union World Conference on Lung Health held in Paris.

“We feel that children are getting much lower serum concentrations of rifampicin than adults,” said Professor Peter Donald of Stellenbosch University who presented the study, “and we think that the World Health Organisation recommendations should be increased.”

Background

Rifampicin is an essential drug in the management of tuberculosis, but there is very little data regarding the pharmacokinetics of the drug in children, and no data whatsoever on its pharmacokinetics in children with HIV.

So from 2004 to 2006, his team enrolled children into a pharmacokinetic study at Brooklyn Hospital for Chest Diseases in Cape Town, South Africa. The children, both HIV-positive and negative, were aged between 3 months to 13 years of age, and had severe forms of tuberculosis. A qualified dietician assessed their nutritional status (anthropometry) using standard methodology.

Glossary

serum

Clear, non-cellular portion of the blood, containing antibodies and other proteins and chemicals.

 

concentration (of a drug)

The level of a drug in the blood or other body fluid or tissue.

p-value

The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 

standard deviation

Provides a measure of the spread of values.

 

body mass index (BMI)

Body mass index, or BMI, is a measure of body size. It combines a person's weight with their height. The BMI gives an idea of whether a person has the correct weight for their height. Below 18.5 is considered underweight; between 18.5 and 25 is normal; between 25 and 30 is overweight; and over 30 is obese. Many BMI calculators can be found on the internet.

Pharmacokinetic evaluations occurred on two occasions, approximately one and four months after starting treatment. After dosing, sequential blood samples were taken at one, one and a half, three, four, and six hours to measure plasma concentrations, with children fasting from midnight onwards. 2 hour concentrations were calculated.

The children were given a fixed dose formulation of the standard TB regimen (made by Sandoz), which supplied a mean dose of 9.61-3 mg per kilogram bodyweight.

Participant characteristics

The study enrolled 60 children, 26 of whom were HIV-positive (with a mean age of 3.73 years) and 34 who were uninfected with a mean age of 4.05 years. 6 subjects dropped out.

Baseline diagnostic, clinical and radiological characteristics were similar between the HIV-positive and negative, with the exception of the TB skin test (Mantoux) which was significantly more likely to be positive in the HIV-uninfected. The HIV-infected children had a worse nutritional status however, with more children with marasmus (38% vs 9%, p<0.01) or marasmic kwashiorkor (19% vs 9%, p<0.04).

Anthropometry and serum CDR (mg/l) one month and four months after treatment

 

 

HIV-infected

N=21 (Standard deviation)

HIV-uninfected

N= 33 (Standard deviation)

p

Month 1 (m1) weight,

12.26 (5.18)

13.97 (6.94)

0.30

Month 4 (m4) weight

13.06 (5.38)

15.04 (8.01)

0.29

M1 Length/Height (cm)

86.80 (16.22)

91.53 (20.85)

0.36

M4 Length/Height (cm)

89.26 (16.39)

93.67 (20.37)

0.40

M1 BMI

15.59 (1.62)

15.71 (1.91)

0.80

M4 BMI

15.74 (1.53)

16.05 (1.71)

0.51

M1 MUAC (cm)

14.28 (2.16)

15.07 (2.39)

0.21

M4 MUAC (cm)

14.44 (2.22)

15.46 (2.63)

0.16

M1 serum CRP

39.97 (54.55)

13.42 (17.96)

0.06

M4 serum CRP

22.47 (22.28)

4.15 (4.96)

0.002

Results

Rifampicin serum concentrations were lower than anticipated, and tended to be slightly lower in HIV-infected children, though the confidence intervals overlapped.

One month after starting treatment, the mean rifampicin concentration in the six hours after dosing (AUC0-6) was 14.9 and 18.1 µg h/ml in the HIV infected and uninfected children respectively. Four months after starting treatment, concentrations were higher at 16.52 and 17.94 µg h/ml respectively (p=0.59).

The mean two-hour concentration was 3.9 and 4.8 µg/ml respectively (p=0.20) at one month after starting treatment and 4.0 and 4.6 µg/ml (p=0.33) at four months after starting treatment.

These values are “very low” according to Professor Donald, as the scientific literature recommends aiming at concentrations closer to 8-20 µg/ml at two hours post dosing. And in order to have a bactericidal effect on mycobacteria, a concentration of around 10-15 mg/L is needed, which is generally accomplished by a dose of 10 mg/kg in adults.

Thus current WHO guidelines recommend that daily and intermittent dosing for adults and children should be around 10 mg/kg (range 8-12).

However, this study suggests that those dose recommendations may not be enough for children. “Close to half of the children in our study had calculated 2-hour concentrations of less than 4 µg/ml,” said Professor Donald, “so adjustment of dosages of rifampicin is necessary, particularly in young children.”

He noted that in other fields, body surface area is used to calculate the appropriate doses for children.

Another paper several years ago applied these calculations to rifampicin

The dose of rifampicin calculated by body surface area (BSA) (Ansel & Stoklosa, 2001).

 

Weight

10 mg/kg dose

Dose according to BSA

BSA dose as mg/kg

2

20

54

27

3

30

69

23

4

40

84

21

5

50

99

19.8

10

100

162

16.2

15

150

216

14.4

20

200

288

14.4

25

250

330

13.2

30

300

372

12.4

35

350

414

11.8

Another doctor in the audience asked if all this was theoretical, since the currently recommended dose seems to work fine in most children.

Professor Donald replied that “many children with TB have really very minimal disease. The currently recommended doses may work fine for those children, but for more severe forms of childhood TB I believe we need a similar concentration as for adults. We tend to use 10-20 mg/kg in children by manipulating the fixed dose formulation.”

Professor Donald also suggested that the dose of isoniazid may be too low in children with severe forms of TB (this will be covered in more detail in an upcoming issue of HATIP).

References

Donald PR et al. Rifampicin plasma concentrations in children hospitalised for the management of severe tuberculosis. 39th IUATLD World Conference on Lung Health, abstract PC-82005-19, Paris, 2008.