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Children with tuberculosis (TB) represent 6–40% of all TB cases globally. Hence, the World Health Organization has identified certain research priorities in childhood TB and one of the main elements is to evaluate the pharmacokinetics of antitubercular drugs under different conditions in children .
Pyrazinamide (PZA) is recommended in a dose range varying from 15 to 40 mg kg−1 by various scientific bodies [2–4]. In India, under the Revised National Tuberculosis Programme the dose of PZA recommended is 25 mg kg−1 for daily dosing and 35 mg kg−1 for intermittent, thrice a week dosing . These recommendations are based on studies of PZA in adults, mostly carried out at an average dose of 30 mg kg−1. Hepatotoxicity is the most important and serious side-effect associated with the use of pyrazinamide. Incidence of PZA associated hepatotoxicity has been shown to be dose dependent .
Rational use of drugs necessitates that their disposition be carefully evaluated in the population in which the drug has to be used . However there are few pharmacokinetic studies of PZA in children . PZA is not routinely prescribed at lower doses due to lack of pharmacokinetic and efficacy data in children at these lower doses.
The effectiveness of antimicrobial agents may be described as a function of the concentration of antimicrobial agents and area under the curve vs. minimum inhibitory concentration (MIC) of the drug for the microorganisms and the time for which the concentration remains above the MIC . Hence this study was conducted to compare the serum concentrations of PZA at doses of 25 mg kg−1 and 15 mg kg−1 in children suffering from TB and to evaluate the pharmacodynamic indices for PZA, i.e. Cmax : MIC, AUC : MIC and Time > MIC.
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All the subjects completed the study protocol. Eleven patients were diagnosed to have pulmonary TB and nine were suffering from tubercular lymphadenitis. In both the groups, patients were comparable in their demographic profile.
Figure 1 summarizes the changes in serum concentration with time. At 6 h the concentration had fallen to 27.1 ± 3.9 μg ml−1 and 24.4 ± 3.0 μg ml−1 in group I and group II, respectively. The serum concentration declined gradually thereafter to 6.3 ± 1.8 μg ml−1 and 5.7 ± 1.7 μg ml−1, respectively, at 24 h.
Figure 1. Mean ± SEM serum concentrations of pyrazinamide over 24 h in group I (25 mg kg−1; continuous line) and group II (15 mg kg−1; dotted line)
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The pharmacokinetic parameters are shown in Table 1. The Cmax and the AUC were higher, as expected, in group I. However, the difference between the two groups was not statistically significant. The t1/2, λz, CL and V were also comparable.
Table 1. Pharmacokinetic parameters (mean (SEM)) of group I (25 mg kg−1) and group II (15 mg kg−1)
| ||Group I||Group II||95% CI of difference|
|Cmax (μg ml−1)||42.4 (3.3)||38.6 (3.9)||−6.9, 4.6|
|tmax (h)||1.7 (0.2)||1.8 (0.1)||−0.5, 0.3|
|AUC(0,24 h) (μg ml−1 h)||453 (67)||385 (43)||−99, 236|
|AUC (μg ml−1 h)||561 (99)||515 (89)||−235, 327|
|t1/2 (h)||9.3 (1.3)||10.5 (2.3)||−6.7, 4.2|
|λz (h−1)||0.09 (0.01)||0.10 (0.02)||−0.6, 0.4|
|V (l kg−1)||0.67 (0.08)||0.46 (0.07)||−0.02, 0.4|
|CL (l h−1 kg−1)||0.06 (0.01)||0.04 (0.01)||−0.004, 0.04|
|Cmax : MIC (20 μg ml−1)||2.1 (0.2)||1.9 (0.2)||−0.4, 0.7|
|Cmax : MIC (25 μg ml−1)||1.7 (0.1)||1.5 (0.2)||−0.3, 0.6|
|AUC : MIC (20 μg ml−1)||22 (11)||19 (7)||−5, 12|
|AUC : MIC (25 μg ml−1)||18 (9)||15 (5)||−4, 9|
|Time (h) > MIC (20 μg ml−1)||5.9 (2.5)||5.4 (3.0)||−2, 3|
|Time (h) > MIC (25 μg ml−1)||4.9 (2.8)||3.8 (3.0)||−2, 4|
The mean serum concentrations were maintained above 25 μg ml−1 for 6 h in group I and for 4 h in group II. Four patients in group I and one patient in group II had serum concentrations above 25 μg ml−1 for more than 8 h, while five patients in group II had serum concentrations maintained above 25 μg ml−1 for more than 6 h.
The mean serum concentrations were maintained above 20 μg ml−1 until 8 h in group I and until 6 h in group II. Five patients in group I and four patients in group II had concentrations above 20 μg ml−1 for 8 h. The Cmax : MIC, AUC : MIC and Time > MIC were comparable for both the doses (Table 1).
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It is recognized across the world that research and drug development specifically for children has been a neglected area . Drug therapy in children requires special consideration of dose calculation . However dosing regimens in children are often based on studies carried out in adults.
There are very few studies on blood concentrations and pharmacokinetics of PZA in children. There is only one detailed study in children at a dose of 35 mg kg−1 and a population pharmacokinetic study at a dose of 25 mg kg−1. In both the studies, pharmacokinetic estimates in children were significantly different from those in adults.
This is the first detailed pharmacokinetic study of PZA in children at the doses of 25 mg kg−1 and 15 mg kg−1. Given the dose dependent incidence of PZA related hepatotoxicity, such data at lower doses would help in dose optimization in children.
The serum concentrations achieved with the two doses were comparable over the 24 h study period. The Cmax and AUC in our study were comparable with those seen in adults at proportionate doses . The tmax has been shown to be higher in 30% of children with delayed absorption as compared with adults [9, 15]. However in our study the tmax (up to 2 h) was comparable with that in adults . The absorption of PZA was not delayed. The elimination half-life was longer than that reported in adults (6.1–9.6 h)  and similar to that previously reported in children (9–10 h) .
As has been suggested, an inverse relationship exists for age and apparent volume of distribution. The volume of distribution in our study appears to be lower in comparison with previously reported data in children (0.86 l kg−1 at a PZA dose of 35 mg kg−1) . The CL observed in our study was comparable with the previously reported clearance of 0.05 l h−1 kg−1 for children  and 0.06 l h−1 kg−1 for adults .
As reported earlier , a wide interindividual variation in the pharmacokinetics of PZA was observed. This is a pilot pharmacokinetic study with multiple sampling points, conducted in children. Hence for ethical reasons, the sample size was small. However, the distribution of patients was normal.
Since the mechanism of action of PZA is only partly understood and allows no predictions as to whether the mycobacterial killing is concentration-dependent or time-dependent, the optimum range of ratio of Cmax : MIC, AUC : MIC and Time > MIC which would be effective for the antimicrobial action of PZA have not been clearly defined. However, considering an MIC90 as 10 μg ml−1, the ratio of Cmax : MIC and AUC : MIC at a PZA dose of 27 mg kg−1 was 3.8 ± 0.6 and 52 ± 10, respectively [6, 16]. These are below the recommended values . The Cmax : MIC and AUC : MIC ratio as calculated in our study at MIC of 20 μg ml−1 were below the recommended values for an MIC90 of 10 μg ml−1 in adults . The ratios were further decreased when calculated for an MIC of 25 μg ml−1. Since the Cmax : MIC and AUC : MIC ratios of 3.8 ± 0.6 and 52 ± 10 at a PZA dose of 27 mg kg−1 have been substantiated by relatively poor bactericidal activity in vivo, it suggests that 25 mg kg−1 and 15 mg kg−1 may not be the appropriate doses for use in children. The suitability of PZA for intermittent therapy is based on higher serum concentrations being achieved with a large intermittently administered dose than with a smaller more frequently administered dose . However, the higher concentration achieved with larger doses also increases the pH range in which the organisms would be inhibited .
Hence both for daily use and for intermittent therapy whether decreasing the dose of PZA further below 27 mg kg−1 provides clinical benefit or not, needs to be evaluated especially when PZA is administered as part of combination therapy and correlated with in vivo observations.
This study has certain limitations. The reported values of MIC of PZA vary over a wide range depending upon the pH of the medium, type of medium, size of innoculum and the strain of tubercle bacilli used . Also it is an in vitro parameter that has been used while in vivo concentrations fluctuate over a wide range due to differences in absorption and elimination rates.
In conclusion, this study is the first attempt to compare the serum concentrations and pharmacokinetics of PZA at 25 mg kg−1 and 15 mg kg−1 in children suffering from tuberculosis. The elimination half-life was longer and volume of distribution was greater than in adults.
However this was a study using PZA alone and more large scale studies need to be conducted to calculate PKPD parameters of PZA when administered at lower doses in combination therapy for TB in children.