Pharmacokinetic study of isoniazid and pyrazinamide in children: impact of age and nutritional status

Dayal, Rajeshwar; Singh, Yatish; Agarwal, Dipti; Kumar, Manoj; Swaminathan, Soumya; Ramachandran, Geetha; Kumar, Santosh; Narayan, Shamrendra; Goyal, Ankur; Kumar, A K Hemant

doi:10.1136/archdischild-2017-313910

Cited by 12 publications

(10 citation statements)

References 21 publications

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“…These studies suggested a clinically relevant impact of malnutrition on the pharmacokinetics of certain PRD drugs. Various studies included in this systematic review addressed the need for dose adjustments in the malnourished population for isoniazid [18,67,76,77,83,84], rifampicin [55,76,77], pyrazinamide [55,77,84,86], ethionamide [55], moxifloxacin [87], stavudine [44], nevirapine [17], chloramphenicol [70], and ivermectin [51]. A specifically adapted treatment regimen in malnourished patients was only suggested for nevirapine [50] and quinine [26].…”

Section: Conclusion and Recommendationsmentioning

confidence: 99%

“…Other studies concluded that the identified effect on pharmacokinetics was of no clinical relevance, and no dose adjustment might be needed for rifampicin [59,65], rifabutin [60], chloramphenicol [52], quinine [58], and pyrimethamine [46]. These results imply a trend between the degree of malnutrition and the pharmacokinetic effect size: a clinically relevant effect was observed in severe malnutrition and kwashiorkor [18,50,67,70,86], except for quinine [58], whereas no dose adjustment was needed in mainly moderately malnourished patients. The clinical impact of these pharmacokinetic effects in severely malnourished patients is highly relevant as these patients are mostly excluded in clinical trials, whereas, in reality, these patients constitute a sizeable proportion of the PRD patient populations.…”

Section: Conclusion and Recommendationsmentioning

confidence: 99%

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Influence of Malnutrition on the Pharmacokinetics of Drugs Used in the Treatment of Poverty-Related Diseases: A Systematic Review

et al. 2021

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Background Patients affected by poverty-related infectious diseases (PRDs) are disproportionally affected by malnutrition. To optimize treatment of patients affected by PRDs, we aimed to assess the influence of malnutrition associated with PRDs on drug pharmacokinetics, by way of a systematic review. Methods A systematic review was performed on the effects of malnourishment on the pharmacokinetics of drugs to treat PRDs, including HIV, tuberculosis, malaria, and neglected tropical diseases. ResultsIn 21/29 PRD drugs included in this review, pharmacokinetics were affected by malnutrition. Effects were heterogeneous, but trends were observed for specific classes of drugs and different types and degrees of malnutrition. Bioavailability of lumefantrine, sulfadoxine, pyrimethamine, lopinavir, and efavirenz was decreased in severely malnourished patients, but increased for the P-glycoprotein substrates abacavir, saquinavir, nevirapine, and ivermectin. Distribution volume was decreased for the lipophilic drugs isoniazid, chloroquine, and nevirapine, and the α1-acid glycoprotein-bound drugs quinine, rifabutin, and saquinavir. Distribution volume was increased for the hydrophilic drug streptomycin and the albumin-bound drugs rifampicin, lopinavir, and efavirenz. Drug elimination was decreased for isoniazid, chloroquine, quinine, zidovudine, saquinavir, and streptomycin, but increased for the albumin-bound drugs quinine, chloroquine, rifampicin, lopinavir, efavirenz, and ethambutol. Clinically relevant effects were mainly observed in severely malnourished and kwashiorkor patients. Conclusions Malnutrition-related effects on pharmacokinetics potentially affect treatment response, particularly for severe malnutrition or kwashiorkor. However, pharmacokinetic knowledge is lacking for specific populations, especially patients with neglected tropical diseases and severe malnutrition. To optimize treatment in these neglected subpopulations, adequate pharmacokinetic studies are needed, including severely malnourished or kwashiorkor patients.

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Section: Conclusion and Recommendationsmentioning

confidence: 99%

Section: Conclusion and Recommendationsmentioning

confidence: 99%

Influence of Malnutrition on the Pharmacokinetics of Drugs Used in the Treatment of Poverty-Related Diseases: A Systematic Review

et al. 2021

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“…The concentration of pyrazinamide was lower in children under three years old and in children with low body mass index, while isoniazid showed no significant differences when these variables were evaluated. 33 …”

Section: Methodsmentioning

confidence: 99%

Tuberculosis in childhood and adolescence: a view from different perspectives

Tahan¹,

Gabardo²,

Vilela³

2020

Jornal de Pediatria

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“…Although this is the typical time of estimated peak, some reports have indicated that INH and PZA could peak earlier, especially among children coinfected with HIV [10,[12][13][14]16]. However, numerous pediatric studies found that average INH concentrations of >3 µg/mL can be achieved 2 hours after a 10 mg/kg dose [19,32,[35][36][37]. This study was not designed to evaluate any effects that tablet crushing might have had on medication bioavailability.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of First-Line Drugs Among Children With Tuberculosis in Rural Tanzania

Justine

Yeconia

Nicodemu

et al. 2018

Journal of the Pediatric Infectious Diseases Society

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Background Dosing recommendations for treating childhood tuberculosis (TB) were revised by the World Health Organization, yet so far, pharmacokinetic studies that have evaluated these changes are relatively limited. We evaluated plasma drug concentrations of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) among children undergoing TB treatment in Tanzania when these dosing recommendations were being implemented. Methods At the end of intensive-phase TB therapy, blood was obtained 2 hours after witnessed medication administration to estimate the peak drug concentration (C2h), measured using high-performance liquid chromatography or liquid chromatography–tandem mass spectrometry methods. Differences in median drug concentrations were compared on the basis of the weight-based dosing strategy using the Mann–Whitney U test. Risk factors for low drug concentrations were analyzed using multivariate regression analysis. Results We enrolled 51 human immunodeficiency virus–negative children (median age, 5.3 years [range, 0.75–14 years]). The median C2hs were below the target range for each TB drug studied. Compared with children who received the “old” dosages, those who received the “revised” WHO dosages had a higher median C2h for RIF (P = .049) and PZA (P = .015) but not for INH (P = .624) or EMB (P = .143); however, these revised dosages did not result in the target range for RIF, INH, and EMB being achieved. A low starting dose was associated with a low C2h for RIF (P = .005) and PZA (P = .005). Malnutrition was associated with a low C2h for RIF (P = .001) and INH (P = .001). Conclusions Among this cohort of human immunodeficiency virus–negative Tanzanian children, use of the revised dosing strategy for treating childhood TB did not result in the target drug concentration for RIF, INH, or EMB being reached.

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Pharmacokinetic study of isoniazid and pyrazinamide in children: impact of age and nutritional status

Abstract: The revised WHO drug dosages were found to be adequate for INH with respect to age and nutritional status, whereas PZA showed significantly lower drug levels in children <3 years and in malnourished children.

Cited by 12 publications

References 21 publications

Influence of Malnutrition on the Pharmacokinetics of Drugs Used in the Treatment of Poverty-Related Diseases: A Systematic Review

Influence of Malnutrition on the Pharmacokinetics of Drugs Used in the Treatment of Poverty-Related Diseases: A Systematic Review

Tuberculosis in childhood and adolescence: a view from different perspectives

Pharmacokinetics of First-Line Drugs Among Children With Tuberculosis in Rural Tanzania

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