Population Pharmacokinetics of Benznidazole in Adult Patients with Chagas Disease

Soy, Dolors; Aldasoro, Edelweiss; Guerrero, Laura; Posada, Elizabeth; Serret, N.; Mejía, Tatiana Raquel Vera; Urbina, Julio A.; Gascón, Jordi

doi:10.1128/aac.05018-14

Cited by 73 publications

(80 citation statements)

References 37 publications

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“…Results obtained do not differ substantially from those previously published for benznidazole from Roche. Although the studies of Raaflaub (4) and Soy et al (6) were performed with patients with chronic Chagas disease and the influence of T. cruzi infection on pharmacokinetic parameters has not been assessed, it seems that the drug used now has the same pharmacokinetics properties as the one used more than 40 years ago.…”

Section: Discussionmentioning

confidence: 99%

“…Two recent studies performed in Argentina and Spain including pediatric and adult populations, respectively, with Chagas disease used a population pharmacokinetic approach (5,6). One of the main differences regarding population pharmacokinetics is that data are obtained for patients treated with benznidazole, while nonpopulation pharmacokinetic studies are performed with healthy volunteers.…”

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confidence: 99%

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Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials

Molina

Salvador

Sánchez-Montalvà

et al. 2017

Antimicrob Agents Chemother

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Despite its toxicity and low efficacy in the chronic phase, benznidazole is the drug of choice in Chagas disease. Scarce information about pharmacokinetics and pharmacodynamics of benznidazole has been published. We performed a phase I, open-label, nonrandomized pharmacokinetic study of benznidazole (Abarax) conducted with 8 healthy adult volunteers at the Infectious Diseases Department of the Vall d'Hebron University Hospital (Barcelona, Spain). The separation and detection of benznidazole were performed on a Waters Acquity ultraperformance liquid chromatography system (UPLC) coupled with a Waters Xevo TQ MS triple quadrupole mass spectrometer. The pharmacokinetic parameters were calculated based on a noncompartmental body model using Phoenix WinNonlin version 6.3 software. Furthermore, computational simulations were calculated for the multiple-dose administration at two dose regimens: 100 mg of benznidazole administered every 8 h and 150 mg of benznidazole administered every 12 h. After benznidazole administration, the median area under the concentration-time curve from time zero to time t (AUC 0 -t ) and extrapolated to infinity (AUC 0 -∞ ) were about 46.4 g · h/ml and 48.4 g · h/ml, respectively. Plasma benznidazole concentrations peaked at 3.5 h, with maximal concentrations of 2.2 g/ml, and benznidazole exhibited a terminal half-life of 12.1 h. The median maximum concentration (C max ) of benznidazole was lower in men than in women (1.6 versus 2.9 g/ml), and median volume of distribution (V) as a function of bioavailability (F) was higher in men than in women (125.9 versus 88.6 liters). In conclusion, dose regimens (150 mg/12 h or 100 mg/8 h) reached a steady-state range concentration above of the minimum experimental therapeutic dose. Sex differences in the benznidazole pharmacokinetics were observed; mainly, men had lower C max and higher V/F than women.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials

Molina

Salvador

Sánchez-Montalvà

et al. 2017

Antimicrob Agents Chemother

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“…The dose for adults of 5.0-7.5mg/kg/day for 30-60 days, divided into 2 or 3 doses per day, has been demonstrated to be effective and without toxic effects 8 . The primary site for benznidazole metabolism is the liver, via the cytochrome P450 system and, to a lesser extent, oxidoreductase, xanthine oxidase, and aldehyde oxidase.…”

Section: Discussionmentioning

confidence: 99%

“…The primary site for benznidazole metabolism is the liver, via the cytochrome P450 system and, to a lesser extent, oxidoreductase, xanthine oxidase, and aldehyde oxidase. The mechanism of action is based on the enzymatic reduction of the nitro group, which leads to the formation of chemically active species, considered free radicals, which interact with deoxyribonucleic acid (DNA), proteins, lipids, and other cellular components 8 . These mechanisms are responsible for both the therapeutic action against Trypanosoma cruzi and the adverse effects.…”

Section: Discussionmentioning

confidence: 99%

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Adverse systemic reaction to benznidazole

Coronel

Frutos

Muñoz

et al. 2017

Rev. Soc. Bras. Med. Trop.

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Benznidazole, drug of choice for Chagas disease (CD), has been associated with a high incidence of adverse reactions that can become serious, necessitating discontinuation of the drug. We describe the case of a Bolivian patient living in Spain for 9 years, who, following treatment with benznidazole for CD in indeterminate chronic phase, presented with fever, skin lesions, digestive symptoms, general malaise, and laboratory abnormalities. After the discontinuation of benznidazole and, the intake of antihistamines and systemic corticosteroids, the patient presented a complete resolution of the symptoms. Optimization of dose strategies and development of more effective, and better-tolerated drugs is advisable.

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The carbonic anhydrase enzymes as new targets for the management of neglected tropical diseases

Renzi,

Ladu,

Carta

et al. 2024

Archiv der Pharmazie

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Diseases caused by protozoan parasites represent a huge challenge to global health care, due to the lack of selective and efficient treatments for the management and spreading of such complex pathologies. The protozoans Trypanosoma cruzi (T. cruzi) and Leishmania spp. are the etiological agents of the so‐called neglected tropical diseases (NTDs), that is, Chagas disease (CD) and leishmaniasis, respectively. In such a context, the metalloenzymes carbonic anhydrases (CAs; EC 4.2.1.1) emerged as potential protozoan druggable enzymes, being involved in the parasites’ life cycle. Several studies suggested the relevance of the protozoan‐expressed CAs as future candidates for the management of NTDs.

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Population Pharmacokinetics of Benznidazole in Adult Patients with Chagas Disease

Cited by 73 publications

References 37 publications

Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials

Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials

Adverse systemic reaction to benznidazole

The carbonic anhydrase enzymes as new targets for the management of neglected tropical diseases

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