Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid

Nix, David E.; Adam, Rodney D.; Auclair, Barbara; Krueger, Todd S; Godo, Paul; Peloquin, Charles A.

doi:10.1016/j.tube.2004.04.001

Cited by 75 publications

(48 citation statements)

References 9 publications

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“…the triggering of phospholipid scrambling of the erythrocyte cell membrane, a key event in suicidal erythrocyte death or eryptosis. The clofazimine concentration (1.5 µg/ml) required for stimulation of erythrocyte cell membrane scrambling was within the range of concentrations observed in vivo [4,54]. It must be kept in mind that the sensitivity of erythrocyte cell membrane scrambling to clofazimine may be enhanced in several clinical conditions associated with enhanced susceptibility to eryptosis, such as dehydration [41], hyperphosphatemia [52] chronic kidney disease (CKD) [30,[55][56][57], hemolytic-uremic syndrome [58], diabetes [59], liver failure [60], malignancy [61], sepsis [62] and Wilsons disease [63].…”

Section: Discussionmentioning

confidence: 66%

Clofazimine Induced Suicidal Death of Human Erythrocytes

Officioso

Alzoubi

Manna

et al. 2015

Cell Physiol Biochem

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Background/Aims: The antimycobacterial riminophenazine clofazimine has previously been shown to up-regulate cellular phospholipase A₂ and to induce apoptosis. In erythrocytes phospholipase A₂ stimulates eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Phospholipase A₂ is in part effective by fostering formation of prostaglandin E₂, which triggers Ca²⁺ entry. Stimulators of Ca²⁺ entry and eryptosis further include oxidative stress and energy depletion. The present study tested, whether and how clofazimine induces eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, hemolysis from hemoglobin release, cytosolic Ca²⁺ activity ([Ca²⁺]_i) from Fluo3-fluorescence, reactive oxygen species (ROS) from 2′, 7′-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, and cytosolic ATP level utilizing a luciferin-luciferase assay kit. Results: A 24-48 hours exposure of human erythrocytes to clofazimine (≥1.5 µg/ml) significantly increased the percentage of annexin-V-binding cells without appreciably modifying forward scatter. Clofazimine significantly increased [Ca²⁺]_i, significantly decreased cytosolic ATP, but did not significantly modify ROS. The effect of clofazimine on annexin-V-binding was significantly blunted, but not fully abolished by removal of extracellular Ca²⁺, and by phospholipase A₂ inhibitor quinacrine (25 µM). Clofazimine further augmented the effect of Ca²⁺ ionophore ionomycin (0.1 µM) on eryptosis. The clofazimine induced annexin-V-binding was, however, completely abrogated by combined Ca²⁺ removal and addition of quinacrine. Conclusion: Clofazimine stimulates phospholipid scrambling of the erythrocyte cell membrane, an effect in part dependent on entry of extracellular Ca²⁺, paralleled by cellular energy depletion and sensitive to phospholipase A₂ inhibitor quinacrine.

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Section: Discussionmentioning

confidence: 66%

Clofazimine Induced Suicidal Death of Human Erythrocytes

Officioso

Alzoubi

Manna

et al. 2015

Cell Physiol Biochem

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“…For paucibacillary treatment, the recommended all oral treatment combination is rifampicin plus dapsone, for multibacillary treatment; this combination should be extended with clofazimine (Table 3). Various PK studies have been conducted on dapsone [56–59], clofazimine [60], and specific drug–drug interaction studies focusing on the interactions between dapsone, clofazimine, and rifampicine using various formulations [61–64]. A few studies focused on thalidomide pharmacokinetics [65, 66], which is currently largely considered obsolete because of its teratogenicity.…”

Section: Resultsmentioning

confidence: 99%

“…Pharmacokinetics of clofazimine has been analyzed using compartmental methods after various fed and fasting conditions to determine food effects and the relative bioavailability [60]. A high-fat meal increased bioavailability significantly and was therefore considered preferable, although exposure–effect relationships for clofazimine in leprosy have not been properly established.…”

Section: Resultsmentioning

confidence: 99%

Lack of Clinical Pharmacokinetic Studies to Optimize the Treatment of Neglected Tropical Diseases: A Systematic Review

Verrest

Dorlo

2016

Clin Pharmacokinet

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IntroductionNeglected tropical diseases (NTDs) affect more than one billion people, mainly living in developing countries. For most of these NTDs, treatment is suboptimal. To optimize treatment regimens, clinical pharmacokinetic studies are required where they have not been previously conducted to enable the use of pharmacometric modeling and simulation techniques in their application, which can provide substantial advantages.ObjectivesOur aim was to provide a systematic overview and summary of all clinical pharmacokinetic studies in NTDs and to assess the use of pharmacometrics in these studies, as well as to identify which of the NTDs or which treatments have not been sufficiently studied.MethodsPubMed was systematically searched for all clinical trials and case reports until the end of 2015 that described the pharmacokinetics of a drug in the context of treating any of the NTDs in patients or healthy volunteers.ResultsEighty-two pharmacokinetic studies were identified. Most studies included small patient numbers (only five studies included >50 subjects) and only nine (11 %) studies included pediatric patients. A large part of the studies was not very recent; 56 % of studies were published before 2000. Most studies applied non-compartmental analysis methods for pharmacokinetic analysis (62 %). Twelve studies used population-based compartmental analysis (15 %) and eight (10 %) additionally performed simulations or extrapolation. For ten out of the 17 NTDs, none or only very few pharmacokinetic studies could be identified.ConclusionsFor most NTDs, adequate pharmacokinetic studies are lacking and population-based modeling and simulation techniques have not generally been applied. Pharmacokinetic clinical trials that enable population pharmacokinetic modeling are needed to make better use of the available data. Simulation-based studies should be employed to enable the design of improved dosing regimens and more optimally use the limited resources to effectively provide therapy in this neglected area.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0467-3) contains supplementary material, which is available to authorized users.

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“…Ritonavir has the potential to reduce plasma concentrations of the active metabolite of albendazole [17]. In two sequential studies, healthy male volunteers were administered either a single oral dose of 400 mg of albendazole or 1000 mg of mebendazole.…”

Section: Potential Interactions With Antiretroviralsmentioning

confidence: 99%

“…A trend towards an increase in mebendazole exposure after short-term intake of ritonavir was seen but long-term administration resulted in a significant decrease in mebendazole AUC (57%) and C max (59%). These reductions for both albendazole and mebenazole are most likely due to ritonavir mediated induction of metabolizing enzymes (CYP2C9, CYP1A2, UGT) or transporters although changes in absorption are possible [17]. The clinical significance of this is unknown but may result in decreased efficacy especially in the treatment of systemic helminthiasis.…”

Section: Potential Interactions With Antiretroviralsmentioning

confidence: 99%

Drug–drug interactions between antiretrovirals and drugs used in the management of neglected tropical diseases

Seden

Khoo

Back

et al. 2013

Aids

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The group of infections known as the neglected tropical diseases (NTDs) collectively affect one billion people worldwide, equivalent to one-sixth of the world's population. The NTDs cause severe physical and emotional morbidity, and have a profound effect on cycles of poverty; it is estimated that NTDs account for 534 000 deaths per year. NTDs such as soil-transmitted helminth infections and the vector-borne protozoal infections leishmaniasis and trypanosomiasis occur predominantly in the most economically disadvantaged and marginalized communities. It is estimated that all low-income countries harbour at least five of the NTDs simultaneously. NTDs are neglected because they do not individually rank highly in terms of mortality data, and because they affect populations with little political voice. There is considerable geographic overlap between areas with high prevalence of NTDs and HIV, raising the possibility of complex polypharmacy and drug-drug interactions. Antiretrovirals pose a particularly high risk for potential drug-drug interactions, which may be pharmacokinetic or pharmacodynamic in nature and can result in raising or lowering plasma or tissue concentrations of co-prescribed drugs. Elevated drug concentrations may be associated with drug toxicity and lower drug concentrations may be associated with therapeutic failure. The aim of this paper is to review the currently available data on interactions between antiretrovirals and drugs used in the management of NTDs. It is intended to serve as a resource for policy makers and clinicians caring for these patients, and to support the recent WHO 2020 Roadmap and the 2012 London Declaration on NTDs.

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Pharmacokinetics and relative bioavailability of clofazimine in relation to food, orange juice and antacid

Cited by 75 publications

References 9 publications

Clofazimine Induced Suicidal Death of Human Erythrocytes

Clofazimine Induced Suicidal Death of Human Erythrocytes

Lack of Clinical Pharmacokinetic Studies to Optimize the Treatment of Neglected Tropical Diseases: A Systematic Review

Drug–drug interactions between antiretrovirals and drugs used in the management of neglected tropical diseases

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