Bioavailability Of Rifampicin Research Articles

The impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs.

In South Africa, an estimated 11% of the population have high alcohol use, a major risk factor for TB. Alcohol and other substance use are also associated with poor treatment response, with a potential mechanism being altered TB drug pharmacokinetics. To investigate the impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs in participants with pulmonary TB. We prospectively enrolled participants ≥15 years old, without HIV, and initiating drug-susceptible TB treatment in Worcester, South Africa. Alcohol use was measured via self-report and blood biomarkers. Other illicit substances were captured through a urine drug test. Plasma samples were drawn 1 month into treatment pre-dose, and 1.5, 3, 5 and 8 h post-dose. Non-linear mixed-effects modelling was used to describe the pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol. Alcohol and drug use were tested as covariates. The study included 104 participants, of whom 70% were male, with a median age of 37 years (IQR 27-48). Alcohol use was high, with 42% and 28% of participants having moderate and high alcohol use, respectively. Rifampicin and isoniazid had slightly lower pharmacokinetics compared with previous reports, whereas pyrazinamide and ethambutol were consistent. No significant alcohol use effect was detected, other than 13% higher ethambutol clearance in participants with high alcohol use. Methaqualone use reduced rifampicin bioavailability by 19%. No clinically relevant effect of alcohol use was observed on the pharmacokinetics of first-line TB drugs, suggesting that poor treatment outcome is unlikely due to pharmacokinetic alterations. That methaqualone reduced rifampicin means dose adjustment may be beneficial.

Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.

The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.

Targeted brain delivery of RVG29-modified rifampicin-loaded nanoparticles for Alzheimer's disease treatment and diagnosis.

Alzheimer's disease (AD) is an aging‐related neurodegenerative disease. The main pathological features of AD are β‐amyloid protein (Aβ) deposition and tau protein hyperphosphorylation. Currently, there are no effective drugs for the etiological treatment of AD. Rifampicin (RIF) is a semi‐synthetic broad‐spectrum antibiotic with anti‐β‐amyloid deposition, anti‐inflammatory, anti‐apoptosis, and neuroprotective effects, but its application in AD treatment has been limited for its strong hydrophobicity, high toxicity, short half‐life, low bioavailability, and blood–brain barrier hindrance. We designed a novel brain‐targeted and MRI‐characteristic nanomedicine via loading rabies virus protein 29 (RVG29), rifampicin, and Gd on poly (l‐lactide) nanoparticles (RIF@PLA‐PEG‐Gd/Mal‐RVG29). The cytotoxicity assay demonstrated that RIF@PLA‐PEG‐Gd/Mal‐RVG29 had favorable biocompatibility and security. Fluorescence imaging in vivo showed that PLA‐PEG‐Gd/Mal‐RVG29 could deliver rifampicin into the brain by enhancing cellular uptake and brain targeting performance, leading to improvement of the bioavailability of rifampicin. In in vivo study, RIF@PLA‐PEG‐Gd/Mal‐RVG29 improved the spatial learning and memory capability of APP/PS1 mice in the Morris water maze, as compared to rifampicin. Immunofluorescence, TEM, immunoblotting, and H&E staining revealed that RIF@PLA‐PEG‐Gd/Mal‐RVG29 reduced Aβ deposition in hippocampal and cortex of APP/PS1 mice, improved the damage of synaptic ultrastructure, increased the expression level of PSD95 and SYP, as well as reduced the necrosis of neurons. These findings suggest that RIF@PLA‐PEG‐Gd/Mal‐RVG29 may be an effective strategy for the treatment of AD.

Impact of diabetes mellitus on rifampicin's plasma concentration and bioavailability in patients with tuberculosis: A systematic review and meta-analysis study

To assess the impact of diabetes mellitus on plasma concentration and bioavailability of rifampicin. Web of Science, Cochrane Library, PubMed and Scopus databases were screened until September 2020 on studies reported rifampicin's plasma concentration, bioavailability among diabetic tuberculosis patients and non-diabetic tuberculosis patients. According to the presence or absence of heterogeneity, the pooled estimate was operated by a random or fixed effect model. Sensitivity analysis or subgroup analysis were conducted. Attributed risk fraction of diabetes mellitus in the incidence of low rifampicin's plasma concentration 2-h after administration was calculated. Seventeen studies including 3478 tuberculosis patients were included in this study. Diabetic tuberculosis patients had 1.59 folds incidence of low rifampicin's plasma concentration 2-h after administrations (risk ratio 1.59, 95% confidence interval (1.16, 2.19), p = 0.004) and lower rifampicin's plasma concentration 2-h after administrations (mean difference -1.4, 95% confidence interval (-2.65,-0.15), p = 0.03) compared with non-diabetic tuberculosis patients. The attributed risk fraction of diabetes mellitus in the incidence of low rifampicin's plasma concentration 2-h after administration was 37%. There were no significant difference in rifampicin's maximum plasma concentration, event of low maximum plasma concentration, bioavailability and half-life between both groups. Diabetes mellitus attributed with 37% of low rifampicin's plasma concentration 2-h after administration but not influenced rifampicin's maximum plasma concentration, bioavailability and half-life. The negative effect of diabetes on plasma concentration 2hours after administration was influenced by diabetes management, income level, type of tuberculosis and its recurrence.

Effect of efavirenz-based ART on the pharmacokinetics of rifampicin and its primary metabolite in patients coinfected with TB and HIV.

ObjectivesTo evaluate the effects of concomitant efavirenz-based ART and genetic polymorphism on the variability in rifampicin and 25-desacetylrifampicin pharmacokinetics.Patients and methodsPlasma concentrations of rifampicin and 25-desacetylrifampicin from 63 patients coinfected with TB and HIV were analysed by LC-MS/MS followed by non-linear mixed-effects modelling. Patients were genotyped for SLCO1B1 (463 C>A, 388 A>G, 11187 G>A, rs4149015, 521 T>C and 1436 G>C) and SLCO1B3 (334 T>G).ResultsOne-compartment disposition models described the observations adequately. The oral clearances of rifampicin and 25-desacetylrifampicin were 140% and 110% higher, respectively, in patients on concomitant efavirenz-based ART. Rifampicin bioavailability was also lower in patients on concomitant ART. Further, although not included in the final model, a lower relative bioavailability in carriers of WT SLCO1B3 334 T>G compared with carriers of mutations in the genotype was estimated.ConclusionsThe results presented indicate both pre-systemic and systemic induction by efavirenz-based ART affecting rifampicin pharmacokinetics. The described drug–drug interaction has a clinical impact on rifampicin exposure prior to steady state and may impact the early bactericidal activity in patients on efavirenz-based ART.

SUSTAINED RELEASE APPROACHES TOWARDS THE CHEMOTHERAPY OF TUBERCULOSIS

Tuberculosis is a most important killer of young adults worldwide and the global blight of multi-drug resistant tuberculosis is reaching epidemic proportions. It is endemic in most developing countries and resurgent in developed and developing countries with high rates of human immune insufficiency virus infection. This article reviews the current situation in terms of drug delivery approaches for tuberculosis chemotherapy. A number of novel implant, microparticulate and a variety of other carrier-based drug delivery systems incorporating the principal anti-tuberculosis agents have been made-up that either target the site of tuberculosis infection or reduce the dosing occurrence with the aim of improving patient outcomes. These developments in drug delivery represent attractive options with noteworthy merit, on the other hand, there is a necessity to manufacture an oral system, which directly addresses issues of unacceptable rifampicin bioavailability in fixed-dose combinations. This is fostered by the need to deliver medications to patients more efficiently and with fewer side effects, especially in developing countries. The fabrication of a polymeric once-daily oral multi particulate fixed-dose combination of the principal anti-tuberculosis drugs, which attains segregated delivery of rifampicin and isoniazid for improved rifampicin bioavailability, could be a step in the right direction in addressing issues of treatment failure due to patient non-compliance.

Pharmacokinetics of rifampicin after repeated intra-tracheal administration of amorphous and crystalline powder formulations to Sprague Dawley rats

Rifampicin is one of the key drugs used to treat tuberculosis and is currently used orally. The use of higher oral doses of rifampicin is desired for better therapeutic efficacy, but this is accompanied by increased risk of systemic toxicity thus limiting its recommended oral dose to 10 mg/kg per day. Inhaled delivery of rifampicin is a potential alternative mode of delivery, to achieve high drug concentrations in both the lung and potentially the systemic circulation. In addition, rifampicin exists either as amorphous or crystalline particles, which may show different pharmacokinetic behaviour. However, disposition behaviour of amorphous and crystalline rifampicin formulations after inhaled high-dose delivery is unknown. In this study, rifampicin pharmacokinetics after intra-tracheal administration of carrier-free, amorphous and crystalline powder formulations to Sprague Dawley rats were evaluated. The formulations were administered once daily for seven days by oral, intra-tracheal and oral plus intra-tracheal delivery, and the pharmacokinetics were studied on day 0 and day 6. Intra-tracheal administration of the amorphous formulation resulted in a higher area under the plasma concentration curve (AUC) compared to the crystalline formulation. For both formulations, the intra-tracheal delivery led to significantly higher AUC compared to the oral delivery at the same dose suggesting higher rifampicin bioavailability from the inhaled route. Increasing the intra-tracheal dose resulted in a more than dose proportional AUC suggesting non-linear pharmacokinetics of rifampicin from the inhaled route. Upon repeated administration for seven days, no significant decrease in the AUCs were observed suggesting the absence of rifampicin induced enzyme auto-induction in this study. The present study suggests an advantage of inhaled delivery of rifampicin in achieving higher drug bioavailability compared to the oral route.

Targeted Brain Delivery of RVG29-Modified Rifampicin-Loaded Nanoparticles for Treatment and Diagnosis of Alzheimer Disease

Alzheimer's disease (AD) is a neurodegenerative disease related to age. The main pathological features of AD are β-amyloid protein (Aβ) deposition and tau protein hyperphosphorylation. Currently, there are not an effective drug for the etiological treatment of AD. Rifampicin (RIF) is a semi-synthetic broad-spectrum antibiotic with anti-β-amyloid deposition, anti-inflammatory, anti-apoptosis and neuroprotective effects, but its application in AD treatment has been limited by its strong hydrophobicity, high toxicity, short half-life, low bioavailability and blood-brain barrier (BBB) hindrance. We designed a novel brain-targeted and MRI-characteristic nanomedicine through loading rabies virus protein 29 (RVG29), rifampicin and Gd on poly(L-lactide) nanoparticles (RIF@PLA-PEG-Gd/Mal-RVG29). The cytotoxicity assay demonstrated that RIF@PLA-PEG-Gd/Mal-RVG29 had good biocompatibility and security. The results of cellular uptake and fluorescence in vivo imaging showed that PLA-PEG-Gd/Mal-RVG29 could deliver rifampicin into brain by enhancing cellular uptake and brain targeting performance, so that improving the bioavailability of rifampicin. In vivo study, compared with rifampicin, RIF@PLA-PEG-Gd/Mal-RVG29 improved the spatial learning and memory capability of APP/PS1 mice in the Morris water maze. Immunofluorescence, TEM, immunoblotting and HE test showed that RIF@PLA-PEG-Gd/Mal-RVG29 could reduce Aβ deposition in hippocampal and cortex of APP/PS1 mice, improve the damage of synaptic ultrastructure, increase the expression level of PSD95 and SYP, as well as reduce the necrosis of neurons. These findings suggest that RIF@PLA-PEG-Gd/Mal-RVG29 may be an effective strategy for the treatment and diagnosis of AD.

Anti-tuberculosis site-specific oral delivery system that enhances rifampicin bioavailability in a fixed-dose combination with isoniazid.

The in vivo release segregation of rifampicin (RIF) and isoniazid (INH) has been proposed as a strategy to avoid RIF acid degradation, which is known as one of the main factors for reduced RIF bioavailability and can result in drug-resistant tuberculosis. So far, this strategy has been scarcely explored. The aims of this study were to investigate the stability and bioavailability of RIF after combination of a very fast release matrix of RIF with a sustained delivery system of INH. A series of INH-alginic acid complexes (AA-INH) was obtained and characterized. Independent and sequential release profile of AA-INH at biorrelevant media of pH 1.20 and 6.80 was explored. In addition, AA-INH was combined with a RIF-carboxymethylcellulose very fast release complex (CMC-RIF) obtained previously and subjected to acid dissolution assays to evaluate RIF acid stability and determine RIF and INH dissolution efficiencies. Finally, a pharmacokinetic study in dogs was carried out. The AA-INH was easily obtained in solid-state. Their characterization revealed its ionic nature, with a loading capacity of around 30%. The dissolution efficiencies (15min) confirmed release segregation in acid media with 7.8 and 65.6% for AA-INH and CMC-RIF, respectively. INH release rate from the AA-INH system was slow in acid media and increased in simulated intestinal media. The complete release of INH was achieved after 2h in simulated intestinal media in the sequential release experiments. The acid degradation of RIF was significantly reduced (36.7%) when both systems were combined and oral administration to dogs revealed a 42% increase in RIF bioavailability. In conclusion, CMC-RIF and AA-INH may be useful for the formulation of a site-specific solid dosage form to overcome some of the main obstacles in tuberculosis treatment. Graphical abstract.

The War against Tuberculosis: A Review of Natural Compounds and Their Derivatives.

Tuberculosis (TB), caused by the bacterial organism Mycobacterium tuberculosis, pose a major threat to public health, especially in middle and low-income countries. Worldwide in 2018, approximately 10 million new cases of TB were reported to the World Health Organization (WHO). There are a limited number of medications available to treat TB; additionally, multi-drug resistant TB and extensively-drug resistant TB strains are becoming more prevalent. As a result of various factors, such as increased costs of developing new medications and adverse side effects from current medications, researchers continue to evaluate natural compounds for additional treatment options. These substances have the potential to target bacterial cell structures and may contribute to successful treatment. For example, a study reported that green and black tea, which contains epigallocatechin gallate (a phenolic antioxidant), may decrease the risk of contracting TB in experimental subjects; cumin (a seed from the parsley plant) has been demonstrated to improve the bioavailability of rifampicin, an important anti-TB medication, and propolis (a natural substance produced by honeybees) has been shown to improve the binding affinity of anti-TB medications to bacterial cell structures. In this article, we review the opportunistic pathogen M. tuberculosis, various potential therapeutic targets, available therapies, and natural compounds that may have anti-TB properties. In conclusion, different natural compounds alone as well as in combination with already approved medication regimens should continue to be investigated as treatment options for TB.

Vesicular elastic liposomes for transdermal delivery of rifampicin: In-vitro, in-vivo and in silico GastroPlus™ prediction studies

This study investigated enhanced bioavailability and sustained delivery of transdermally delivered rifampicin (RIF) in elastic liposomes (ELs). F3, F5, and F7 were optimized formulations comprising of 200, 140 and 80 mg of tween 80, respectively, and PhospholiponⓇ 90 G (300 mg). They were optimized based on in vitro and ex vivo parameters. Using the Franz diffusion cell, an ex vivo study was conducted by utilizing the rat skin for permeation profiles. Also, pharmacokinetic parameters, mechanistic evaluation of penetration, and histopathological investigation were conducted in the rat model for complete dynamic evaluations. Vesicle sizes of suspensions and gels were found to be similar whereas zeta potential of gel attained more negativity due to acidic carbopol. Permeation parameters of gels were significantly (p < 0.05) higher compared to respective ELs due to increased residence time and the composition of the formulations (ethanol, tween 80, d-limonene and lipid). Bioavailability of RIF (F5 gel) was improved by transdermal absorption as evidenced with AUC0→24 of transdermal F5 gel (56.23±2.7 µg.hr/mL) and oral drug suspension (41.71±5.2 µg.hr/mL). A lower value of transdermal Cmax (6.9 ± 0.8 µg/mL) validated sustained delivery for improved tuberculosis management than oral delivery (10.5 ± 1.46.9 ± 0.8 µg/mL). In vivo skin interaction, biopsy and in silico prediction studies corroborated suitable alternative for sustained and prolonged delivery of RIF with high patient compliance to control cutaneous tuberculosis and related infections.

Improved Stability of Rifampicin in the Presence of Gastric-Resistant Isoniazid Microspheres in Acidic Media.

The degradation of rifampicin (RIF) in an acidic medium to form 3-formyl rifamycin SV, a poorly absorbed compound, is accelerated in the presence of isoniazid, contributing to the poor bioavailability of rifampicin. This manuscript presents a novel approach in which isoniazid is formulated into gastric-resistant sustained-release microspheres and RIF into microporous floating sustained-release microspheres to reduce the potential for interaction between RIF and isoniazid (INH) in an acidic environment. Hydroxypropyl methylcellulose acetate succinate and Eudragit® L100 polymers were used for the manufacture of isoniazid-loaded gastric-resistant sustained-release microspheres using an o/o solvent emulsification evaporation approach. Microporous floating sustained-release microspheres for the delivery of rifampicin in the stomach were manufactured using emulsification and a diffusion/evaporation process. The design of experiments was used to evaluate the impact of input variables on predefined responses or quality attributes of the microspheres. The percent degradation of rifampicin following 12 h dissolution testing in 0.1 M HCl pH 1.2 in the presence of isoniazid gastric-resistant sustained-release microspheres was only 4.44%. These results indicate that the degradation of rifampicin in the presence of isoniazid in acidic media can be reduced by encapsulation of both active pharmaceutical ingredients to ensure release in different segments of the gastrointestinal tract, potentially improving the bioavailability of rifampicin.

Multicomponent crystals of anti-tuberculosis drugs: a mini-review.

Tuberculosis (TB) is the leading cause of death from a single infectious agent globally. Some of the early research on TB treatment indicated drug resistance as one of the key challenges in fighting this disease. The discovery that administering two or more drugs simultaneously could lead to much more effective treatment, with reduced drug resistance and shorter periods of chemotherapy, was, therefore, a very significant breakthrough in TB drug research. Pursuant to this discovery, the World Health Organisation (WHO) recommended TB treatment employing fixed-dose combinations (FDCs) containing first line anti-TB drugs; rifampicin, isoniazid, pyrazinamide, streptomycin and ethambutol. Regardless, certain challenges associated with FDCs remain and these include chemical instability and reduced bioavailability of rifampicin. Therefore, some research effort has been directed towards finding ways to deal with these challenges. One such effort involves the use of pharmaceutical co-crystals of the active pharmaceutical ingredients. Consequently, several pharmaceutical co-crystals of isoniazid and pyrazinamide have been reported. This paper aims at reviewing the multicomponent crystal structures of two first-line anti-TB drugs; isoniazid and pyrazinamide. The review will first set out a brief history of the disease, milestones in TB chemotherapy and the challenges associated with current treatment regimens. This will then be followed by a brief introduction to pharmaceutical co-crystals and how they can improve the physical and chemical properties of the active pharmaceutical ingredients. Secondly, multicomponent crystals of the two active pharmaceutical ingredients will be analysed by manual inspection for common supramolecular synthons between the drug molecules as well as between drug molecules and co-formers. Lastly; stability, solubility and dissolution experiments carried out on the pharmaceutical co-crystals of pyrazinamide and isoniazid will be analysed to gain insights into progress made with regards to improving stability and solubility of the active pharmaceutical ingredients.

Enhancement of rifampicin bioavailability by immune enhancing nutrient (Ascorbic acid) as chitosan nanoparticles for tuberculosis therapy

Enhancement of rifampicin bioavailability by immune enhancing nutrient (Ascorbic acid) as chitosan nanoparticles for tuberculosis therapy

Rifampicin Bioavailability in Fixed-Dose Combinations for Tuberculosis Treatment: Evidence and Policy Actions

Purpose: The pharmacokinetics (PK) of anti-tuberculosis drugs, including their bioavailability (BA), significantly impacts the efficacy and effectiveness of tuberculosis (TB) treatment regimens. Rifampicin, one of the most important drugs in the treatment of drug-sensitive tuberculosis, has been used increasingly in fixed-dose combinations (FDCs). This paper reviews and analyzes available data on BA and PK of rifampicin with a focus on FDCs, from published studies and reports. Methods: Using PubMed as the primary database, Cochrane and other relevant databases, a systematic review of literature was conducted to identify studies on the bioavailability and efficacy of rifampicin in FDCs versus single drug formulations. A number of keywords including “bioavailability”, “rifampicin”, “fixed dose combinations”, and “pharmacokinetics” were used in various combinations. The search covered the period 1980 to 2016. Priority was given to articles on rifampicin bioavailability in fixed dose combinations used in the program setting, and human studies that used the World Health Organization (WHO) approved BA/PK protocol and sample size (≥22 patients). Findings: More than 450 original peer-reviewed articles, reviews and reports, were assessed for this analysis. Eleven papers, which included data from high-TB-burden countries (South Africa, India, and China), raised significant concerns about rifampicin bioavailability within FDCs; the authors of the studies discussed multiple factors associated with low bioavailability, including drug formulation and quality, storage environment, patient factors, and concomitant diseases. Implications: Recent studies and reviews point to the problem of low bioavailability of rifampicin in fixed dose combinations. However, in the field, it remains a hidden or unrecognized factor leading to poor treatment outcomes. It is difficult to study the issue thoroughly unless there is awareness among TB program personnel of its existence, and adequate laboratory and research support is available to national tuberculosis programs (NTPs). In stemming the tide of tuberculosis multi-drug resistance (MDR) and extensive drug resistance (XDR), it is paramount to ensure that rifampicin bioavailability is adequate in FDCs, and to detect and address any deviation from recommended target ranges. There is a need for strategies to minimize the undesirable clinical effects of reduced rifampicin bioavailability in FDCs, and for effective utilization of quality-assured drugs within NTPs programs; these can help NTPs support effective case management in line with the international TB care standards, while taking into consideration the factors affecting drug absorption and therapeutic concentration.

Effects of tannins in Galla Chinensis on pharmacokinetics of rifampicin in vivo and in vitro

This study was aimed to explore the effects of tannins in Galla Chinensis on rifampicin in vivo. In the experiment in vitro, UV spectrophotometry and high performance liquid chromatography (HPLC) were used to investigate the solubility of rifampin in pH 1.3, 6.8, artificial gastric juice environment and artificial intestinal fluid environment as well as the effects of tannins on solubility of rifampin in the above conditions. In the experiment in vivo, the process of rifampicin was studied after intragastric administration of rifampicin and rifampicin+ tannins in Galla Chinensis, and then the pharmacokinetic parameters were calculated. The results showed that rifampicin was constantly precipitated in the artificial gastric juice environment over time, and nearly 85% of the rifampicin was precipitated after 6 hours; it showed a good solubility in the artificial intestinal juice environment. After adding the said tannins, the concentration of rifampicin was decreased significantly in both environments, and the concentration of rifampicin in artificial intestinal juice remained relatively stable, while that in artificial gastric juice remained the original downward trend. The pharmacokinetic parameters displayed that as compared with rifampicin alone, AUC0-t and Cmax were decreased significantly, MRT0-t slowed down significantly, Tmax doubled to 7.0 h and the bioavailability was only 31.65% in rifampicin + tannins in Galla Chinensis group. The experiment indicated rifampicin had a poor solubility in acidic environment and the decrease of bioavailability of rifampicin when in combination with tannin was mainly due to the reduction of rifampicin solubility in intestinal tract by complexation of rifampicin with tannin, thus affecting its absorption in intestinal tract. Therefore, rifampicin and the Chinese herbal medicines or Chinese patent medicines rich in tannin should not be taken simultaneously.

Formulation, optimization, and characterization of rifampicin-loaded solid lipid nanoparticles for the treatment of tuberculosis

Mycobacterium tuberculosis, being the causative infectious agent, is the leading cause of death worldwide amongst the infectious disease. The low bioavailability of rifampicin (RIF), one of the vital constituent of antitubercular therapy, instigates an urge to develop nanocarrier, which can prevent its degradation in the acidic pH of the stomach. Solid lipid nanoparticles (SLNs) have been proven to be promising versatile platform for oral delivery of lipophilic drugs. Therefore, the current investigation demonstrates development of RIF-loaded solid lipid nanoparticles (RIF-SLNs) using high-pressure homogenization technique by employing a three-level, three-factor Box–Behnken design. Concentration of drug, concentration of emulsifier, and homogenization pressure were selected as an independent variables, and %drug loading (%DL), %entrapment efficiency (%EE), and particle size were selected as dependent variables. The developed RIF-SLNs were characterized for particle size, polydispersity index, zeta potential, %EE, %DL, differential scanning calorimetry, X-ray diffraction, and TEM analysis. The mean diameter of RIF-SLNs was found to be 456 ± 11 nm, %EE of 84.12 ± 2.78%, and %DL of 15.68 ± 1.52%. The in vitro lipolysis experiments revealed that RIF-SLNs stabilized using poloxamer 188, exhibited antilipolytic effect. Furthermore, the in vitro GI stability studies (at pH 1.2, pH 4.5, pH 6.8, and pH 7.4) revealed that the developed system could withstand various gastrointestinal tract media. The in vitro dissolution studies depicted biphasic drug release profile for drug-loaded SLNs revealing best fit with Weibull model. The accelerated stability studies for 6 months does not revealed any significant change in characteristics of developed RIF-SLNs.

High dose oral and intravenous rifampicin for improved survival from adult tuberculous meningitis: a phase II open-label randomised controlled trial (the RifT study)

Background: Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration. With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis. Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined. Protocol: We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin on survival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment. Discussion: HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial. Trial registration: ISRCTN42218549 (24 th April 2018)

High dose oral and intravenous rifampicin for improved survival from adult tuberculous meningitis: a phase II open-label randomised controlled trial (the RifT study).

Background: Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration. With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis. Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined. Protocol: We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin onsurvival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment. Discussion: HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial. Trial registration: ISRCTN42218549 (24 th April 2018).

Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.

SETTING:Rifampicin (RMP) drives treatment response in drug-susceptible tuberculosis. Low RMP concentrations increase the risk of poor outcomes, and drug quality needs to be excluded as a contributor to low RMP exposure.OBJECTIVES AND DESIGN:We performed an open-label, three-way cross-over study of three licensed RMP-containing formulations widely used in South Africa to evaluate the bioavailability of RMP in a two-drug fixed-dose combination tablet (2FDC) and a four-drug FDC (4FDC) against a single-drug reference. RMP dosed at 600 mg was administered 2 weeks apart in random sequence. Plasma RMP concentrations were measured pre-dose and 1, 2, 3, 4, 6, 8 and 12 h post-dose. The area under the concentration-time curve (AUC0–12) of the FDCs was compared to the single drug reference. Simulations were used to predict the impact of our findings.RESULTS:Twenty healthy volunteers (median age 22.8 years, body mass index 24.2 kg/m2) completed the study. The AUC0–12 of the 4FDC/reference (geometric mean ratio [GMR] 78%, 90%CI 69–89) indicated an average 20% reduction in RMP bioavailability in the 4FDC. The 2FDC/reference (GMR 104%, 90%CI 97–111) was bioequivalent. Simulations suggested dose adjustments to compensate for the poor bioavailability of RMP with the 4FDC, and revised weight-band doses to prevent systematic underdosing of low-weight patients.CONCLUSION:Post-marketing surveillance of in vivo bioavailability of RMP and improved weight band-based dosing are recommended.