Bioavailability Of Rifampicin Research Articles

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.

Markers of gut dysfunction do not explain low rifampicin bioavailability in HIV-associated TB.

Rifampicin is the key drug responsible for sterilizing activities in the first-line TB treatment regimen. Damage to the gut during acute and chronic HIV infection may inhibit drug absorptive capacity. We sought to test the hypothesis that markers of intestinal damage, bacterial translocation and systemic immune activation would relate to rifampicin bioavailability among HIV/TB patients. We conducted a prospective cohort study of rifampicin pharmacokinetics in HIV/TB patients in Gaborone, Botswana. We performed two intensively sampled pharmacokinetic visits, before and after ART initiation. Non-linear mixed-effects modelling was performed to determine whether variability in markers of gut damage, microbial translocation or systemic immune activation contributed to variability in rifampicin bioavailability before and after the initiation of ART. We enrolled 40 HIV/TB patients in the first pharmacokinetic visit and 24 patients returned for the second pharmacokinetic visit after initiating ART. Low rifampicin exposure, as defined by the maximum serum concentration, was observed in 40% of patients prior to initiating ART and 46% of patients after initiating ART. In the non-linear mixed-effects model, we did not observe significant covariate effects of markers of gut damage, microbial translocation or immune activation on rifampicin bioavailability before and after ART initiation. Markers of intestinal damage, microbial translocation and systemic immune activation did not explain variability in rifampicin bioavailability. The a priori identification of HIV/TB patients at risk for low rifampicin concentrations remains a challenge, supporting a role for therapeutic drug monitoring during HIV/TB therapy.

Pharmacological indices and pulmonary distribution of rifampicin after repeated oral administration in healthy foals.

The treatment of equine lung infections by Rhodococcus equi with rifampicin is empirically based because pharmacokinetic/pharmacodynamic (PK/PD) indices and pivotal clinical outcome data are not available. To evaluate the pharmacokinetics and pulmonary distribution of rifampicin into epithelial lining fluid (ELF) and bronchoalveolar lavage cells (BALC) to predict antimicrobial activity in the lung using PK/PD indices. Controlled, randomised, two-period, crossover, repeated-dose study with an initial arm to measure disposition after i.v. administration of rifampicin. Pharmacokinetics and lung distribution were evaluated in six healthy foals treated with 10 mg/kg bwt rifampicin i.v. (initial arm) and with repeated oral doses of rifampicin at 10 mg/kg bwt and 20 mg/kg bwt once per day for 10 days (crossover arms). ELF and BALC were sampled by bronchoalveolar lavage 24 h after the last oral dosing. Rifampicin and 25-O-desacetyl rifampicin were quantified using liquid chromatography tandem-mass spectrometry. Enzyme induction by rifampicin was confirmed by evaluation of plasma 4β-OH-cholesterol:cholesterol ratios. The distribution volume of rifampicin administered i.v. was ~0.85 L/kg. Terminal elimination half-life was ~11 h. Orally given rifampicin was slowly absorbed (Tmax , range: 2.5-8.0 h) and eliminated with apparent half-lives of ~6-8 h. Trough concentrations in ELF and BALC were 1.01 ± 0.20 μg/mL and 1.25 ± 0.29 μg/mL, respectively, after 10 mg/kg bwt rifampicin and 2.71 ± 1.25 μg/mL and 3.09 ± 1.63 μg/mL, respectively, after 20 mg/kg bwt rifampicin. The average ratios of area under the plasma concentration time curve during an administration interval of 24 h (AUC0-24 h ) to minimum inhibitory concentration (MIC) were 145 and 322 h, respectively, for less susceptible strains of R. equi (MIC90 : 0.5 μg/mL). The clearance and bioavailability of rifampicin after repeated oral dosing were not evaluated. Treatment with rifampicin at 10 mg/kg bwt administered once per day is suitable to generate drug concentrations above the MIC90 in the ELF and BALC of foals. Future clinical studies with rifampicin in combination with macrolide antibiotics with low drug interaction potential are required to translate the PK/PD indices into protocols for the treatment of R. equi lung infections.

Very fast dissolving acid carboxymethylcellulose-rifampicin matrix: Development and solid-state characterization

One of the main obstacles to the successful treatment of tuberculosis is the poor and variable oral bioavailability of rifampicin (RIF), which is mainly due to its low hydrophilicity and dissolution rate. The aim of this work was to obtain a hydrophilic new material that allows a very fast dissolution rate of RIF and therefore is potentially useful in the development of oral solid dosage forms.The acid form of carboxymethylcellulose (CMC) was co-processed with RIF by solvent impregnation to obtain CMC-RIF powder, which was characterized by polarized optical microscopy, powder x-ray diffraction, DSC-TGA, hot stage microscopy, 13C and 15N solid-state NMR and FT-IR spectroscopy. In addition, the CMC-RIF matrices were subjected to water uptake and dissolution studies to assess hydrophilicity and release kinetics.CMC-RIF is a crystalline solid dispersion. Solid-state characterization indicated that no ionic interaction occurred between the components, but RIF crystallized as a zwitterion over the surface of CMC, which drastically increased the hydrophilicity of the solid. The CMC-RIF matrices significantly improved the water uptake of RIF and disintegrated in a very short period immediately releasing RIF. As CMC improves the hydrophilicity and delivery properties of RIF, CMC-RIF is very useful in the design of oral solid dosage forms with very fast dissolution of RIF, either alone or in combination with other antitubercular drugs.

Effect of cholecystectomy on bile acids as well as relevant enzymes and transporters in mice: Implication for pharmacokinetic changes of rifampicin

Background and purposeLong-term medical consequences of cholecystectomy are believed to be uncommon. It has been reported that bile acids (BAs) changed after cholecystectomy. As important signaling molecules, the alternations of BAs might favour the regulatory effect on enzymes and transporters involved in BAs physiological homeostasis at the transcriptional level, which could lead to pharmacokinetic changes of drugs. Here, we determined the effect of cholecystectomy on BAs, relevant enzymes and transporters and pharmacokinetic parameters of rifampicin, and explored the potential mechanisms at the transcriptional regulatory level via nuclear receptors. MethodsParameters of BAs in different specimens, mRNA and protein expression of enzymes, transporters and nuclear receptors that relate to BAs homeostasis in liver and ileum, and the pharmacokinetic character of rifampicin were measured in sham-operated and cholecystectomized mice. Key resultsCholecystectomy associated with considerable decreased BAs pool size that could attribute to increased fecal excretion. Most notably, as the Fxr and Pxr ligands, the alternations of hepatic and ileal individual BAs affected expression of enzymes Cyp3a11 and transporters Ntcp and Bsep in liver and Asbt in ileum significantly following cholecystectomy. Eventually, the rifampicin bioavailability was improved with depressed clearance in mice without gallbladders. ConclusionAs natural ligands for Fxr and Pxr, the alternations of individual BAs lead to the regulation of hepatic and ileal relevant enzymes and transporters after cholecystectomy. Especially, the down-regulation of hepatic Cyp3a11 suggests that undesirable pharmacokinetic alternations of drugs especially Cyp3a11 substrates like rifampicin might occur in phase with cholecystectomy.

In Vitro-In Vivo Evaluation of Novel Co-spray Dried Rifampicin Phospholipid Lipospheres for Oral Delivery.

The objective of this study comprises of developing novel co-spray dried rifampicin phospholipid lipospheres (SDRPL) to investigate its influence on rifampicin solubility and oral bioavailability. Solid-state techniques were employed to characterize the liposphere formulation. SDRPL solubility was determined in distilled water. BACTEC 460TB System was employed to evaluate SDRPL antimycobacterial activity. The oral bioavailability of the lipospheres was evaluated in Sprague Dawley rats. Lipospheres exhibited amorphous, smooth spherical morphology with a significant increase (p < 0.001) in solubility of SDRPL (2:1), 350.9 ± 23 versus 105.1 ± 12μg/ml and SDRPL (1:1) 306.4 ± 20 versus 105.1 ± 12μg/ml in comparison to rifampicin (RMP). SDRPL exhibited enhanced activity against Mycobacterium tuberculosis, H37Rv strain, with over twofolds less minimum inhibitory concentration (MIC) than the free drug. Lipospheres exhibited higher peak plasma concentration (109.92 ± 25 versus 54.31 ± 18μg/ml), faster T max (two versus four hours), and enhanced area under the curve (AUC0-∞) (406.92 ± 18 versus 147.72 ± 15μgh/L) in comparison to pure RMP. Thus, SDRPL represents a promising carrier system exhibiting enhanced antimycobacterial activity and oral bioavailability of rifampicin.

Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment-naive TB patients: a randomized cross-over trial.

Concomitant food intake influences pharmacokinetics of first-line anti-TB drugs in healthy volunteers. However, in treatment-naive TB patients who are starting with drug treatment, data on the influence of food intake on the pharmacokinetics are absent. This study aimed to quantify the influence of food on the pharmacokinetics of isoniazid, rifampicin, ethambutol and pyrazinamide in TB patients starting anti-TB treatment. A prospective randomized cross-over pharmacokinetic study was conducted in treatment-naive adults with drug-susceptible TB. They received isoniazid, rifampicin and ethambutol intravenously and oral pyrazinamide on day 1, followed by oral administration of these drugs under fasted and fed conditions on two consecutive days. Primary outcome was the bioavailability while fasting and with concomitant food intake. This study was registered with clinicaltrials.gov identifier NCT02121314. Twenty subjects completed the study protocol. Absolute bioavailability in the fasted state and the fed state was 93% and 78% for isoniazid, 87% and 71% for rifampicin and 87% and 82% for ethambutol. Food decreased absolute bioavailability of isoniazid and rifampicin by 15% and 16%, respectively. Pyrazinamide AUC0-24 was comparable for the fasted state (481 mg·h/L) and the fed state (468 mg·h/L). Food lowered the maximum concentrations of isoniazid, rifampicin and pyrazinamide by 42%, 22% and 10%, respectively. Time to maximum concentration was delayed for isoniazid, rifampicin and pyrazinamide. The pharmacokinetics of ethambutol were unaffected by food. Food decreased absolute bioavailability and maximum concentration of isoniazid and rifampicin, but not of ethambutol or pyrazinamide, in treatment-naive TB patients. In patients prone to low drug exposure, this may further compromise treatment efficacy and increase the risk of acquired drug resistance.

Development and validation of RP-HPLC method for simultaneous estimation of rifampicin, isoniazid and pyrazinamide in human plasma

A rapid, simple, sensitive and cost effective stability indicating high performance liquid chromatographic method for the simultaneous determination of rifampicin, isoniazid and pyrazinamide in human plasma was developed and validated in accordance to Food and Drug Administration (FDA) guidelines. The three drugs were eluted under isocratic mode using a 250 × 4.0 mm i.d., 5 μm Phenomenex ODS 2 C18 column. The mobile phase was composed of a mixture of acetonitrile, methanol and water in the ratio of 30: 5: 65 (v/v, pH adjusted to 5.2) at a flow rate of 1.0 mL/min. The limits of detection and quantification for rifampicin were 0.13 and 0.4 μg/mL, for isoniazid—0.6 and 1.8 μg/mL; and for pyrazinamide—0.5 and 1.6 μg/mL, respectively. The method can be successfully applied for pharmacokinetic, bioavailability or bioequivalence studies of rifampicin, isoniazid and pyrazinamide combination in human subjects.

In vitro controlled release of Rifampicin through liquid-crystalline folate nanoparticles

Rifampicin is one of the frontline drugs for tuberculosis therapy but poor bioavailability of Rifampicin in combination with other anti-tuberculosis drugs is a subject of concern. Nano-based formulations for sustained release of anti-tubercular drugs have been shown to increase antibacterial efficacy and pharmacokinetic behavior. In the present study, liquid-crystalline folate nanoparticles were designed for sustained delivery of Rifampicin and its in vitro release study is reported. Liquid-crystalline nanoparticles of biocompatible folate ions consist of self assembled structures, resulting in high encapsulation, controlled release and low drug losses of about 20-30%, which is significant in itself. This study reports the size-control method of forming Rifampicin encapsulated folate nanoparticles as well as the parameters to control the release profiles of Rifampicin through these nanoparticles. These designs are able to present sustained release for over 25 days. The effect of different parameters such as nanoparticles size, type of cross-linking cation, cross-linking cation concentration and drug-loading on Rifampicin release was studied in vitro. The intracellular uptake and low cytotoxicity of nanoparticles by alveolar macrophages was also demonstrated using fluorescence microscopy and MTT assay respectively.

Relative bioavailability of rifampicin in four Chinese fixed-dose combinations compared with rifampicin in free combinations.

Background:Decreases in the bioavailability of rifampicin (RFP) can lead to the development of drug resistance and treatment failure. Therefore, we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination (FDC; formulation A) and three two-drug FDCs (formulations B, C, and D) used in China, compared with RFP in free combinations of these drugs (reference), in healthy volunteers.Methods:Eighteen and twenty healthy Chinese male volunteers participated in two open-label, randomized two-period crossover (formulations A and C) or one three-period crossover (formulations B and D) study, respectively. The washout period between treatments was 7 days. Bioequivalence was assessed based on 90% confidence intervals, according to two one-sided t-tests. All analyses were done with DAS 3.1.5 (Mathematical Pharmacology Professional Committee of China, Shanghai, China).Results:Mean pharmacokinetic parameter values of RFP obtained for formulations A, B, C, and D products were 11.42 ± 3.41 μg/ml, 7.86 ± 5.78 μg/ml, 13.05 ± 6.80 μg/ml, and 16.18 ± 3.87 μg/ml, respectively, for peak plasma concentration (Cmax), 91.43 ± 30.82 μg·h−1 ·ml−1, 55.49 ± 37.58 μg·h−1 ·ml−1, 96.50 ± 47.24 μg·h−1 ·ml−1, 101.47 ± 33.07 μg·h−1 ·ml−1, respectively, for area under the concentration-time curve (AUC0−24 h).Conclusions:Although the concentrations of RFP for formulations A, C, and D were within the reported acceptable therapeutic range, only formulation A was bioequivalent to the reference product. The three two-drug FDCs (formulations B, C and D) displayed inferior RFP bioavailability compared with the reference (Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451).

A validated high-performance thin-layer chromatographic method for the determination of bioenhanced first-line antituberculosis drugs in pharmaceutical formulation

Piperine (PIN), a bioenhancer, is co-formulated with rifampicin (RFN) and isoniazid (INZ) to enhance the bioavailability of RFN. RFN and INZ are the drugs of first choice for the treatment of tuberculosis and recommended by the World Health Organization (WHO). A new high-performance thin-layer chromatographic (HPTLC) method was optimized for the separation and determination of RFN, INZ, and PIN in the bioenhanced pharmaceutical formulation. Separation was performed on a precoated silica gel 60 F254 plate, and an acceptable separation was achieved using a mobile phase comprising toluene-ethyl acetate-methanol (7:3:3, v/v); detection was performed at 300 nm. The proposed method was validated for specificity, accuracy, repeatability, limit of detection, limit of quantification, stability, and robustness. The correlation coefficient (R2) values for RFN, INZ, and PIN were 0.9997, 0.9995, and 0.9987, respectively. The spots were identified by matching with the RF values and absorbance spectrum with authentic co...

Increased bioavailability of rifampicin from stimuli-responsive smart nano carrier.

Stimuli responsive polymeric nanocarrier (RCOP-2) functionalized with frontline antituberculosis drug (Rifampicin) is demonstrated for sustained release. Bioavailability of Rifampicin is taken care of by conjugating this drug through a acylhydrazine linker to the polymeric backbone. The poly(ethylene glycol) structural motif is introduced in the copolymer architecture for water solubility. Releasing retinal along with Rifampicin is hypothesized to reduce the risk of side effects due to Rifampicin. The self-assembly of RCOP-2, due to the amphiphilicity present in the copolymer, is explored in detail. The pH responsiveness of RCOP-2 is demonstrated in mild acidic environment as well as in cell lines. The 4T cell line, due to its acidic nature, shows time-dependent cellular internalization. On the basis of the results, our unique design is expected to provide an increased bioavalaibility of Rifampicin with reduced side effects. From the flow cytometry results on A549 cell lines, it is clear that the newly designed copolymer RCOP-2 can internalize efficiently and serve as an effective Rifampicin delivery system.

Ascorbic acid improves stability and pharmacokinetics of rifampicin in the presence of isoniazid

Bioavailability of rifampicin (RIF) from fixed dose combination (FDC) products remains problematic for effective control of tuberculosis (TB) owing to its degradation in the presence of isoniazid (INH) in the stomach acid environment. Ascorbic acid (ASC) is being added to the dissolution medium as well as the plasma sample as anti-oxidant to prevent degradation of RIF and also daily intake of ascorbic acid is recommended to control TB infection. However the role of ASC on the interaction between dissolution stability and in vivo bioavailability of RIF in the presence of INH has not been explored and therefore examined in the present study. RIF and its degradation product 3-FRSV were measured by dual wavelength spectroscopy. ASC significantly reduced RIF degradation or formation of 3-FRSV in the presence of INH (p<0.001) in the dissolution medium (pH 1.2) and showed increase in Cmax, AUC0–24, AUC0–∞ and t1/2 of RIF (p<0.001) as compared to that without ASC in rabbits. The study demonstrates that co-administration of ASC with RIF-INH combination can protect RIF from degradation in the acid environment and improve its bioavailability with effective control of TB.

The rifampicin drug delivery system based on phospholipid nanoparticles

Low bioavailability of rifampicin, one of the main antituberculous agents, stimulates searches of its new optimized formulations. The present study has shown a possibility of rifampicin incorporation into nanoparticles from plant phosphatidylcholine (diameter of 20–30 nm). Addition of sodium oleate to the phospholipid system caused a 2-fold increase in the percent of rifampicin incorporation. The maximal concentration of rifampicin assayed in plasma samples by LC/MS was observed 1 h after oral administration to rats (6 mg/kg) and represented 0.5 and 4.2 μg/mL for free rifampicin and rifampicin incorporated in the phospholipids-oleate nanoparticles, respectively. These levels were maintained for more than 2 h of the experiment. High rifampicin bioavailability in the oleate containing phospholipid nanosystem suggests its prospects for practical use.

The Comparison of Conventional and Novel Fixed Dose Combination of Rifampicin and Isoniazid to Improve Bioavailability of Rifampicin for Treatment of Tuberculosis

Background: Fixed-dose combinations (FDCs) of anti-tubercular drugs have been recommended as a step towards ensuring better treatment and compliance of patients receiving anti-tubercular therapy (ATT). Methods: The study was an open-label and randomized controlled trial. Patients were randomized to receive daily treatment with the conventional FDC dosage formulation or the novel FDC formulation of rifampicin and isoniazid as a part of 4 drug ATT regimen. The outcome measures were sputum conversion rates, radiological response and clinical response. Results: Of the 105 patients who were randomized 55 received the conventional FDC formulation while 50 received the novel FDC formulation. Of the 105 participants, 51 (48.6%) had PTB with the rest having extrapulmonary tuberculosis (EPTB). Of the 87 patients could be assessed at the end of 6 months treatment,10/42 (23.8%) of the patients in group A and 13/45 (28.9%) of the patients in group B had some evidence of disease activity at the end of 6 months of treatment on the CT scan or in the Chest X-Ray. A total of 6 (5.8%) patients, three in each group (5.6% in group A and 6.4% in Group B) experienced treatment failure. Of these 3 were classified as treatment failure due to radiological deterioration and 3 due to persistent culture positivity. There was no significant difference in the microbiological, clinical or radiological response rates between the two groups. There was no significant difference in the plasma concentrations of rifampicin and isoniazid at various time points between the two groups. Conclusion: In conclusion, we found no difference in the clinical efficacy of rifampicin and isoniazid drug levels of the novel FDC formulation as compared to the conventional FDC formulation. Further studies are required with larger sample size to study the usefulness of novel FDC formulation.

Novel rifampicin–phospholipid complex for tubercular therapy: Synthesis, physicochemical characterization and in-vivo evaluation

To enhance the oral bioavailability of rifampicin (RMP), the newly emerging phospholipid complexation technique was employed. Rifampicin-phospholipid complex (RMP-PC) was prepared by solvent-evaporation method. Infrared spectroscopy (IR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and hot stage microscopy (HSM) analysis were employed to confirm the formation of phospholipid complex. The results reveal hydrogen bond formation and electrostatic interaction between RMP and phospholipid molecule play an important role in the formation of RMP-PC without the formation of a new compound. In comparison with the physical mixture and RMP, solubility studies indicated an enhancement in the aqueous solubility of RMP-PC. Stability studies of RMP-PC in presence of isoniazid showed a remarkable improvement of the stability of the phospholipid complex in comparison to free RMP. Oral bioavailability of RMP-PC was evaluated in Sprague-Dawley (SD) rats and plasma rifampicin estimated by LCMS. RMP-PC exhibited higher peak plasma concentration (54.3 vs. 48.5 μg/mL), increased AUC0-∞ (472.4 vs. 147.71 5.812 ± 0.49 μg h/mL), increased T1/2 (8.3 vs. 1.5h) when compared to free RMP implying improved bioavailability of the drug. This enhancement can be attributed to the improvement of the aqueous solubility of rifampicin-phospholipid complex. Hence, phospholipid complexation holds a promising potential for increasing oral bioavailability of poorly water soluble drugs.

Mixed micelles of sodium cholate and Brij30: Their rheological behaviour and capability towards solubilization and stabilization of rifampicin

Rifampicin is wide-spectrum antibiotic but being poorly water soluble and unstable towards oxidation, it requires high dose in order to reach therapeutic plasma concentrations thereby making its adverse effects like hepatotoxicity more prominent. Sodium cholate (NaC), Brij30 and their mixed micellar systems were evaluated for their solubilization and stabilization capability towards rifampicin. NaC aggregates showed micellar growth upon addition of Brij30 surfactant inferred by characterization using rheology and were found to form both wormlike micelles and vesicles. The solubility of rifampicin was found to be higher in NaC micellar systems due to an appreciable interfacial solubilization favoured by electrostatic interactions. The solubilization capacity of mixed micellar systems decreased with increase in Brij30 surfactant concentration. A comparative study of stability of rifampicin against oxidation with H2O2 showed that the micelles were able to stabilize the drug. The mixed micellar systems possessed much more solubilization efficiency than Brij30 micellar systems and at the same time proved markedly more protective against oxidation of rifampicin when compared to NaC besides being stable to large stress and having the desirable characteristics of their viscoelasticity, thus proving to be the ideal systems for solubilization and stabilization of rifampicin. These experimental results are expected to be important for enhancing the solubility, stability and hence bioavailability of rifampicin.

Oral Bioavailability of Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide in a 4-Drug Fixed-Dose Combination Compared With the Separate Formulations in Healthy Chinese Male Volunteers

BackgroundFixed-dose combination (FDC) formulations for the treatment of tuberculosis are now being recommended by the World Health Organization and used worldwide for reducing the risk of emerging drug resistance. China also plans that the FDC coverage will be achieved 100% in 2015 in every county in the country. However, the quality of FDCs with respect to variable bioavailability is a major issue. ObjectivesThis study was conducted in healthy Chinese subjects to compare the bioavailability of rifampicin, isoniazid, ethambutol, and pyrazinamide from a 4-drug FDC formulation versus that of the separate formulations. MethodsThe study was designed as randomized, single-dose, 2-treatment, 2-period crossover trial with a washout period of 1 week. Blood samples were collected at 0 (baseline), 10, 20, and 40 minutes and at 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose. Plasma concentrations of the 4 drugs were measured by using a rapid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated by using noncompartmental methods. Bioequivalence was determined if the 90% CIs of the log-transformed test/reference ratios AUC0–24, AUC0–∞, and Cmax were within the predetermined range of 80% to 125%. Tolerability was assessed by using clinical parameters and subject reports. ResultsA total of 18 male subjects (mean [SD] age, 36.4 [10.6] years) were enrolled and completed the study. In the case of rifampicin, the 90% CIs for the log-transformed ratios of Cmax, AUC0–24, and AUC0–∞ were 81.8 to 100.9, 89.5 to 100.2, and 87.1 to 98.0, respectively. For ethambutol, these values were 84.7 to 105.7, 93.5 to 105.1, and 92.1 to 105.4. For pyrazinamide, these values were 83.3 to 93.9, 95.8 to 101.4, and 97.0 to 104.1. For isoniazid, the 90% CIs for the log-transformed ratios of AUC0–24, and AUC0∞ were 83.5 to 94.6 and 83.4 to 94.4. However, the point estimates for Cmax (62.2–86.7) were outside the limit for bioequivalence. No adverse events were observed during the study. ConclusionsThe findings from this single-dose study in healthy Chinese male volunteers suggest that the combined formulation was bioequivalent to separate formulations of rifampicin, ethambutol, and pyrazinamide at the same dose levels. However, isoniazid was not bioequivalent based on Cmax values. Both formulations were well tolerated. Chinese Clinical Trials registration number: ChiCTR-TTRCC-12002451.

Drug delivery system on the base of phospholipid nanoparticles for rifampicin

Low bioavailability of rifampicin, one of the main antituberculous drug, stimulates searches of its new optimized formulations. The present study has showen possibility of rifampicin embedding into nanoparticles from plant phosphatidylcholine (diameter of 20-30 nm). Addition of sodium oleate to the phospholipid system caused a 2-fold increase of the percent of rifampicin incorporation. After oral administration to rats, the maximal drug observed in plasma one hour after was 0.5 and 4.2 mkg/ml for free rifampicin for rifampicin in phospholipids-oleate nanoparticles, respectively. These levels were maintained for more than two hours of the experiment. High rifampicin bioavailability in the oleate containing phospholipid nanosystem suggests prospectivity of its pharmaceutical elaboration.

Design and evaluation of enteric-coated tablets for rifampicin and isoniazid combinations

In order to improve the bioavailability of rifampicin (RIF) from rifampicin and isoniazid (INH) combination formulations, the physicochemical characteristics of RIF, stability of RIF in different pH buffers in the presence of INH, as well as the effect of particle size of RIF materials on the dissolution rate were investigated. On the basis of the above examinations, enteric-coated tablets for RIF and INH combinations were designed and prepared. RIF showed low solubility and high apparent distribution coefficient in the intestinal pH (pH 4.0–7.4). With the decrease in pH, the degradation of RIF increase and the presence of INH deepen the degradation. Enteric-coated tablets were prepared after grinding the RIF materials by dry granulation technique. The pharmacokinetics of RIF and INH of self-made enteric-coated tablets in dogs were studied by comparing with the reference tablets. The AUC0–48 of RIF in both reference and test tablets were 304.77 ± 42.27 and 353.79 ± 31.63 µg·h·mL−1, respectively. The AUC0–48 of INH in both reference and test tablets were 17.14 ± 8.59 and 19.62 ± 10.57 µg·h·mL−1, respectively. Enteric-coated tablets may minimize the decomposition of RIF in gastrointestinal tract and improve the bioavailability.