Rifapentine Concentrations Research Articles

Clinical Predictors of 3-Months Isoniazid Rifapentine (3HP) - Related Adverse Drug Reactions (ADR) During Tuberculosis Preventive Therapy. (PAnDoRA-3HP study): An Observational Study Protocol.

Tuberculosis (TB) is the leading infectious cause of death globally. Despite WHO recommendations for Tuberculosis Preventive Therapy (TPT), challenges persist, including incompletion of treatment and adverse drug reactions (ADRs). There is limited data on the 3-month isoniazid and rifapentine (3HP) pharmacokinetics, pharmacogenomics and their relation with ADRs. Our study aims to describe the pharmacokinetic and pharmacogenomics of 3HP used for TPT, the ADRs and their association with completion rates, and TPT outcomes, providing vital insights for TB control strategies in resource-limited settings. This is an observational cohort study with a nested case-control study. We enrolled consecutive patients initiated on TPT using the 3HP regimen. These are followed up bi-weekly and then monthly during the active phase of treatment and 3 monthly for 2 years following completion of TPT. ADR evaluation includes clinical assessment and liver function tests. Cases are selected from those who experience ADRs, and controls from those who do not. Serum isoniazid and rifapentine concentrations are measured and pharmacogenomic analysis for NAT2 and CYP2E1 polymorphisms are done. Participants are followed up for 2 years to determine TPT outcomes. The safety profile of 3HP will be assessed using descriptive statistics, including proportions of patients experiencing ADRs and grade 3 or above events related to treatment. Chi-square tests and regression models will determine predictors of ADRs and their impact on treatment completion. Pharmacokinetic-pharmacodynamic modeling will establish population parameters and factors influencing rifapentine and isoniazid concentrations.

Development of dual delivery antituberculotic system containing rifapentine microspheres and adipose stem cells seeded in hydroxyapatite/tricalcium phosphate.

BackgroundLow drug concentration in the tuberculosis (TB) lesion and bone defects or nonunion after debridement are two major problems that occur in the course of treating osteo-articular TB. Thus, the combination of drug-delivery system and bone tissue repair appears to be the most promising option for osteoarticular TB treatment.Materials and methodsHerein, we report a novel anti-TB dual delivery system based on rifapentine polylactic acid microspheres (RPMs) to treat infections, with the addition of adipose-derived mesenchymal stem cells (ASCs) seeded in hydroxyapatite/tricalcium phosphate (HA/TCP) to promote bone formation. Cell proliferation, osteogenesis, and apoptosis were performed to investigate the effects of rifapentine on ASCs. The RPMs were synthesized by emulsion-solvent evaporation method, and then the monolayer composite (ASC + RPM) and three-dimensional (3D) composite scaffold (ASC + RPM + HA/TCP) were constructed, respectively. The alkaline phosphatase (ALP) activity and real-time PCR were used for determining the osteogenic differentiation. The concentrations of rifapentine resulting from the composites were detected.ResultsThe results showed that rifapentine has no influence on ASCs proliferation and osteogenesis when the drug concentration was below 20 µg/mL, which was significantly higher than minimal inhibitory concentration. The drug loading and encapsulation efficiency of RPMs were 40.56%±2.63% and 70.24%±2.18%, respectively. The proliferation of the cells in monolayer was higher than that in 3D composite, and the addition of RPMs slightly increased the proliferation. The ALP activity and gene expression of osteocalcin and osteopontin were higher in the 3D composite than those in the monolayer. Good biocompatibility was observed by microscopic image and H&E stain. The release tests revealed that the 3D composite exhibited sustained release profiles of rifapentine for 76 days. The dual delivery systems in 3D composite could moderate the burst release and extend the length of release time when compared to single delivery in monolayers.ConclusionIn conclusion, such dual delivery antituberculotic scaffold represents a potential new strategy for TB infections and bone defects.

Release characteristics of bone‑like hydroxyapatite/poly amino acid loaded with rifapentine microspheres invivo.

Bone-like hydroxyapatite/poly amino acid (BHA/PAA) is a potential bone repair material. Rifapentine-loaded poly(lactic‑co‑glycolic acid) microspheres (RPMs) are bioactive and efficient controlled‑release delivery systems used invitro. The aim of the present study was to investigate the invivo drug release characteristics of RPM‑loaded BHA/PAA on a rabbit model of bone defect. RPM was combined with BHA/PAA to obtain the drug‑loaded, slow‑releasing bioactive material. Bone defects were generated in New Zealand white rabbits and the rabbits were then implanted with RPM‑loaded BHA/PAA. High‑performance liquid chromatography (HPLC) was used to determine the concentrations of rifapentine in the plasma and the local muscle tissues of the treated rabbits. Hematoxylin and eosin (H&E) staining and biochemical analyses were performed to elucidate potential side effects of RPM‑loaded BHA/PAA on the heart, liver and kidney histopathology and functions of the treated rabbits. The biocompatibility and osteogenic ability of RPM‑loaded BHA/PAA was evaluated by H&E staining. The results demonstrated that the material was completely degraded and absorbed at 12weeks following implantation and new trabecular bone and cartilage tissues had formed. The invivo release tests revealed that RPM‑loaded BHA/PAA exhibited sustained release profiles of rifapentine and the drug concentration in the muscle tissues remained higher than the minimum inhibitory concentration of rifapentine against Mycobacteriumtuberculosis for as long as 12weeks. In addition, RPM‑loaded BHA/PAA had no long‑term side effects to the heart, liver and kidney of the treated rabbits. In conclusion, the present study demonstrated that RPM‑loaded BHA/PAA slowly and continuously released rifapentine invivo and exhibited no side effects on heart, liver and kidney tissues and function. Furthermore, RPM‑loaded BHA/PAA promoted new bone formation, while it was gradually degraded and absorbed. The present study provided a theoretical basis for the potential advancement in developing novel treatments for osteoarticular tuberculosis.

Drug Release Characteristics and Tissue Distribution of Rifapentine Polylactic Acid Sustained-Release Microspheres in Rabbits after Paravertebral Implantation.

BackgroundRates of drug-resistant tuberculosis (TB) and TB associated with human immunodeficiency virus (HIV) infection have increased dramatically, intensifying challenges in TB control. New formulations of TB treatment drugs that control drug release and increase local drug concentrations will have a significant impact on mitigating the toxic side effects and increasing the clinical efficacy of anti-TB drugs.ObjectivesThe aim was to observe the sustained release characteristics of rifapentine polylactic acid sustained-release microspheres in vivo and the accumulation of rifapentine in other tissues following paravertebral implantation.MethodsThis study is a basic animal experimental study that began on July 17, 2014 in the Fifth Affiliated hospital of Xinjiang Medical University. One hundred and eight New Zealand white rabbits (weighing 2.8 - 3.0 kg, male and female, China) were randomly divided into three groups of 36 rabbits each. Blood and tissue samples from the liver, lungs, kidneys, vertebrae, and paravertebral muscle were collected at different time points post-surgery. High performance liquid chromatography (HPLC) analysis with a biological internal standard was used to determine the drug concentrations in samples.ResultsIn group A, no significant differences in rifapentine concentrations in the liver were detected between any two time points (P > 0.05). However, the differences in rifapentine concentrations between day 10 and day 21 were statistically significant (P < 0.05); for days 21, 35, 46, and 60, the differences in rifapentine concentrations between two sequential time points were not statistically significant (P > 0.05). In group B, the differences in rifapentine concentration between days 3 and 10 in vertebral bone and in paravertebral muscles were statistically significant (P < 0.05). Rifapentine was detected in the vertebral bone tissue in the group C animals. The rifapentine concentrations between two sequential time points were statistically significant (P < 0.05). Rifapentine could not be detected in the paravertebral muscles 46 days after the operation. The differences in rifapentine concentrations between two sequential time points among days 3, 10, 21, and 35 were statistically significant (P < 0.05).ConclusionsAfter paravertebral implantation of rifapentine polylactic acid sustained-release microspheres, the concentration of rifapentine in local vertebral bone tissues was maintained above the TB minimum inhibitory concentration for up to 60 days with no apparent accumulation of the drug in other tissues.

Murine pharmacokinetics of rifapentine delivered as an inhalable dry powder

A novel inhalable rifapentine dry powder formulation could improve pulmonary rifapentine concentrations resulting in a significantly shorter time to treat tuberculosis infection. The pharmacokinetics of rifapentine (20mg/kg) in healthy mice was compared following intratracheal (IT) and intraperitoneal (IP) administration. Plasma, bronchoalveolar lavage (BAL) and tissue samples were collected and drug levels were quantified at time points up to 24h. Concentration–time data were analysed using a mixed-effects modelling approach to provide model-based estimates of area under the concentration–time curve from time 0 to infinity (AUC0–∞). IT delivery had considerably higher peak rifapentine lung and BAL concentrations and associated AUC0–∞ compared with IP delivery. The plasma AUC0–∞ following IT dry powder delivery was ca. four-fold smaller than the value for IP delivery. Inhaled delivery of rifapentine has the potential to selectively enhance therapeutic efficacy at the pulmonary site of infection whilst minimising systemic exposure and related toxicity.

Single-dose pharmacokinetics of rifapentine in women.

Gender can be an important variable in the absorption and disposition of some drugs. In this open-label study, 15 healthy, nonsmoking women received a single 600-mg oral dose of rifapentine. Plasma samples were obtained at frequent intervals for up to 72 hr after the dose to determine the pharmacokinetic (PK) parameters of rifapentine and its active metabolite, 25-desacetyl-rifapentine. Peak plasma rifapentine concentrations (Cmax) were observed 5.9 hr after ingestion of the single dose. The mean area under the rifapentine plasma concentration-time curve [AUC(0-->infinity)] was 325 micrograms.hr ml and the mean elimination half-life (t1/2) was 16.3 hr. Plasma concentrations for the 25-desacetyl metabolite peaked at 15.4 hr after the rifapentine dose and declined with a terminal half-life of 17.3 hr. These rifapentine and 25-desacetyl-rifapentine PK data in women were compared to data generated previously in healthy men. Striking similarities in the PK profiles of parent drug and metabolite were found in the two populations. Mean differences in rifapentine CL/F (12%) and t1/2 (2%) were small. The only adverse event reported in the female subjects was discoloration of the urine. Based on these PK and safety data, no dosage adjustments for rifapentine based on gender are recommended.

Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages

The activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human monocyte-derived macrophages were determined. The MICs and MBCs of rifapentine for intracellular bacteria were two- to fourfold lower than those of rifampin. For extracellular bacteria, this difference was less noticeable. Nevertheless, the more favorable pharmacokinetics of rifapentine over rifampin was addressed in other experimental models. These models showed substantial differences after short pulsed exposures of the infected macrophages to the drugs and when the infected macrophages were exposed to changing drug concentrations that imitated the pharmacokinetic curves observed in blood. Once-a-week exposures to rifapentine concentrations equivalent to those attained in blood after one 600-mg dose resulted during the first week in a dramatic decline in the number of bacteria, and this decline was maintained at a minimal level for a period of four weeks. The results of this study have shown the suitability of rifapentine for intermittent-treatment regimens. The prolonged effect of rifapentine found in this study may be associated with high ratios of intracellular accumulation, which were four- to fivefold higher than those found for rifampin. Further studies on the intracellular distribution of rifamycins and on the sites of actual interaction between the drugs and bacteria residing in macrophages are necessary.