Search Results (9)

Background/Objectives: Exudative age-related macular degeneration (AMD) is a disease of choroidal neovascularization that causes blindness. Current treatments to preserve vision in this prevalent and blinding condition are repeat intraocular injections of anti-vascular endothelial growth factor medicines for a patient’s lifetime to preserve and prevent vision loss leading to blindness. Rifampicin, a small-molecule antibiotic, has previously been reported to exhibit anti-angiogenic properties and a topical safety profile that is well-tolerated. Based on this evidence, we investigated the feasibility of formulating rifamycin as an ophthalmic drop capable of delivering therapeutic concentrations to the posterior segment of the eye. Methods: Inhibition of neovascularization by administration of rifampicin was analyzed in the rat oxygen-induced retinopathy (OIR) and mouse laser-induced choroidal neovascularization (CNV) models. Pharmacokinetic (PK) studies were conducted in mice, rats, and rabbits by dosing various formulations containing rifampicin, and the compound was quantified by LC/MS analysis. Results: Results from dose escalation studies in the mouse laser-induced CNV model suggested the minimum effective dose of rifampicin required for inhibiting neovascularization in subretinal tissues to be 0.7 mg/kg, which is substantially lower than the 20 mg/kg dosage approved for infectious disease treatments. The previous studies did not report the minimum effective dose in the anti-angiogenesis effects. The effective area under the concentration-time curve (AUC) in the sub-retina was evaluated as 0.27 h·ng/mg. In rabbits, rifampicin was delivered to the sub-retina by a single topical application of various formulations in a dose-dependent manner. The topical application of the formulations containing 1% rifampicin, which was well-tolerated in clinical trials previously reported for ocular trachoma, achieved subretinal delivery approximately 2–32 times greater than the effective AUC. Plasma exposure of the compound by the topical application was evaluated to range approximately 0.5–10 ng/mL. Conclusions: Rifampicin was delivered to the sub-retina in rabbits with an efficiency greater than the effective dose required for inhibiting neovascularization. Limited amounts of plasma exposure by the topical application were detected. These results suggested the therapeutic potential of the rifampicin formulations for the topical treatment of exudative macular degeneration. Full article

Background: The drug candidate BI 730357 is a Biopharmaceutics Classification System (BCS) Class II compound showing atypical absorption after oral administration in fasted and fed healthy individuals, for which conventional traditional deconvolution methods could not explain formulation dependencies. Methods: A physiologically based pharmacokinetic (PBPK) model of BI 730357 was developed using the Open Systems Pharmacology (OSP) PBPK software tool PK-Sim^®, which could describe the pharmacokinetics in fasted and fed subjects after single and multiple doses. A Weibull function was used to describe the in vivo formulation kinetics, whereas colonic absorption was adopted as the main driver to describe the late phases of observed pharmacokinetics after oral administration. The food effect was applied using the implemented feature PK-Sim^®. Results: The model accurately predicted an observed itraconazole drug–drug interaction (DDI) in fasted subjects and was used to explore the effects of the strong CYP3A4 inducer rifampicin on the pharmacokinetics of BI 730357 after administration in fed subjects. Conclusions: The combined results suggest that the BI 730357 PBPK model with semi-mechanistic absorption can prospectively explore the effects of CYP3A4 inhibitors and inducers on the pharmacokinetics after administration in fed or fasted subjects within the given dose range. Full article

The World Health Organization is encouraging countries to include contact screening and single-dose rifampicin administration as preventive chemotherapy for contacts of leprosy patients in their leprosy control activities. However, no study has been conducted to assess the safety of SDR-PEP and the acceptability and feasibility of this intervention in Togo. To assess the safety of SDR-PEP, we used a cohort design, and for acceptability and feasibility, we used a mixed method, combining a quantitative study to assess the safety of SDR-PEP in a cohort of contacts from recently diagnosed leprosy patients followed by a qualitative study to identify the social, cultural, or institutional factors that would influence the adoption of single-dose rifampicin as post-exposure prophylaxis for contacts of leprosy patients in Togo. For the quantitative study, all identified index patients agreed to the disclosure of their status to their contacts and provided a list of their contacts. All the contacts found agreed to take part in the study, and an appointment was made for screening. However, some contacts were absent on the screening day for no reason. All eligible contacts agreed to take SDR and were followed up after taking the drug. No severe adverse events were reported during the follow-up. For the qualitative study, 72 interviews (66 semi-structured interviews and 6 focus groups) were carried out, and it emerged that, overall, opinions were favorable on the acceptability and feasibility of implementing single-dose rifampicin as post-exposure prophylaxis for contacts of leprosy patients in Togo. However, a number of conditions need to be considered for more effective results. Full article

Background: To achieve zero leprosy cases in Santa Cruz, Bolivia, we designed a community-based active detection and provision of single-dose rifampicin post-exposure prophylaxis (SDR-PEP) to household contacts with new leprosy patients. Methods: From July to August 2021, we assessed the current knowledge, attitude, and practices through structured interviews and focus group discussions with community representatives and health staff. This was followed by sensitization sessions, the training of health staff, and the reinforcement of referral mechanisms. Teams, including health staff and community volunteers, visited all new leprosy patients detected in 2021–2023 and household contacts. Results: Among 115 community representatives, knowledge about leprosy etiology was attributed to non-biological factors (74%); fear accounted for 77%, and access to care was perceived as weak (74%), but the outlook was improved by SDR-PEP (80%). Among the 217 health staff interviewed, the programmatic barriers identified were a lack of referral feedback (67%), limited supplies for diagnosis and prevention, and ineffective training (64%). We visited 70 new patients and 258 household contacts. The median age in household contacts was 25 years old; 49% were women, 98% were eligible for SDR-PEP, and all who were eligible accepted it. Those who were non-eligible included one tuberculosis patient and six newly detected leprosy patients (23‰). Conclusions: A community-based intervention was successful in Santa Cruz, Bolivia. Misbeliefs and a lack of knowledge were identified as barriers. Programmatic components should be reinforced for SDR-PEP extension. Full article

Genetic polymorphisms can exert a considerable impact on drug pharmacokinetics (PK) and the development of adverse drug reactions (ADR). However, the effect of genetic polymorphisms on the anti-tuberculosis (anti-TB) drug, and particularly rifampicin (RIF), exposure or anti-TB drug-induced liver injury (DILI) remains uncertain. Here, we evaluated the relationship between single nucleotide polymorphisms (SNPs) detected in the RIF pharmacogenes (AADAC, SLCO1B1, SLCO1B3, ABCB1, and NR1I2) and RIF PK parameters, as well as anti-TB treatment-associated DILI. In total, the study enrolled 46 patients with drug-susceptible pulmonary TB. The RIF plasma concentration was measured using the LC-MS/MS method in the blood samples collected pre-dose and 2 and 6 h post-dose, whilst the DILI status was established using the results from blood biochemical analysis performed before and 10–12 days after treatment onset. The genotyping was conducted using a targeted NGS approach. After adjustment for confounders, the patients carrying the rs3732357 GA/AA genotype of the NR1I2 gene were found to have significantly lower RIF plasma AUC_{0–6 h} in comparison to those with GG genotype, while the difference in RIF plasma C_max was insignificant. None of the analyzed SNPs was related to DILI. Hence, we are the first to report NR1I2 intronic SNP rs3732357 as the genetic component of variability in RIF exposure. Regarding anti-TB treatment-associated DILI, the other preexisting factors promoting this ADR should be considered. Full article

Kiribati is a Pacific Island nation with a widely dispersed population and one of the highest rates of leprosy worldwide. Single-dose rifampicin post-exposure prophylaxis (SDR-PEP) of leprosy contacts has reduced new case detection rates in controlled trials. In 2018, an SDR-PEP programme was introduced in Kiribati that included screening and chemoprophylaxis of household contacts of leprosy cases retrospectively (2010–2017) and prospectively (2018–2022). We conducted a retrospective audit to determine the comprehensiveness, timeliness and feasibility of the SDR-PEP programme. Overall, 13,641 household contacts were identified (9791 in the retrospective and 3850 in the prospective cohort). In the retrospective cohort, 1044 (11%) contacts were absent, 403 (4%) were ineligible for SDR, and 42 new cases were detected (0.4%) Overall, SDR coverage was 84.7%. In the prospective cohort, 164 (4%) contacts were absent, 251 (7%) were ineligible for SDR, and 23 new cases were diagnosed (0.6%). Overall, SDR coverage was 88.1%. Across both cohorts, there were 23 SDR refusals. The median time to SDR administration was 220 days (IQR 162–468) and 120 days (IQR 36–283) for the retrospective and prospective cohorts, respectively. SDR was readily accepted in both cohorts. The new case detection rate (0.5%) is consistent with that in other studies. Overall SDR coverage in both the retrospective and prospective phases met programmatic expectations. Full article

Introduction: Calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are utilized primarily in organ transplantation and the treatment of autoimmune diseases. Since patients depend on these drugs over long periods, they face a potential risk of intoxication. This risk increases substantially when patients are overdosed or inadvertently exposed to cytochrome P450 (CYP) 3A4 inhibitors. Objectives: To analyze the utility of CYP inducers as a plausible treatment modality for acute CNI intoxication using real-world data from the WHO global pharmacovigilance database (VigiBase™) and supporting evidence from published data. Methodology: We explored all individual case safety reports (ICSRs) regarding CNI intoxications registered in VigiBase™. The queries “overdose” or “drug intoxication” were applied against the active ingredients “ciclosporin” and “tacrolimus”. Regarding the utility of CYP inducers, an extensive literature analysis was undertaken. We also report an index clinical case of a 60-year-old liver transplant patient that developed severe tacrolimus intoxication with multiple organ dysfunction at a peak concentration of 33.1 μg/L after a single dose of intravenous fluconazole. Results: Out of 143,710 documented ICSRs reported in VigiBase™ since 1992, 0.26% and 0.02% were registered as CNI overdoses and intoxications, respectively. The main etiological factor for CNI intoxication was the interaction with CYP 3A4 inhibitors (40.0% vs. case reports: 50.0%). The most commonly reported manifestation was acute kidney injury (36.7% vs. case reports: 46.3%). A total of 16.7% of intoxications led to fatal outcomes after drug withdrawal or dose reduction; however, in 43.0% of cases the exact actions undertaken were not reported. In peer-reviewed reports, 34 distinct clinical cases were treated with CYP inducers. Diverse pharmacoenhancement strategies with phenobarbital (5), phenytoin (23) and rifampicin (6) were described with a mean time of achieving the therapeutic target after 2.7 (±0.7), 3.1 (±0.5) and 4.6 (±1.0) days, respectively. In the index case, a therapeutic concentration of 4.9 [4–6 μg/L] was achieved after a 3-day regimen of rifampicin. Conclusion: In addition to general supportive treatment, the administration of phenobarbital, phenytoin, or rifampicin to reverse acute CNI intoxication is a viable treatment modality. The relatively long half-life of phenobarbital coupled with its exclusive renal elimination are potential pitfalls to reckon with. In spite of the favorable pharmacokinetic advantages of rifampicin, phenytoin offers a competitive pharmacodynamic advantage that is indisputable in patients with overt neurotoxicity. Full article

The treatment of drug-resistant Mycobacterium tuberculosis relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography–mass spectrometry (HPLC–MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20–25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients. Full article

The physiologically based pharmacokinetic (PBPK) approach facilitates the construction of novel drug–disease models by allowing incorporation of relevant pathophysiological changes. The aim of the present work was to explore and identify the differences in rifampicin pharmacokinetics (PK) after the application of its single dose in healthy and diseased populations by using PBPK drug–disease models. The Simcyp^® simulator was used as a platform for modeling and simulation. The model development process was initiated by predicting rifampicin PK in healthy population after intravenous (i.v) and oral administration. Subsequent to successful evaluation in healthy population, the pathophysiological changes in tuberculosis and cirrhosis population were incorporated into the developed model for predicting rifampicin PK in these populations. The model evaluation was performed by using visual predictive checks and the comparison of mean observed/predicted ratios (ratio_(Obs/pred)) of the PK parameters. The predicted PK parameters in the healthy population were in adequate harmony with the reported clinical data. The incorporation of pathophysiological changes in albumin concentration in the tuberculosis population revealed improved prediction of clearance. The developed PBPK drug–disease models have efficiently described rifampicin PK in tuberculosis and cirrhosis populations after administering single drug dose, as the ratio_(Obs/pred) for all the PK parameters were within a two-fold error range. The mechanistic nature of the developed PBPK models may facilitate their extension to other diseases and drugs. Full article