Population pharmacokinetic model of rifampicin for personalized tuberculosis pharmacotherapy: Effects of SLCO1B1 polymorphisms on drug exposure.

BACKGROUND: Rifampicin (RIF) exhibits high pharmacokinetic (PK) variability among individuals; a low plasma concentration might result in unfavorable treatment outcomes and drug resistance. This study evaluated the contributions of non- and genetic factors to the interindividual variability of RIF exposure, then suggested initial doses for patients with different weight bands. METHODS: This multicenter prospective cohort study in Korea analyzed demographic and clinical data, the solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotypes, and RIF concentrations. Population PK modeling and simulations were conducted using nonlinear mixed-effect modeling. RESULTS: In total, 879 tuberculosis (TB) patients were divided into a training dataset (510 patients) and a test dataset (359 patients). A one-compartment model with allometric scaling for effect of body size best described the RIF PKs. The apparent clearance (CL/F) was 16.6% higher among patients in the SLCO1B1 rs4149056 wild-type group than among patients in variant group, significantly decreasing RIF exposure in the wild-type group. The developed model showed better predictive performance compared with previously reported models. We also suggested that patients with body weights of <40 kg, 40-55 kg, 55-70 kg, and >70 kg patients receive RIF doses of 450, 600, 750, and 1050 mg/day, respectively. CONCLUSIONS: Total body weight and SLCO1B1 rs4149056 genotypes were the most significant covariates that affected RIF CL/F variability in Korean TB patients. We suggest initial doses of RIF based on World Health Organization weight-band classifications. The model may be implemented in treatment monitoring for TB patients.

Recommendation of pharmacokinetics/pharmacodynamics target of ethambutol to suppress tuberculosis resistance: A population pharmacokinetics study on a large prospective cohort.

BACKGROUND: The ability of ethambutol (EMB) to suppress bacterial resistance has been demonstrated in a time-dependent manner. Through the development of a population pharmacokinetics (PK) model, this study aimed to suggest the PK/pharmacodynamics (PD) target and identify the significant covariates that influence interindividual variability (IIV) in the PK of EMB. METHODS: In total, 837 patients from 20 medical centres across Korea were enrolled in this study. The non-linear mixed-effect method was used to establish and validate the population PK model. RESULTS: A two-compartment model with transit compartment absorption was sufficient to describe the PK of EMB. Body weight and renal function were identified as significant covariates that affect IIV of the apparent clearance (CL/F) of EMB. Patients with moderate renal function showed 35% and 55% lower CL/F (CL/F 89.9 L/h) compared with those with mild and normal renal function, respectively. All the renal function groups with simulated doses ranging from 800 to 1200 mg achieved area under the curve over minimum inhibitory concentration (MIC) >119, and maintained T>MIC for >23 h for MIC of 0.5 µg/mL. Based on our simulation result, it is suggested that doses of 800, 1000, and 1200 mg should obtain the T>MIC target of 4, 6, and 8 h, respectively. This model was validated internally and externally. CONCLUSION: This study provides insight into the PK/PD indexes of EMB for three different renal function groups and T>MIC targets for different doses. The results could be used to provide optimal-dose suggestions for EMB.

Advancing personalized medicine for tuberculosis through the application of immune profiling.

While early and precise diagnosis is the key to eliminating tuberculosis (TB), conventional methods using culture conversion or sputum smear microscopy have failed to meet demand. This is especially true in high-epidemic developing countries and during pandemic-associated social restrictions. Suboptimal biomarkers have restricted the improvement of TB management and eradication strategies. Therefore, the research and development of new affordable and accessible methods are required. Following the emergence of many high-throughput quantification TB studies, immunomics has the advantages of directly targeting responsive immune molecules and significantly simplifying workloads. In particular, immune profiling has been demonstrated to be a versatile tool that potentially unlocks many options for application in TB management. Herein, we review the current approaches for TB control with regard to the potentials and limitations of immunomics. Multiple directions are also proposed to hopefully unleash immunomics' potential in TB research, not least in revealing representative immune biomarkers to correctly diagnose TB. The immune profiles of patients can be valuable covariates for model-informed precision dosing-based treatment monitoring, prediction of outcome, and the optimal dose prediction of anti-TB drugs.

Lay provider HIV testing: A promising strategy to reach the undiagnosed key populations in Vietnam.

BACKGROUND: In Vietnam, reaching the remaining one-third of undiagnosed people living with HIV and facilitating their antiretroviral therapy (ART) enrollment requires breakthrough approaches. We piloted lay provider HIV testing as an innovative approach to reach at-risk populations that never or infrequently HIV test at facility-based services. METHODS: We conducted a cross-sectional survey and analysis of routine program data in two urban provinces (Hanoi and Ho Chi Minh City) and two rural mountainous provinces (Nghe An and Dien Bien) from October 2015 through September 2017. Acceptability of lay provider testing was defined as the proportion of first-time HIV testers utilizing the service, and effectiveness was measured by HIV positivity and ART initiation rates. Univariate and multivariate analyses were used to determine lay provider testing preference and factors associated with that preference. RESULTS: Among 1,230 individuals recruited for face-to-face interviews, 74% belonged to key populations: people who inject drugs accounted for 31.4%; men who have sex with men, 60.4%; and female sex workers, 8.2%. Most clients (67%) reported being first-time HIV testers, and the majority (85.8%) preferred lay provider testing to facility-based testing. Multivariate analysis found that clients in urban areas (adjusted odds ratio [aOR] = 2.50; 95% confidence interval [CI]: 1.30-4.90) and those who had a university or higher education (aOR = 1.83; 95% CI: 1.05-3.20) were more likely to prefer lay provider testing. Lay provider testing yielded a higher HIV positivity rate (4.1%), particularly among first-time testers (6.8%), compared to facility-based testing (nationally estimated at 1.6% in 2016) and had a high ART initiation rate (91%). CONCLUSIONS: Our findings suggest that lay provider HIV testing is an effective approach to reach previously unreached at-risk populations, and, therefore, a critical addition to accelerating Vietnam's attainment of the Joint United Nations Programme on HIV/AIDS 90-90-90 goals.