Development of population pharmacokinetics model and Bayesian estimation of rifampicin exposure in Indonesian patients with tuberculosis.

BACKGROUND: Interindividual variability in the pharmacokinetics (PK) of anti-tuberculosis (TB) drugs is the leading cause of treatment failure. Herein, we evaluated the influence of demographic, clinical, and genetic factors that cause variability in RIF PK parameters in Indonesian TB patients. METHODS: In total, 210 Indonesian patients with TB (300 plasma samples) were enrolled in this study. Clinical data, solute carrier organic anion transporter family member-1B1 (SLCO1B1) haplotypes *1a, *1b, and *15, and RIF concentrations were analyzed. The population PK model was developed using a non-linear mixed effect method. RESULTS: A one-compartment model with allometric scaling adequately described the PK of RIF. Age and SLCO1B1 haplotype *15 were significantly associated with variability in apparent clearance (CL/F). For patients in their 40s, each 10-year increase in age was associated with a 10% decrease in CL/F (7.85 L/h). Patients with the SLCO1B1 haplotype *15 had a 24% lower CL/F compared to those with the wild-type. Visual predictive checks and non-parametric bootstrap analysis indicated good model performance. CONCLUSION: Age and SLCO1B1 haplotype *15 were significant covariates of RIF CL/F. Geriatric patients with haplotype *15 had significantly greater exposure to RIF. The model could optimize TB pharmacotherapy through its application in therapeutic drug monitoring (clinical trial no. NCT05280886).

Development of population pharmacokinetics model of isoniazid in Indonesian patients with tuberculosis.

OBJECTIVES: No population pharmacokinetics (PK) model of isoniazid (INH) has been reported for the Indonesian population with tuberculosis (TB). Therefore, we aimed to develop a population PK model to optimize pharmacotherapy of INH on the basis of therapeutic drug monitoring (TDM) implementation in Indonesian patients with TB. MATERIALS AND METHODS: INH concentrations, N-acetyltransferase 2 (NAT2) genotypes, and clinical data were collected from Dr. Soetomo General Academic Hospital, Indonesia. A nonlinear mixed-effect model was used to develop and validate the population PK model. RESULTS: A total of 107 patients with TB (with 153 samples) were involved in this study. A one-compartment model with allometric scaling for bodyweight effect described well the PK of INH. The NAT2 acetylator phenotype significantly affected INH clearance. The mean clearance rates for the rapid, intermediate, and slow NAT2 acetylator phenotypes were 55.9, 37.8, and 17.7 L/h, respectively. Our model was well-validated through visual predictive checks and bootstrapping. CONCLUSIONS: We established the population PK model for INH in Indonesian patients with TB using the NAT2 acetylator phenotype as a significant covariate. Our Bayesian forecasting model should enable optimization of TB treatment for INH in Indonesian patients with TB.

Wedge resection on recurrent pneumothorax, failed lung expansion after needle aspiration: A case report.

BACKGROUND: Pneumothorax has several classifications, including based on etiology, location, extent, and degree of collapse as well as by mechanism and type. CASE PRESENTATION: A 61-years-old man with the main complaint of sudden shortness of breath after lifting a birdcage. The complaint worsened, and it was accompanied by nausea, sweating, and decreased vital signs. The patient was in a life-threatening condition with a tension pneumothorax and treated with needle aspiration (NA). On the second day of treatment, a clinical evaluation showed recurrent dyspnea. Lung physical examination and chest X-ray evaluation showed recurrent pneumothorax with subcutaneous emphysema. Installation of chest tube drainages (CTD) with active continuous suction of -20 cmH2O. High-resolution CT (HRCT) showed right pneumothorax with multiple blebs, bullae, and bronchopleural fistula. Video-assisted thoracic surgery (VATS) was carried out to repair bronchopleural fistula (BPF). However, pre-surgery found multiple bullae and multiple fistulas accompanied by adhesion to the chest wall, thus the procedure could not be conducted. As an alternative, thoracotomy was performed, followed by wedge resection and fistula reparation. DISCUSSION: Diagnosis of pneumothorax is based on clinical manifestations. Conservative management by providing oxygen or NA/CTD insertion. Needle aspiration is a simple and alternative treatment and performed for an outpatient indication, whereas CTD requiring hospitalization and is performed by experts. Management aims to restore clinical symptoms, restore lung expansion and prevent a recurrence. CONCLUSION: The choice of thoracoscopy/VATS or thoracotomy needs to be considered according to the indications so that complications do not occur and have a good prognosis.