None listed
Conditions
Brief summary
Therapeutic drug monitoring (TDM) is recommended for anti-tuberculosis (TB) drugs. Some drugs can penetrate into saliva and urine sufficiently enough to be used as alternative sampling. Our primary aim is to develop a salivary pharmacokinetic model for levofloxacin. The secondary objectives are to study the salivary penetration ratios for TB drugs, determine the relationship between the genotype of NAT2 and isoniazid level, and determine the feasibility of using saliva or urine for TDM. A prospective, open-label, observational study will be conducted in 30 adult patients receiving TB drugs. Plasma, saliva, and urine samples will be collected around week 2 for drug analysis. The population PK model will be developed using Nonlinear Mixed Effects Modeling (NONMEM®). Expected outcomes include a salivary pharmacokinetic model for levofloxacin, the relationship between NAT2 genotype and isoniazid level, and an assessment of the feasibility of using saliva and/or urine for TDM of TB drugs.
Interventions
Patients will receive one week of levofloxacin (15 mg/kg, rounded to 750mg-1000mg daily using oral tablets) added to the standard of care regimen which will include isoniazid, rifampicin, ethambutol, and pyrazinamide.
Levofloxacin will be started after a week of starting the standard care regimen.
After a week of levofloxacin which corresponds to Day 14±2 of the start of first-line drugs, patients will have a blood sample for NAT2 genetic testing, paired saliva and plasma samples (0, 1, 2, 4, 6
Patients will receive one week of levofloxacin (15 mg/kg, rounded to 750mg-1000mg daily using oral tablets) added to the standard of care regimen which will include isoniazid, rifampicin, ethambutol, and pyrazinamide. Levofloxacin will be started after a week of starting the standard care regimen. After a week of levofloxacin which corresponds to Day 14±2 of the start of first-line drugs, patients will have a blood sample for NAT2 genetic testing, paired saliva and plasma samples (0, 1, 2, 4, 6, 8 hours post-dose) and urine samples (0-4, 4-8, 8-12 and 12-24 hours post-dose). If inpatient, patient's medication administration will be monitored by the ward nurse/clinician. If outpatient, patient's medication adherence will be monitored in the clinic under Directly Observed Therapy. Saliva samples will be collected using Salivette®. Saliva will be filtered through a syringe with filter (Millex®-GP or Millex®-GV) for removal of Mycobacterium tuberculosis before transport. Drug concentrations (isoniazid, rifampicin, pyrazinamide, ethambutol, levofloxacin) in saliva and plasma samples will be analysed on liquid chromatography with mass spectrometry (LCMS). Saliva samples will be additionally analysed on a UV spectrophotometer (NanoPhotometer NP80®). Urine samples will be collected in collection tubes and stored at -20 °C until analysis. Drug concentrations in urine will also be analysed on LCMS and explored for their feasibility of measurement on the UV spectrophotometer (NanoPhotometer NP80®). For genetic testing, DNA will be extracted from the EDTA blood samples (3 to 5 mls), using manual or automated Qiagen extraction methods. DNA will then be amplified, the product sequenced and sequence analysis performed. The combination of SNPs identified will be categorised according to published guidelines to identify the NAT2 genotype of the patient and expected isoniazid acetylator status.
Sponsors
Western Sydney Local Health District
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
-Patients 18 years old or older -Diagnosis of bacteriologically confirmed active pulmonary and/or extrapulmonary drug-susceptible TB. -Started treatment with a standard-of-care regimen containing isoniazid, rifampicin, pyrazinamide and ethambutol. -Provided informed consent for this study.
Exclusion criteria
-Patients who avoid levofloxacin or with contra-indications for levofloxacin including: • hypersensitivity to fluoroquinolones • patients with known aortic aneurysm or Marfan's syndrome • agranulocytosis (absolute neutrophil count < 500 cells/mm³) • thrombocytopenia (count below 50,000 platelets /mm³) • myasthenia gravis • renal function loss (creatinine clearance <50ml/min) • hepatic dysfunction (aspartate aminotransferase and or alanine aminotransferase > 3 times upper level of normal). -Patients with bleeding mucositis or ulcers which will not allow saliva collection. -Patients with recently proven C.difficile infection.
Outcome results
None listed