Abstract• Therapeutic drug monitoring may be useful intuberculosis management, but programmaticimplementation is understudied.• Type of study: retrospective cohort study• Objective:– determine prevalence of lower than expected levels ofAnti-Tb drugs measured at time of estimated peakserum concentration– Effect of debilitating diseases (DM) on drug response– Effect of dose adjustment
About Tuberculosis• 1.4 million deaths occurred in 2008 alone..• delayed diagnosis and ineffective or in-complete treatment..• With appropriate therapy; cure rate exceeds 95%• Effect of slow response:– prolonged infection– extended treatment duration– acquired drug resistance– recurrence of TB after treatment.• Causes of slow response:– Malabsorption– inaccurate dosing– altered metabolism– drug–drug interactions
About TDM• A useful tool to uncover the causes of slow response• Still considered optional in the TB management guideline and a few TB control programs has access to TDM,so best implementation methods are still to be studied• other issues:– Variation of definition of slow response– Proper selection of drugs for TDM varies– Still difficult to implement TDM in the general population• Benefits:– Proper monitoring in patients with other debilitatingdiseases– Application in early course of slow response patients mayprevent further complications and may shortens treatmentduration.
• Identification of slow response patients:>30 days from the start of treatment the patient has>2 of the following findings:– sputum smear positive for acid-fast bacilli– no improvement in TB-specific symptoms including:• fever, cough, weight loss, and/or night sweats;– no improvement in chest radiograph lesions previouslyidentified as consistent with TB.
Aim of this study• Perform a retrospective cohort study among patientsslow to respond to pulmonary TB treatment todetermine the prevalence of lower than expected levelsof isoniazid, rifampin, ethambutol, and pyrazinamidemeasured at the time of estimated peak serumconcentration (Cmax)• Secondary objectives:– investigation of risk factors for levels below the expectedrange– evaluation of the mean change and likelihood of achieving alevel within the expected range after dose adjustment– comparison of outcomes between persons with slowresponses with those with low and expected levels
Patients• Selection:– All patients who were >18 years of age– had confirmed Mycobacterium tuberculosis cultures– started TB therapy treated for pulmonary TB and extra-pulmonary TB and who began a regimen of iso-niazid,rifampin, ethambutol, and pyrazinamide.• Exclusions of this study:– resistance to ≥1 first-line medication.– Patients were also excluded if they had TDM performedfor reasons other than slow response.• Full medical history and information were collectedfrom the patients
TDM• daily dose of TB medications in the morning whilefasting and then observed for 2 hours (fasting)• At 2 hours after medication administration, venousblood was collected and serum was separated beforetransport on dry ice to the regional referral laboratory• (C2hr) were used to estimated (Cmax) and weredetermined by using:– HPLC (for isoniazid and rifampin)– GC-MS (for ethambutol and pyrazinamide).• Expected C2hr ranges were provided and were consistentwith published normal values
Data Analysis• Demographic and clinical characteristics were com-pared with χ2 statistic or, for nonparametric data,the Mann-Whitney U test.• Risk factors were determined using Bivariate andmultivariate logistic regression analyses• mean change in C2hr levels following doseadjustment was determined using Paired Student ttests.• Daily doses were calculated for each drug• Data were analyzed with SPSS 17 software
• 311 patients were included in the study, of whom42 (14%) met criteria for slow response• Of the 23 patients with initial smear-positivesputum specimens, 17 (74%) had specimens thatremained smear positive• The only significant predictor of slow response wasdiabetes
Risk Factors for Low Isoniazid or Rifampin Levels
• small sample size precluded meaningful analysis ofrisk factors for low ethambutol levels.• Patients with diabetes were at significantlyincreased risk of having a low rifampin level• Patients who received isoniazid biweekly were lesslikely to have low isoniazid levels than those whoreceived isoniazid daily, but this association was notstatistically significant in multivariate analysisOther issues
Follow-up C2hr Levels after Dose Adjustment• 18 patients with rifampin below expected range all increased from the initial to the follow-up level– 16 (89%) had levels in the expected range• 14 patients with daily-dosed INH below expectedrange increased levels in 12 patients– 4 had levels in the expected range• 4 (29%) patients had follow-up TDM for biweekly-dosed isoniazid levels below the expected range all had increased levels
• Rifampin correction to the expected range wasmore likely following the first dose adjustment thanwere daily-dosed isoniazid levels below theexpected range (p = 0.01).• There was no significant difference in the likelihoodof correction to the expected range between dailyand biweekly dosed isoniazid.• No follow-up levels of ethambutol or pyrazinamidewere reported.• There were no reported medication-related adverseevents following dose increase.
Treatment Outcomes• 32 patients (76%) had complete outcomes• 10 continued receiving treatment• 3 died:1. INH, rifampin, ehambutol, pyrazinamide (levels withinexpected range)2. INH, rifampin, ehambutol (levels within expected range)3. INH, rifampin, ehambutol (levels below expected range)• 2 moved out of the state (incomplete follow up)• Median therapy completion time was 45 weeks• No report for relapse over median of 14.5 months• No resistance incidences while on treatment
Major findings• In patients treated for Pulmonary TB and had slowresponse most of them had C2h levels of INH,rifampin (and ethambutol in many) below the expectrange• TDM strategy is useful for:– Detecting low drug concentration levels– Dose adjustment.• Treatment duration in patients with lower thanexpected levels of rifampin was shorter by 2 monththan in patients with normal levels (specific correlationis unkown) may benefit in treatment cost
• About 90% of patients with lower rifampin levelsachieved the target level after the first adjusteddose bactericidal activity↑Rifampin could be the drug of choice in early TDM forpatients with failing TB therapy• DM was significantly associated with slow responseanti-TB ↓C2h– (↓rifampin exposure, absorption??)• Other factors may include: drug-drug interaction
Author’s recommendations• Further investigation for TDM applicability in otherclinical settings and centers.• Include other factors affecting PK in considerations:– Pt weight-time of TDM-Livers cirrhosis- chronic kidneydisease…• Consider other study limitations…– (blood sampling time-C2h-C6h…etc)– Inclusion of patients with normal response in TDM• The big challenge: TDM cost vs. giving high dose forpt. at risk
summary• TDM for slow responding TB patients found in mostof them C2h below expected level of Rifampin andINH (and in some ethambutol)• TDM performed after dose adjustment foundexpected levels suggesting a strong clinicalindication for TDM• Rifampin could be a target drug for programmaticTDM intervention• Further prospective studies are need to evaluatethe benefit of TDM for Rifampin in various group ofTB slow responding patients.