Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?

Abstract

Antituberculosis drugs display large pharmacokinetic variability, which may be influenced by several factors, including body size, genetic differences, and drug-drug interactions. We set out to determine these factors, quantify their effect, and determine the dose adjustments necessary for optimal drug concentrations. HIVinfected Ugandan adults with pulmonary tuberculosis treated according to international weight-based dosing guidelines underwent pharmacokinetic sampling (1, 2, and 4 h after drug intake) 2, 8, and 24 weeks after treatment initiation. Between May 2013 and November 2015, we enrolled 268 patients (148 males) with a median weight of 53.5 (interquartile range [IQR], 47.5 to 59.0) kg and a median age of 35 (IQR, 29 to 40) years. Population pharmacokinetic modeling was used to interpret the data and revealed that patients weighing Ͻ55 kg achieved lower concentrations than those in higher weight bands for all drugs in the regimen. The models predicted that this imbalance could be solved with a dose increment of one fixed-dose combination (FDC) tablet for the weight bands of 30 to 37 and 38 to 54 kg. Additionally, the concomitant use of efavirenz increased isoniazid clearance by 24.1%, while bioavailability and absorption of rifampin and isoniazid varied up to 30% in patients on different formulations. Current dosing guidelines lead to lower drug exposure in patients in the lower weight bands. Simply adding one FDC tablet to current weight band-based dosing would address these differences in exposure and possibly improve outcomes. Lower isoniazid exposures due to efavirenz deserve further attention, as does the quality of currently used drug formulations of anti-TB drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT01782950.)

Current research toward optimizing dosing of first-line antituberculosis treatment

“…Between patient variability was reduced and dosing simplified by adding one FDC tablet for patients under 55 kg ( Figure 1, right panel). Very similar results were obtained when a similar approach was applied to these drugs based on data from Uganda [33]. The results of these studies confirm that higher mg/kg doses are needed in patients in the lower weight bands, and guidelines should be revised to avoid systematic underdosing of low weight patients.…”

“…Similarly, a more recent study from China found that four of five FDCs failed bioequivalence criteria for rifampin [32]. Observational studies in patients have attributed massively compromised bioavailability to product or batch quality [12,14,[33][34][35][36]. Recently, a 20% reduction in the bioavailability of rifampin was described in the 4-drug FDC used in approximately 450 000 South African patients annually [37].…”

“…Dosing guidelines for antituberculosis drugs typically advocate a uniform milligram per kilogram of body weight (mg/kg) dose, and the drugs are typically dosed by weight band to achieve a narrow mg/kg range using the available formulations [40,41]. A consistent finding of pharmacokinetic studies in adults and children dosed in this way is that lower weight patients have lower drug exposures [5,10,13,18,33,37,[42][43][44]. This can be attributed to the nonlinear relationship between clearance and size whereby smaller people need higher maintenance doses per kilogram of body weight [45].…”

Pharmacokinetics and Drug‐Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings: Importance of Genotyping

“…Our analysis did not detect any difference in isoniazid exposure among different ARTs (efavirenz-based, nevirapine-based, lopinavir/ritonavir-based, and atazanavir/ritonavir-based), which contrasts with previous reports. 36,37 However, it may be that our analysis was not powered to detect these differences because 88% of the participants were on efavirenz-based ART.…”

Pharmacokinetic and pharmacodynamic considerations of rifamycin antibiotics for the treatment of tuberculosis

“…Patients with HIV infection may have reduced serum concentrations of rifampicin, particularly in the setting of severe immunocompromised [5]. Patients who are underweight also have up to 30% reduction in rifampicin exposures, related to malnutrition coupled with low dosing when mg/kg-based dosing algorithms are applied [6,7]. In our opinion, higher rifampicin dosing should routinely be applied in low-weight patients or those with advanced HIV.…”