Optimizing ethambutol dosing among HIV/tuberculosis co-infected patients: a population pharmacokinetic modelling and simulation study

Mehta, Krina; Ravimohan, Shruthi; Pasipanodya, Jotam G.; Srivastava, Shashikant; Modongo, Chawangwa; Zetola, Nicola M.; Weissman, Drew; Ivaturi, Vijay; Gumbo, Tawanda; Bisson, Gregory P.; Vinnard, Christopher

doi:10.1093/jac/dkz265

Cited by 9 publications

(25 citation statements)

References 34 publications

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“…A two-compartment model with creatinine clearance and total body weight included as covariates best described the pharmacokinetics of ethambutol for the patients enrolled in the present study, and this is supported by previously published studies [ 15 , 19 ]. The differences between the primary pharmacokinetic parameters of ICU and outpatients were all statistically significant (as reported in Table 3 ).…”

Section: Discussionsupporting

confidence: 82%

“…In our study, the volume of the peripheral compartment in ICU patients is similar to the outpatients. There has been a wide range of volumes of the peripheral compartment reported in outpatients (typical values of 16.5 (bioavailability fixed to 1) to 512 (bioavailability fixed to 0.65) [ 15 , 19 ]), and the results of our study fit within these results.…”

Section: Discussionsupporting

confidence: 80%

“…Relative clearance was significantly lower in ICU patients compared to outpatients ( p < 0.0001) and lower than that reported for outpatients in other studies, where results range from 2.2 to 77 L/h (bioavailability fixed to 1) [ 11 , 15 , 19 , 24 ]. With up to 70% of ethambutol being excreted unchanged in urine [ 25 ], the use of creatinine clearance as a covariate on relative clearance is an important inclusion in the final model.…”

Section: Discussioncontrasting

confidence: 67%

“…The difference in bioavailability of ICU patients was greater than 5-times higher than outpatients ( p < 0.0001). Unlike the model reported here, most studies do not evaluate the variability of bioavailability and fix it to 1 or 0.65 [ 11 , 15 , 19 ]. For ICU patients the tablet is crushed and delivered via a nasogastric tube, whereas oral administration was used for outpatients.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the successful use of FDC tablets in outpatients [ 13 ], it limits the opportunity to tailor doses in special cases, including ICU patients, patients with kidney injury, obese patients or those whose recovery is not progressing as expected. TB treatment using FDC tablets with weight-based regimens for patients in ICU may be suboptimal and lead to poor outcomes [ 14 , 15 , 16 ]. Comparing the pharmacokinetics of ethambutol as part of an FDC regimen by studying ICU and outpatients would enable a greater understanding as to whether other approaches to optimize this drug may be required.…”

Section: Introductionmentioning

confidence: 99%

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Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study

et al. 2021

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Background: Tuberculosis (TB) patients admitted to intensive care units (ICU) have high mortality rates. It is uncertain whether the pharmacokinetics of first-line TB drugs in ICU patients are different from outpatients. This study aims to compare the pharmacokinetics of oral ethambutol in TB patients in ICU versus TB outpatients and to determine whether contemporary dosing regimens achieve therapeutic exposures. Methods: A prospective population pharmacokinetic study of ethambutol was performed in Amazonas State, Brazil. Probability of target attainment was determined using AUC/MIC > 11.9 and Cmax/MIC > 0.48 values. Optimized dosing regimens were simulated at steady state. Results: Ten ICU patients and 20 outpatients were recruited. Ethambutol pharmacokinetics were best described using a two-compartment model with first-order oral absorption. Neither ICU patients nor outpatients consistently achieved optimal ethambutol exposures. The absorption rate for ethambutol was 2-times higher in ICU patients (p < 0.05). Mean bioavailability for ICU patients was >5-times higher than outpatients (p < 0.0001). Clearance and volume of distribution were 93% (p < 0.0001) and 53% (p = 0.002) lower in ICU patients, respectively. Conclusions: ICU patients displayed significantly different pharmacokinetics for an oral fixed-dose combination administration of ethambutol compared to outpatients, and neither patient group consistently achieved pre-defined therapeutic exposures.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 80%

Section: Discussioncontrasting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study

et al. 2021

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Progress in Pharmacometrics Implementation and Regulatory Integration in Africa: A Systematic Review

Ndzamba,

Egieyeh,

Fasinu

2024

Clin Pharma and Therapeutics

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The availability of clinical trial data, advocacy, and increased funding has facilitated the implementation of pharmacometrics in Africa, resulting in the establishment of additional training programs for pharmacometricians. This study conducted a systematic review to evaluate the progress made from the implementation of pharmacometrics in clinical drug development and its adoption into drug approval by regulatory authorities in Africa. We performed a comprehensive literature search using major databases such as PubMed and Google Scholar. The study included articles published until 2024, with no lower cutoff. Articles were excluded if not addressing the research question or of pharmacometrics studies done outside Africa with no collaboration with African researchers (study setting). For the review, a total of 121 articles were included for analysis. Among the reported pharmacometrics approaches, Population pharmacokinetics modeling approaches are the most used (95 (78.5%)). South Africa and Uganda researchers have the most research output in pharmacometrics in Africa (82 (89.1%) and 7 (7.61%), respectively), with the University of Cape Town (South Africa) producing the highest (71 (78.8%)) of all article in Africa. The most studied conditions are TB (43 (35.5%)), HIV (33 (27.3%), TB and HIV (22 (18.2%)), and malaria (12 (9.92%). Pharmacometrics is gaining momentum in Africa, and the progress made since inception will significantly improve the safety and efficacy of therapeutic agents used to treat HIV, TB, and other emerging conditions.

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Diagnostic Accuracy of Therapeutic Drug Monitoring During Tuberculosis Treatment

Anderson

Vinnard

2022

The Journal of Clinical Pharma

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Patients with tuberculosis (TB) coinfected with HIV are more likely to have low blood concentrations of the first‐line anti‐TB drugs (associated with poor outcomes). Therapeutic drug monitoring (TDM) is recommended for certain patient populations with TB at increased risk for a poor outcome. Our objective was to estimate the diagnostic accuracy of a 2‐hour TDM serum sample for the first‐line anti‐TB drugs among patients with HIV/TB and evaluate the information gained by an additional 6‐hour sample. We created a virtual (n = 1000) HIV/TB patient population and performed pharmacokinetic simulations using published population models for isoniazid, rifampin, pyrazinamide, and ethambutol. We performed receiver operating characteristic analysis to compare the diagnostic performance of a single 2‐hour serum sample with samples obtained at 2 and 6 hours after dosing. The sensitivity of a single 2‐hour serum concentration to identify patients with HIV/TB with adequate serum exposures was lowest for rifampin (54.9%; 95%CI, 50.79%‐59.41%) and highest for ethambutol (70.8%; 95%CI, 66.06%‐72.61%) for maximum concentration (Cmax) targets. Diagnostic accuracy of a single 2‐hour serum sample for the area under the concentration‐time curve (AUC) from time 0 to 24 hours target was highest for isoniazid (93%; 95%CI, 90.9%‐94.1%) and lowest for pyrazinamide (66.3%; 95%CI, 62.6%‐70.0%). In summary, the diagnostic performance of TDM for Cmax and AUC from time 0 to 24 hours targets demonstrated variability across the first‐line anti‐TB drugs. The addition of a 6‐hour serum sample led to the highest statistically significant improvement (P < .001) and highest increase in diagnostic accuracy (area under the receiver operating characteristic curve) for rifampin for Cmax and AUC. The other first‐line drugs had modest/negligible increases in diagnostic accuracy.

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Optimizing ethambutol dosing among HIV/tuberculosis co-infected patients: a population pharmacokinetic modelling and simulation study

Cited by 9 publications

References 34 publications

Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study

Is Dosing of Ethambutol as Part of a Fixed-Dose Combination Product Optimal for Mechanically Ventilated ICU Patients with Tuberculosis? A Population Pharmacokinetic Study

Progress in Pharmacometrics Implementation and Regulatory Integration in Africa: A Systematic Review

Diagnostic Accuracy of Therapeutic Drug Monitoring During Tuberculosis Treatment

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