Limited sampling strategy for predicting isoniazid exposure in patients with extrapulmonary tuberculosis

Alshaikheid, Mohammed; Chaabane, Amel; Fredj, Nadia Ben; Brahim, H. Ben; Fadhel, Najah Ben; Chadli, Zohra; Slama, Ahlem; Boughattas, Naceur A.; Chakroun, M.; Aouam, Karim

doi:10.1111/jcpt.13098

Cited by 9 publications

(7 citation statements)

References 27 publications

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“…Limited sampling strategy models, based on multiple linear regression (MLR) or maximum a posteriori (MAP) analysis, were established for the estimation of AUC in patients who were administered INH. Alshaikheid et al (2020) established an LSS model, based on 25 patients using the MLR analysis. They found that C 3 , C 2 -C 6 , C 0 - C 1 -C 6 are suitable for estimation of INH AUC 0–24h .…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Isoniazid and its Metabolite Acetylisoniazid in Chinese Population

et al. 2022

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Objective: We aimed to establish a population pharmacokinetic (PPK) model for isoniazid (INH) and its major metabolite Acetylisoniazid (AcINH) in healthy Chinese participants and tuberculosis patients and assess the role of the NAT2 genotype on the transformation of INH to AcINH. We also sought to estimate the INH exposure that would achieve a 90% effective concentration (EC90) efficiency for patients with various NAT2 genotypes.Method: A total of 45 healthy participants and 157 tuberculosis patients were recruited. For healthy subjects, blood samples were collected 0–14 h after administration of 300 mg or 320 mg of the oral dose of INH; for tuberculosis patients who received at least seven days therapy with INH, blood samples were collected two and/or six hours after administration. The plasma concentration of INH and AcINH was determined by the reverse-phase HPLC method. NAT2 genotypes were determined by allele-specific amplification. The integrated PPK model of INH and AcINH was established through nonlinear mixed-effect modeling (NONMEM). The effect of NAT2 genotype and other covariates on INH and AcINH disposition was evaluated. Monte Carlo simulation was performed for estimating EC90 of INH in patients with various NAT2 genotypes.Results: The estimated absorption rate constant (Ka), oral clearance (CL/F), and apparent volume of distribution (V2/F) for INH were 3.94 ± 0.44 h−1, 18.2 ± 2.45 L⋅h−1, and 56.8 ± 5.53 L, respectively. The constant of clearance (K30) and the volume of distribution (V3/F) of AcINH were 0.33 ± 0.11 h−1 and 25.7 ± 1.30 L, respectively. The fraction of AcINH formation (FM) was 0.81 ± 0.076. NAT2 genotypes had different effects on the CL/F and FM. In subjects with only one copy of NAT2 *5, *6, and *7 alleles, the CL/F values were approximately 46.3%, 54.9%, and 74.8% of *4/*4 subjects, respectively. The FM values were approximately 48.7%, 63.8%, and 86.9% of *4/*4 subjects, respectively. The probability of target attainment of INH EC90 in patients with various NAT2 genotypes was different.Conclusion: The integrated parent-metabolite PPK model accurately characterized the disposition of INH and AcINH in the Chinese population sampled, which may be useful in the individualized therapy of INH.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Isoniazid and its Metabolite Acetylisoniazid in Chinese Population

et al. 2022

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“…In our study, we chose C 3 as our monitoring point, as it was demonstrated in the study by Vivien and Thibier 8 that this sample time point is an excellent correlation with isoniazid total exposure and could be considered a good marker in isoniazid TDM. Furthermore, a limited sampling strategy developed by our team for predicting isoniazid exposure in patients with extrapulmonary TB demonstrated that a 1‐time‐point limited sampling strategy including C 3 had an acceptable correlation coefficient ( r ² = 0.9) 17 . As mentioned, most C 2 studies use a range of 3 to 5 µg/mL.…”

Section: Discussionmentioning

confidence: 89%

“…Furthermore, a limited sampling strategy developed by our team for predicting isoniazid exposure in patients with extrapulmonary TB demonstrated that a 1-time-point limited sampling strategy including C 3 had an acceptable correlation coefficient (r 2 = 0.9). 17 As mentioned, most C 2 studies use a range of 3 to 5 μg/mL. However, it has also been suggested that a concentration of 1.5 μg/mL at the third hour is an optimum effective amount of drug against mycobacteria 9 and that a cutoff value of C 3 >3.69 μg/mL is associated with isoniazid-induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Isoniazid Therapeutic Drug Monitoring in Tunisian Patients With Tuberculosis

Alshaikheid

Romdhane

Fredj

et al. 2021

The Journal of Clinical Pharma

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A regular therapeutic drug monitoring (TDM) of isoniazid could be useful to predict the acetylation profile and to prescribe doses associated with optimal efficacy and safety. We aimed to assess the usefulness of isoniazid TDM in the Tunisian population, to describe the acetylation profile distribution in this population, and to investigate the influence of certain parameters on acetylation phenotype. We performed a retrospective study including Tunisian patients with tuberculosis underwent an isoniazid TDM. Isoniazid concentrations were measured 3 hours after drug intake (C3). Subsequent isoniazid doses were adjusted to maintain the C3 within the recommended target (1‐2 µg/mL). Patients were qualified as slow acetylators (SAs) or rapid acetylators (RAs) according to their acetylation index. Among the 255 patients, 58% were SAs and 42% were RAs. Of all patients, only 30.6% had a C3 value within the target range. A dose adjustment has been performed for patients with C3 outside the target range. C3 was controlled in 77 patients. It became within the target range in 39 patients (50.6%). The median recommended isoniazid weight doses for SAs and RAs were 2.1 ± 0.7 mg/kg and 4.2 ± 1.4 mg/kg, respectively. The multivariate analysis showed that body weight, C3, and C3/isoniazid dose were found to be significantly different between the 2 acetylation groups. In the pediatric group, only 9 had a C3 value within the target range, and all of them were RAs. The irrevocable interest of isoniazid TDM has been shown in Tunisian patients with tuberculosis, in both adult and pediatric patients, as isoniazid demonstrates an unpredictable pharmacokinetic profile.

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“…Besides, estimating the AUC requires several blood samples and could, therefore, be impractical in routine practice. C3 was selected for use in this study as it has been demonstrated that this sample time point has excellent correlation with INH total exposure, and could be considered a good marker in INH TDM (Vivien et al, 1973;Alshaikheid et al, 2020). Modelling of INH exposure using single time point concentration data alone has been performed in one previous study (Jung et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetic model of isoniazid in patients with tuberculosis in Tunisia

Fredj

Romdhane

Woillard

et al. 2021

International Journal of Infectious Diseases

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To develop a pharmacokinetic model of isoniazid (INH) concentration taking into account demographic factors and genetic variables [N-acetyltransferase 2 (NAT2) genotype], and to propose an initial INH dosage that could maximize the probability of achieving the desired INH concentration. Methods: A retrospective analysis was undertaken of INH concentration data collected from patients with tuberculosis in Tunisia. Results: In total, 118 patients were included in this study. The one-compartment model [volume of distribution (V), elimination rate (Ke)] was found to have good predictive performance. Multi-variate analysis showed that NAT2 affected both V and Ke significantly, but age, gender and weight did not. Internal validation of the final model showed correlation of 0.95 between individual predicted INH concentration 3 h after drug intake (C3) and observed C3. External validation showed that percentage mean absolute prediction error and percentage root mean squared error were 9.11% (range 0.62-35.8%) and 11.6%, respectively. Monte-Carlo simulation showed that doses of at least 225 mg/24 h and at least 450 mg/24 h attained a therapeutic concentration in >80% of patients in the NAT2 slow acetylator group and the NAT2 rapid/intermediate acetylator group, respectively. Conclusion:The pharmacokinetic model allowed optimization of individual dosing regimens of INH in patients with tuberculosis in Tunisia. This tool may facilitate improved efficacy of INH and prevent its toxicity in this population.

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Limited sampling strategy for predicting isoniazid exposure in patients with extrapulmonary tuberculosis

Cited by 9 publications

References 27 publications

Population Pharmacokinetics and Pharmacodynamics of Isoniazid and its Metabolite Acetylisoniazid in Chinese Population

Population Pharmacokinetics and Pharmacodynamics of Isoniazid and its Metabolite Acetylisoniazid in Chinese Population

Isoniazid Therapeutic Drug Monitoring in Tunisian Patients With Tuberculosis

Population pharmacokinetic model of isoniazid in patients with tuberculosis in Tunisia

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