Dataset Information

Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis.

ABSTRACT:

Aim

We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin.

Materials & methods

Genotypes for SLCO1B1, NAT2, PXR, ABCB1 and UGT1A genes were determined using a TaqMan^® Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics.

Results

Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patients contributing drug concentrations, rapid and intermediate acetylators had 2.3- and 1.6-times faster isoniazid clearance than slow acetylators. No association was observed between rifampicin pharmacokinetics and SLCO1B1, ABCB1, UGT1A or PXR genotypes.

Conclusion

Clinical relevance of the effects of genetic variation on isoniazid concentrations and low first-line tuberculosis drug exposures observed require further investigation.

SUBMITTER: Naidoo A

PROVIDER: S-EPMC6562923 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis.

Naidoo Anushka A Chirehwa Maxwell M Ramsuran Veron V McIlleron Helen H Naidoo Kogieleum K Yende-Zuma Nonhlanhla N Singh Ravesh R Ncgapu Sinaye S Adamson John J Govender Katya K Denti Paolo P Padayatchi Nesri N

Pharmacogenomics 20190215 4

<h4>Aim</h4>We report the prevalence and effect of genetic variability on pharmacokinetic parameters of isoniazid and rifampicin.<h4>Materials & methods</h4>Genotypes for SLCO1B1, NAT2, PXR, ABCB1 and UGT1A genes were determined using a TaqMan<sup>®</sup> Genotyping OpenArray™. Nonlinear mixed-effects models were used to describe drug pharmacokinetics.<h4>Results</h4>Among 172 patients, 18, 43 and 34% were classified as rapid, intermediate and slow NAT2 acetylators, respectively. Of the 58 patie ...[more]

PMID: 30767706

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Project description:BackgroundPatients with tuberculosis resistant to isoniazid but susceptible to rifampicin (Hr-Rs TB) remain a neglected demographic, despite a high disease burden and poor outcomes of these patients. The aim of this study was to investigate the characteristics of isoniazid-resistance-related mutations in Mycobacterium tuberculosis and resistance rates to drugs included in WHO-recommended regimens for Hr-Rs patients.MethodsMycobacterium tuberculosis isolates (n = 4922) obtained from national tuberculosis drug-resistance surveillance were subjected to whole-genome sequencing to identify Hr-Rs strains. The minimal inhibitory concentrations (MICs) were established for the Hr-Rs strains to determine the isoniazid resistance levels. We also identified drug-resistance-associated mutations for five drugs (fluoroquinolones, ethambutol, pyrazinamide, streptomycin, and amikacin) in the Hr-Rs strains.ResultsOf the 4922 strains, 384 (7.8 %) were Hr-Rs. The subculture of seven strains failed, so 377 (98.2 %) strains underwent phenotypic MIC testing. Among the 384 genotypic Hr-Rs strains, 242 (63.0 %) contained the katG Ser315Thr substitution; 115 (29.9 %) contained the -15C>T in the promoter region of the fabG1 gene; and 16 (4.2 %) contained Ser315Asn in the katG gene. Of the 239 strains with the Ser315Thr substitution, 229 (95.8 %) had MIC ≥ 2 µg/mL, and of the 114 strains with the -15C>T mutation, 103 (90.4 %) had 0.25 µg/mL ≤ MIC ≤ 1 µg/mL. The genotypic resistance rates were 0.8 % (3/384) for pyrazinamide, 2.3 % (9/384) for ethambutol and fluoroquinolones; 39.6 % (152/384) of the strains were resistant to streptomycin, but only 0.5 % (2/384) of the strains were resistant to amikacin.ConclusionSer315Thr in katG was the predominant mutation conferring the Hr-Rs phenotype, followed by the fabG1 -15C>T mutation. The combination of rifampicin, pyrazinamide, ethambutol, and levofloxacin should be effective in the treatment of patients with Hr-Rs tuberculosis because the resistance rates for these drugs in China are low.

Project description:Levofloxacin is increasingly used in the treatment of multidrug-resistant tuberculosis (MDR-TB). There are limited pediatric pharmacokinetic data to inform dose selection for children. Children routinely receiving levofloxacin (250-mg adult tablets) for MDR-TB prophylaxis or disease in Cape Town, South Africa, underwent pharmacokinetic sampling following receipt of a dose of 15 or 20 mg/kg of body weight given as a whole or crushed tablet(s) orally or via a nasogastric tube. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Model-based simulations were performed to estimate the doses across weight bands that would achieve adult exposures with 750-mg once-daily dosing. One hundred nine children were included. The median age was 2.1 years (range, 0.3 to 8.7 years), and the median weight was 12 kg (range, 6 to 22 kg). Levofloxacin followed 2-compartment kinetics with first-order elimination and absorption with a lag time. After inclusion of allometric scaling, the model characterized the age-driven maturation of clearance (CL), with the effect reaching 50% of that at maturity at about 2 months after birth and 100% of that at maturity by 2 years of age. CL in a typical child (weight, 12 kg; age, 2 years) was 4.7 liters/h. HIV infection reduced CL by 16%. By use of the adult 250-mg formulation, levofloxacin exposures were substantially lower than those reported in adults receiving a similar dose on a milligram-per-kilogram basis. To achieve adult-equivalent exposures at a 750-mg daily dose, higher levofloxacin pediatric doses of from 18 mg/kg/day for younger children with weights of 3 to 4 kg (due to immature clearance) to 40 mg/kg/day for older children may be required. The doses of levofloxacin currently recommended for the treatment of MDR-TB in children result in exposures considerably lower than those in adults. The effects of different formulations and formulation manipulation require further investigation. We recommend age- and weight-banded doses of 250-mg tablets of the adult formulation most likely to achieve target concentrations for prospective evaluation.

Dataset Information

Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis.

Aim

Materials & methods

Results

Conclusion

Publications

Effects of genetic variability on rifampicin and isoniazid pharmacokinetics in South African patients with recurrent tuberculosis.

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