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Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania.

Denti P, Jeremiah K, Chigutsa E, Faurholt-Jepsen D, PrayGod G, Range N, Castel S, Wiesner L, Hagen CM, Christiansen M, Changalucha J, McIlleron H, Friis H, Andersen AB - PLoS ONE (2015)

Bottom Line: The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model.Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment.The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

ABSTRACT
Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients.

No MeSH data available.


Related in: MedlinePlus

In the left panels, scatter plots showing ethambutol exposure vs. patient age.In the right small panels, box and whiskers plots summarizing the same values. The top panels refer to AUC0-24 and the bottom panels to Cmax. For all patients for whom 2 PK profiles were available, geometric mean was used to obtain summary values.
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pone.0141002.g007: In the left panels, scatter plots showing ethambutol exposure vs. patient age.In the right small panels, box and whiskers plots summarizing the same values. The top panels refer to AUC0-24 and the bottom panels to Cmax. For all patients for whom 2 PK profiles were available, geometric mean was used to obtain summary values.

Mentions: For ethambutol, the best-fitting model was a two-compartment disposition, with first-order elimination, and transit compartment absorption with no separate estimate of ka. The final parameter estimates are shown in Table 5and a visual predictive check is shown in Fig 6. Although the inclusion of two-compartment disposition kinetics significantly improved the model fit (-30 points OFV), the parameter estimates for the volume of the peripheral compartment (Vp) and the inter-compartmental clearance (Q) proved unstable. To stabilise the model while allowing the inclusion of the two-compartment kinetics, a prior was included [28], based on parameter estimates from a PK model of ethambutol developed on data from a similar population of TB patients [29]. After applying allometric scaling to adjust for differences in body weight amongst the studies, the typical values for the priors of Vp and Q were 420.7 L/h and 64.4 L/h, respectively. The priors were assumed to have a Gaussian distribution around these typical values, and were included in the model imputing a large uncertainty (50% CV) to make them weakly informative. Testing different settings for the prior distributions showed that the estimates of the other parameters in the model were not significantly affected. After the inclusion of the priors, the two-compartment model proved stable and provided a significantly better fit than the one-compartment model, and was used for the analysis. The best predictor for allometric scaling of all clearance and volume parameters was total body weight. Additionally, older age was associated with lower clearance, with every year of age causing a decrease of 1.41% in clearance (-23.4 OFV, p<10 -5). No other factors tested in the model, including HIV status, nutritional supplementation, sex, CD4 count, and time on TB treatment, significantly affected the PK. The relationship between the individual values of ethambutol exposure and age is shown in Fig 7. Median ethambutol AUC0-24 was 23.6 h·mg/L (IQR: 20.5; 28.9) and Cmax was 2.44 mg/L (IQR: 2.09; 2.86).


Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania.

Denti P, Jeremiah K, Chigutsa E, Faurholt-Jepsen D, PrayGod G, Range N, Castel S, Wiesner L, Hagen CM, Christiansen M, Changalucha J, McIlleron H, Friis H, Andersen AB - PLoS ONE (2015)

In the left panels, scatter plots showing ethambutol exposure vs. patient age.In the right small panels, box and whiskers plots summarizing the same values. The top panels refer to AUC0-24 and the bottom panels to Cmax. For all patients for whom 2 PK profiles were available, geometric mean was used to obtain summary values.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4621059&req=5

pone.0141002.g007: In the left panels, scatter plots showing ethambutol exposure vs. patient age.In the right small panels, box and whiskers plots summarizing the same values. The top panels refer to AUC0-24 and the bottom panels to Cmax. For all patients for whom 2 PK profiles were available, geometric mean was used to obtain summary values.
Mentions: For ethambutol, the best-fitting model was a two-compartment disposition, with first-order elimination, and transit compartment absorption with no separate estimate of ka. The final parameter estimates are shown in Table 5and a visual predictive check is shown in Fig 6. Although the inclusion of two-compartment disposition kinetics significantly improved the model fit (-30 points OFV), the parameter estimates for the volume of the peripheral compartment (Vp) and the inter-compartmental clearance (Q) proved unstable. To stabilise the model while allowing the inclusion of the two-compartment kinetics, a prior was included [28], based on parameter estimates from a PK model of ethambutol developed on data from a similar population of TB patients [29]. After applying allometric scaling to adjust for differences in body weight amongst the studies, the typical values for the priors of Vp and Q were 420.7 L/h and 64.4 L/h, respectively. The priors were assumed to have a Gaussian distribution around these typical values, and were included in the model imputing a large uncertainty (50% CV) to make them weakly informative. Testing different settings for the prior distributions showed that the estimates of the other parameters in the model were not significantly affected. After the inclusion of the priors, the two-compartment model proved stable and provided a significantly better fit than the one-compartment model, and was used for the analysis. The best predictor for allometric scaling of all clearance and volume parameters was total body weight. Additionally, older age was associated with lower clearance, with every year of age causing a decrease of 1.41% in clearance (-23.4 OFV, p<10 -5). No other factors tested in the model, including HIV status, nutritional supplementation, sex, CD4 count, and time on TB treatment, significantly affected the PK. The relationship between the individual values of ethambutol exposure and age is shown in Fig 7. Median ethambutol AUC0-24 was 23.6 h·mg/L (IQR: 20.5; 28.9) and Cmax was 2.44 mg/L (IQR: 2.09; 2.86).

Bottom Line: The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model.Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment.The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.

ABSTRACT
Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients.

No MeSH data available.


Related in: MedlinePlus