Pharmacokinetics of rifampicin and isoniazid in a Peruvian population under tuberculosis treatment
- Autores: Ana Requena Mendez
- Directores de la Tesis: David Aj Moore (dir. tes.), José Muñoz Gutiérrez (dir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2016
- Idioma: inglés
- Tribunal Calificador de la Tesis: Julià González Martín (presid.), Maria Luiza De Souza Galvao (secret.), Rob Aarnoutse (voc.)
- Programa de doctorado: Programa de Doctorado en Medicina e Investigación Traslacional por la Universidad de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX Dipòsit Digital de la UB
- Resumen
BACKGROUND For drug-compliant patients, poor responses to tuberculosis (TB) treatment might be attributable to subtherapeutic drug concentrations. An impaired absorption of rifampin and isoniazid was previously reported for patients with diabetes mellitus (DM) or HIV or those who took the drugs with food. OBJECTIVES The objectives of the first study were to determine whether TB drug pharmacokinetics differed in Peruvian TB patients with DM or HIV and to evaluate the treatment outcome. The objectives of the second study were determine the effect of taking TB treatment on an empty stomach upon the sputum smear and culture conversion times and also the end-of-treatment (EOT) and EOT+6 month disease outcomes compared to TB patients who take the treatment as they do usually (with food); and to determine if there is difference in the pharmacokinetics of TB drugs in these two groups. METHODS In the first study, a cross-sectional study, TB patients, recruited from health centers in Lima, Peru, had blood samples taken at 2 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampicin and isoniazid. In the second study, pulmonary TB patients (sputum smear positive) recruited were given a diet diary where they annotated what they had eaten during the drug intake and they had blood samples taken at 2, 4 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampicin and isoniazid. RESULTS Study 1 Of 105 patients, 50 had TB without a co-morbidity, 26 had coexistent DM, and 29 had coexistent HIV. Unexpectedly, the overall median 2- and 6-h levels of rifampicin were 1.6 and 3.2 mg/liter, respectively, and the time to the peak concentration was 6 h instead of 2 h for 62% patients. The geometric mean peak concentration of drug in serum (Cmax) was significantly higher in fast absorbers than in slow absorbers (5.0 versus 3.8 mg/liter;p:0.05). Neither slow nor fast absorbers with comorbidities (DM or HIV) had significantly different Cmax results compared to those of TB patients without comorbidities. An analysis of variance regression analysis showed that female gender (P<0.001) and the time to maximum concentration of drug in serum (Tmax) at 2 h (P:0.012) were independently correlated with increased exposure to rifampicin Concerning isoniazid results, 42.1% of patients received biweekly isoniazid. The mean biweekly dose (12.8 mg/kg of body weight/day) was significantly lower than the nominal dose of 15 mg/kg/day (p<0.001), and this effect was particularly marked in patients with concurrent diabetes and in males. The median maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 6 h (AUC0–6) were 2.77 mg/liter and 9.71 g·h/liter, respectively, for daily administration and 8.74 mg/liter and 37.8 mg·h/liter, respectively, for biweekly administration. There were no differences in the Cmax with respect to gender, diabetes mellitus (DM) status, or HIV status. Low levels of rifampicin or isoniazid were not associated with poorer clinical outcomes Study 2 Sixty patients were included but only 37 of them were finally included for the treatment outcome evaluation and only one of them had an early relapse after completing the therapy. It was observed a difference in the rifampicin AUC0-6 in the non-fasting blood sampling day (24.31 mg·h/l) compared with the rifampicin AUC0-6 during the fasting day (28.64 mg·h/l) (p: 0.002). Moreover, there were significantly differences in the Tmax in the non-fasting day compared with the fasting day. (p: 0.005). In the multivariate analysis, rifampicin Cmax in the fasting day was found to be 15% higher than rifampicin Cmax during the non-fasting day (Confident Interval: 1.01 – 1.3, p<0.036). Females had 20% levels higher than males (p: 0.027). Rifampicin AUC0-6 in the fasting day was found to be 14% higher than rifampicin AUC0-6 during the non-fasting day ( p:0.021). Females had 2% levels higher than males (p: 0.027). When Tmax occurred at 4h, rifampicin AUC0-6 decreased 20% (p:0.002) and when it occurred at 6h, the AUC0-6 decreased 50% (p<0.001). There were significantly difference in the Cmax at the non-fasting blood-sampling day (3.51 mg/L) compared with the isoniazid Cmax at the fasting blood-sampling day (4.54 mg/L) (Wilcoxon Signed rank test p< 0.001). The AUC0-6 was 12.11 mg·h/L in the non-fasting day vs. 13.31 mg·h/L during the fasting blood-sampling day (p: 0.001). Moreover, there were significant differences in the isoniazid Tmax in the non-fasting day compared with the fasting day. (p: 0.023). In the multivariate analysis, the isoniazid dose received had an effect upon the isoniazid levels (1.26, p:0.038). Isoniazid exposure in the fasting day was found to be 14% higher than those in the non-fasting day of females. Isoniazid AUC0-6 in the fasting day was found to be 22% higher than those in the non-fasting day (Confident Interval: 1.09 – 1.38, p<0.001. When isoniazid Tmax occurred at 6h, AUC0-6 decreased 47% (p:0.013). Chest-radiography evaluation When the score was determined, the ICC between the 2 raters was 0.995 (0.991-0.997, p<0.001. CONCLUSIONS Rifampicin and isoniazid exposure may be affected by weight-adjusted dose. Most of this Peruvian study population had impaired rifampicin and isoniazid pharmacokinetics with delayed absorption for rifampicin and low plasma concentrations, independent of the presence co-morbidities. Rifampicin in particular and also isoniazid pharmacokinetics were significantly affected by the intake of the drug with food. A clear relationship between the pharmacokinetics parameters and treatment outcome was not demonstrated. Therapeutic drug monitoring based on targets for pharmacokinetics parameters for TB drugs is currently neither widely used nor recommended during TB treatment Intestinal parasitosis did not affect both rifampicin and isoniazid pharmacokinetics. Rifampicin exposure was significantly lower in men compared to women. The acetylators status, may have contributed to low and variable isoniazid exposure.
