Background & objectives:Variations in the N-acetyltransferase (NAT2) gene among different populations could affect the metabolism and disposition of isoniazid (INH). This study was performed to genotype NAT2 gene polymorphisms in tuberculosis (TB) patients from Chennai, India, and compare plasma INH concentrations among the different genotypes.Methods:Adult patients with TB treated in the Revised National TB Control Programme (RNTCP) in Chennai, Tamil Nadu, were genotyped for NAT2 gene polymorphism, and two-hour post-dosing INH concentrations were compared between the different genotypes. Plasma INH was determined by high-performance liquid chromatography. Genotyping of the NAT2 gene polymorphism was performed by real-time polymerase chain reaction method.Results:Among the 326 patients genotyped, there were 189 (58%), 114 (35%) and 23 (7%) slow, intermediate and fast acetylators, respectively. The median two-hour INH concentrations in slow, intermediate and fast acetylators were 10.2, 8.1 and 4.1 μg/ml, respectively. The differences in INH concentrations among the three genotypes were significant (P<0.001).Interpretation & conclusions:Genotyping of TB patients from south India for NAT2 gene polymorphism revealed that 58 per cent of the study population comprised slow acetylators. Two-hour INH concentrations differed significantly among the three genotypes.

A high performance liquid chromatographic method for determination of rifabutin in human plasma was developed. The method involved deproteinisation of the sample with acetonitrile and analysis of the supernatant using a reversed-phase C 18 column (250mm) and UV detection at a wavelength of 265nm. The assay was specifi c for rifabutin and linear from 0.025 to 10.0μg/ml. The relative standard deviation of intra-and inter-day assays was lower than 10%. The method was able to remove interfering materials in plasma, yielding an average recovery of rifabutin from plasma of 101%. Due to its simplicity, the assay can be used for pharmacokinetic studies of rifabutin.

Background & objectives: The National Tuberculosis (TB) Control Programme has transitioned from thrice-weekly to daily drug treatment regimens in India. This preliminary study was conceived to compare the pharmacokinetics of rifampicin (RMP), isoniazid (INH) and pyrazinamide (PZA) in TB patients being treated with daily and thrice weekly anti-TB treatment (ATT). Methods: This prospective observational study was undertaken in 49 newly diagnosed adult TB patients receiving either daily ATT (n=22) or thrice-weekly ATT (n=27). Plasma RMP, INH and PZA were estimated by high-performance liquid chromatography. Results: The peak concentration (C max ) of RMP was significantly higher (RMP: 8.5 µg/ml vs . 5.5 µg/ml; P =0.003) and C max of INH was significantly lower (INH: 4.8 µg/ml vs . 10.9 µg/ml; P <0.001) in case of daily dosing compared to thrice-weekly ATT. C max of drugs and doses was significantly correlated. A higher proportion of patients had subtherapeutic RMP C max (8.0 µg/ml) during thrice-weekly compared to daily ATT (78% vs . 36%; P =0.004). Multiple linear regression analysis showed that C max of RMP was significantly influenced by the dosing rhythm, pulmonary TB and C max of INH and PZA by the mg/kg doses. Interpretation & conclusions: RMP concentrations were higher and INH concentrations were lower during daily ATT, suggesting that INH doses may need to be increased in case of a daily regimen. Larger studies are, however, required using higher INH doses when monitoring for adverse drug reactions and treatment outcomes.

Aim To compare the pharmacokinetics of isoniazid (INH) at doses 5 and 10 mg/kg/day. Methods INH concentrations were estimated by high‐performance liquid chromatography in 24 Indian children aged 1 to 15 years on antituberculosis therapy. Blood samples were collected at 0, 2, 4, 6, 8 hours after administration of INH. Patients were randomly given INH at 5 or 10 mg/kg/day and maximum concentrations (Cmax) and area under the curve (AUC(0‐8)) were determined in each group. The 2‐hour concentration of INH was used as Cmax for this study. Results Mean (standard deviation) Cmax was reached in 2 hours and was 2.68 ± 1.19 µg/mL in 5 mg/kg/day group and 8.86 ± 3.94 µg/mL in 10 mg/kg/day group (P < .05). The normal therapeutic range at 2‐hour concentrations for INH in adults achieving good clinical response is between 3 and 5 µg/mL. Among 5 mg/kg/day, only 4 (33%) patients had INH concentrations within the 2‐hour concentrations therapeutic range whereas in 10 mg/kg/day group, 11 (91%) patients achieved Cmax higher than the 2‐hour concentrations therapeutic range and 1 (9%) patient had Cmax within the 2‐hour concentrations therapeutic range. The mean AUC(0‐8) in 5 mg/kg/day group was 10.04 ± 6.12 and 35.93 ± 25.37 µg·h/mL in 10 mg/kg/day group (P = .0001). Conclusion Children on daily INH 10 mg/kg/day have higher AUC and Cmax than the required therapeutic range whereas over 65% of children with daily 5 mg/kg/day INH therapy failed to achieve the optimal therapeutic range.

Aims:To study single dose pharmacokinetics of lamivudine (3TC) in healthy subjects. Methods: Twelve healthy subjects were administered 3TC (150 mg) followed by timed blood and urine collections up to 24 hours. Pharmacokinetic variables and percent dose of 3TC in urine were calculated. Results: Plasma exposure and percent dose of 3TC in urine were highly correlated (p < 0.001; r = 0.96). 3TC concentration at 24 hours was undetectable in all study subjects. Conclusions: Timed urine measurements could be used to study bioavailabilty of 3TC. Plasma 3TC measurements could be used to monitor adherence among HIV-infected patients on antiretroviral treatment.