Population pharmacokinetics of levetiracetam in neonates with seizures.

WHAT IS KNOWN AND OBJECTIVE: This study developed a population pharmacokinetic (PK) model of levetiracetam (LEV) for treating neonatal seizures (NS) and determined the influence of clinically relevant covariates to explain the interindividual variability and residual error. METHODS: Twenty newborns admitted to the Neonatal Intensive Care Unit at the Hospital Central "Dr. Ignacio Morones Prieto" were included. LEV doses were administered by intermittent infusion. Blood samples were drawn 3 times post-infusion. Levetiracetam was quantified by a chromatographic technique. NONMEM software was used to determine the population PK model of LEV in neonates and the influence of clinical covariates on drug disposition. RESULTS AND DISCUSSION: The LEV PK in neonates is described by a one-compartment open model with first-order elimination. The influence of creatinine clearance (CRCL) and body weight (BW) on clearance (CL[L/h] = 0.47*CRCL), as well as the volume of the distribution (Vd[L] = 0.65*BW) of LEV, were confirmed, considering interindividual variabilities of 36% and 22%, respectively, and a residual error of 13%. WHAT IS NEW AND CONCLUSION: Based on the PK of LEV in neonates and the influence of the final PK model, a priori dosing guidelines are proposed considering CRCL, BW and LEV plasma concentrations between 6 and 20 mg/L for NS treatment.

Clinical Pharmacokinetics of Rifampin in Patients with Tuberculosis and Type 2 Diabetes Mellitus: Association with Biochemical and Immunological Parameters.

Tuberculosis (TB) remains a major public health issue due to the increasing incidence of type 2 diabetes mellitus (T2DM), which exacerbates the clinical course of TB and increases the risk of poor long-term outcomes. The aim of this study was to characterize the pharmacokinetics of rifampin (RIF) and its relationship with biochemical and immunological parameters in patients with TB and T2DM. The biochemical and immunological parameters were assessed on the same day that the pharmacokinetic evaluation of RIF was performed. Factors related to the metabolic syndrome that is characteristic of T2DM patients were not detected in the TB-T2DM group (where predominant malnutrition was present) or in the TB group. Percentages of CD8(+) T lymphocytes and NK cells were diminished in the TB and TB-T2DM patients, who had high tumor necrosis factor alpha (TNF-α) and low interleukin-17 (IL-17) levels compared to healthy volunteers. Delayed RIF absorption was observed in the TB and TB-T2DM patients; absorption was poor and slower in the latter group due to poor glycemic control. RIF clearance was also slower in the diabetic patients, thereby prolonging the mean residence time of RIF. There was a significant association between glycemic control, increased TNF-α serum concentrations, and RIF pharmacokinetics in the TB-T2DM patients. These altered metabolic and immune conditions may be factors to be considered in anti-TB therapy management when TB and T2DM are concurrently present.

Expression of NAT2 in immune system cells and the relation of NAT2 gene polymorphisms in the anti-tuberculosis therapy in Mexican mestizo population.

Arylamine N-acetyltransferase 2 (NAT2) metabolizes isoniazid (INH) and Single Nucleotide Polymorphisms (SNP) responsible for its activity has been reported. The aim of this study in the Mexican mestizo population was to evaluate NAT2 expression at the protein level in immune cells, as well as the distribution and frequency of six NAT2 SNPs and their association with anti-TB therapy, by measuring the plasma levels of INH and Acetyl-INH (AcINH). We performed genotyping assays of NAT2 SNPs in 40 TB patients and 121 healthy volunteers by real-time PCR. A method for detecting NAT2 in immune cells using flow cytometry was developed. Plasma concentrations of INH and AcINH were obtained by HPLC in TB patients and the Metabolic Ratio (MR) was calculated. The phenotypes obtained in the healthy volunteers were as follows; 18.87 % of subjects had the rapid acetylator phenotype, 45.45 % had the intermediate phenotype and 39.66 % exhibited the slow acetylator phenotype. In the TB patient group, 35 % of patients had the rapid acetylator phenotype, 32.5 % were intermediate and 32.5 % showed the slow acetylator phenotype. A higher expression level of NAT2 in innate immune cells from TB patients compared to those from healthy volunteers was detected (P < 0.013). In TB patients the MR showed a bimodal distribution with an antimode of 0.7, which was used as a threshold value for acetylator classification. A high correspondence between the rapid and slow acetylator phenotype with MR was demonstrated. In conclusion, the 282C>T, 341T>C, 481C>T, 590G>A, 803A>G, 857G>A SNPs of NAT2 gene provides accurate for prediction of the acetylator phenotype in Mexican mestizo population. A statistical difference was found in frequency of rapid metabolizer phenotype, which was higher in TB patients. In addition, the expression of NAT2 protein in immune cells can lead to further studies related to its functional role in the innate immune response against M. tuberculosis and other xenobiotics metabolized by this enzyme.

Relative bioavailability of isoniazid in a fixed-dose combination product in healthy Mexican subjects.

SETTING: Subtherapeutic plasma isoniazid (INH) concentrations and the development of bacterial resistance may be attributed to poor quality and reduced bioavailability of fixed-dose combination (FDC) formulations. The bioavailability of INH from a generic and that of a branded FDC formulation had not been compared in the Mexican population. OBJECTIVE: To evaluate the bioequivalence of a generic three-drug FDC formulation (3FDC) in comparison with a 3FDC reference with doses of 300 mg INH in 20 healthy Mexican adults, and to generate data regarding the oral relative bioavailability of the drug in this population. DESIGN: A single-dose, randomised-sequence, open-label, two-period crossover study. RESULTS: Both formulations were well tolerated. The pharmacokinetic parameters of INH showed wide inter-individual variability. The average relative bioavailability calculated for maximum serum concentration area under the concentration-time curve (AUC), AUC(0-24h) and AUC(0-∞) of the test 3FDC formulation vs. the 3FDC reference were respectively 64.84% (90%CI 56.01-75.06), 59.05% (90%CI 50.27-69.36) and 57.26% (90%CI 46.93-69.84). CONCLUSIONS: The 3FDC test and reference formulations were not bioequivalent because the 90%CI for the geometric mean ratios did not meet the regulatory requirements for bioequivalence (range 80-125%) based on the rate and extent of absorption.

Population pharmacokinetics of rifampicin in Mexican patients with tuberculosis.

WHAT IS KNOWN AND OBJECTIVE: Rifampicin (RIF) shows wide variability in its pharmacokinetics. The purpose of this study was to develop and validate a population pharmacokinetic model to characterize the inter- and intra-individual variability in pharmacokinetic parameters of RIF in Mexican patients. METHODS: Ninety-four patients receiving antituberculosis therapy participated in this prospective study. Plasma concentration-time data were described using a one-compartment model with lag time, absorption and first-order elimination. The potential influence of demographic and clinical characteristics of the patients, and the pharmaceutical formulation (A, B, C and D) on the pharmacokinetics parameters, was evaluated by non-linear mixed-effect modelling (nonmem). Seventy-seven additional patients participated in the validation of the model. RESULTS AND DISCUSSION: The final population pharmacokinetic model obtained was as follows: apparent clearance CL/F = 8·17 L/h (1·40 as high for males), apparent distribution volume V(d)/F = 50·1 L (1·29 as high for males), absorption rate constant K(aA) = 0·391/h, K(aB,C,D) = 2·70/h, relative bioavailability F(A) = 0·468, F(B,C,D) = 1, lag time in the absorption phase T(lag) = 0·264 h. The final model improved the precision on the parameter estimates (CL/F, V(d) /F and K(a) by 31·9%, 16·7% and 92·9%, respectively). The residual variability was 27·3%. WHAT IS NEW AND CONCLUSION: Gender was associated with changes in CL/F and V(d) /F whereas the pharmaceutical formulation was associated with changes in F and altered the K(a) . The validation data set showed that the model could be used in clinical practice for Bayesian dose adjustment of RIF in TB patients.

Relative bioavailability of rifampicin in a three-drug fixed-dose combination formulation.

SETTING: In a previous monitoring study of rifampicin (RMP) in tuberculosis (TB) patients treated with a generic formulation of a three-drug fixed-dose combination (3FDC), very low RMP levels were found. This led us to investigate the bioavailability of the product. OBJECTIVE: To investigate the relative bioavailability of RMP from a generic 3FDC formulation used in the Mexican health care system, in comparison to the reference product, in healthy volunteers. DESIGN: Two-period, two-sequence crossover study. RESULTS: Mean pharmacokinetic parameter values obtained for the test and reference product were respectively 3.13 ± 2.01 µg/ml and 9.95 ± 2.66 µg/ml for peak plasma concentration (C(max)), 15.51 ± 9.77 µg.h/ml and 58.03 ± 16.1 µg.h/ml for area under the concentration (AUC) time curve to the last measurable concentration (AUC(0-12h)) and 17.92 ± 10.66 and 68.43 ± 22.39 µg.h/ml for AUC up to time infinity (AUC(0-∞)). The test/reference ratio of the means (90%CI) was 25.36% (17.33-37.10) for C(max), 21.25% (14.61-30.89) for AUC(0-12h) and 22.08% (15.44-31.56) for AUC(0-∞). These results did not meet the criteria for bioequivalence. CONCLUSION: The test product displayed delayed absorption and markedly inferior RMP bioavailability in comparison to the reference product. RMP-containing generic formulations should only be used if their bioavailability has been evaluated to ensure interchangeability with the reference product and to avoid the risk of markedly inferior RMP exposure through the use of such a product.