Population pharmacokinetics and pharmacokinetic-pharmacodyamic modeling of antitubercular drugs

Includes abstract.Includes bibliographical references.The pharmacokinetics of rifampicin, isoniazid, pyrazinamide and ethambutol in 78 patients with tuberculosis were described using non-linear mixed effects modeling. Pharmacodynamic data was comprised of weekly sputum liquid culture (using mycobacterial growth indicator tubes) time to detection results from 144 patients during the first 2 months of treatment. The effect of drug exposure on patient outcomes was investigated. To determine the adequacy of ofloxacin drug exposure, the probability of attaining the required area-under-the-curve to minimum inhibitory concentration ratio (AUC/MIC) of ofloxacin was determined in 65 patients on treatment for multidrug resistant tuberculosis. To improve efficiency in the clinical development of new drug regimens, clinical trial simulation was used to determine the optimal study design for a study investigating the efficacy of a new antitubercular drug regimen. The SLCO1B1 rs4149032 polymorphism existed at a high frequency of 0.70 in South Africans and resulted in a 28% decrease in bioavailability of rifampicin. The rifampicin peak concentration was a significant predictor of the 2 month treatment outcomes. A semimechanistic time to event model was developed to analyze days to positivity (time to detection) data. The model was comprised of a biexponential decay model describing bacillary decline in sputum from patients, followed by a logistic model with a lag time for growth of the mycobacteria in liquid culture. For the current 800 mg daily dose of ofloxacin, the probability of attaining an AUC/MIC target ratio of at least 100 was only 0.45. Based on clinical trial simulation, the optimum parallel study design was comprised of 125 study participants in each of 2 arms to achieve a study power of at least 80%. Increasing the study length beyond 42 days reduced study power perhaps due to increased amounts of censored data. Higher doses of rifampicin are required in the majority of South African patients with tuberculosis. A novel pharmacodynamic model of tuberculosis treatment is presented, which can be used for investigation of covariates such as drug exposure. Ofloxacin should be replaced with a more potent fluoroquinolone for treatment of multidrug resistant tuberculosis. Clinical trials should not be unduly long otherwise this may compromise study power

Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in newly diagnosed pulmonary TB patients in Tanzania

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

Pharmacogenetic considerations in the treatment of co-infections with HIV/AIDS, tuberculosis and malaria in Congolese populations of Central Africa

Background: HIV-infection, tuberculosis and malaria are the big three communicable diseases that plague sub-Saharan Africa. If these diseases occur as co-morbidities they require polypharmacy, which may lead to severe drug-drug-gene interactions and variation in adverse drug reactions, but also in treatment outcomes. Polymorphisms in genes encoding drug-metabolizing enzymes are the major cause of these variations, but such polymorphisms may support the prediction of drug efficacy and toxicity. There is little information on allele frequencies of pharmacogenetic variants of enzymes involved in the metabolism of drugs used to treat HIV-infection, TB and malaria in the Republic of Congo (ROC). The aim of this study was therefore to investigate the occurrence and allele frequencies of 32 pharmacogenetic variants localized in absorption distribution, metabolism and excretion (ADME) and non-ADME genes and to compare the frequencies with population data of Africans and non-Africans derived from the 1000 Genomes Project. Results: We found significant differences in the allele frequencies of many of the variants when comparing the findings from ROC with those of non-African populations. On the other hand, only a few variants showed significant differences in their allele frequencies when comparing ROC with other African populations. In addition, considerable differences in the allele frequencies of the pharmacogenetic variants among the African populations were observed. Conclusions: The findings contribute to the understanding of pharmacogenetic variants involved in the metabolism of drugs used to treat HIV-infection, TB and malaria in ROC and their diversity in different populations. Such knowledge helps to predict drug efficacy, toxicity and ADRs and to inform individual and population-based decisions

Genetic polymorphism of drug metabolizing enzymes in the Shona and the San in Zimbabwe and the clinical impact of CYP2D6 polymorphism on safety in the use of psychotropics

INTRODUCTION: Interindividual variability to drug response is a well known phenomenon and dates back to the 1950s with isoniazid. When the same dose of the same drug is given to different individuals, some may respond well, while others may respond but with side effects, whilst others may not even respond at all. In a number of instances, this variability has been shown to be due to genetic differences. The best documented are pharmacokinetic differences due to polymorphism of drug metabolising enzymes, in particular CYP2D6 which metabolises about 25% of clinically used drugs. The frequencies of these mutations have been studied to a great extent in Caucasians and Orientals, and some have shown to be variable among different ethnic groups. Africans have also been studied but to a much lesser extent, yet they may be even more diverse. We sought to investigate the frequencies of mutations of some drug metabolising enzymes in Zimbabwean ethnic groups and the impact of CYP2D6 polymorphism in psychiatric patients on routine drug therapy in a naturalistic setting. MATERIALS AND METHODS: The study was approved by the Medical Research Council of Zimbabwe and the volunteers gave written informed consent. Seventy-eight Shona volunteers were recruited from the University of Zimbabwe Medical School whilst 63 San volunteers were recruited from the Plumtree district in Zimbabwe. Fifty psychiatric patients were interviewed at the Parirenyatwa Hospital Psychiatric unit. Five mL blood samples were drawn from all volunteers and stored at minus 20 °C until required for genotyping. An additional 5 mL blood sample was drawn from each of the psychiatric patients and the plasma was stored at minus 20 °C until required for analysis. PCR-RFLP methods were used to genotype for CYP2C19*2, CYP2B6*6, CYP2D6*4, *17 and *29 mutations. LC-MS was used for the measurement of plasma concentrations of chlorpromazine, thioridazine, fluphenazine, haloperidol, amitriptyline and nortriptyline. Drug plasma levels were then correlated against CYP2D6 genotype. RESULTS: Frequencies for CYP2C19*2, CYP2B6*6, CYP2D6*4, *17 and *29 in the Shona were 0.16, 0.38, 0.05, 0.22, and 0.16, whilst in the San they were 0.12, 0.40, 0.10, 0.22 and 0.02 respectively. Differences between drug concentrations stratified by CYP2D6 genotype were observed for thioridazine versus CYP2D6*29 and for fluphenazine versus CYP2D6*17 genotypes. No significant correlations were found for the other drugs. DISCUSSION: Genetic polymorphism of the drug metabolising enzymes CYP2B6, CYP2C19 and CYP2D6 was similar between the San and the Shona, except for the frequency of, CYP2D6*29, an African-specific mutation, which was virtually absent in the San. The most prevalent mutation in both populations was CYP2B6*6, which has implications for a lower population-specific dose of the antiretroviral drug efavirenz to avoid central nervous system side effects. Carriers of CYP2D6*29 and CYP2D6*17 mutations need lower doses of thioridazine and fluphenazine respectively to avoid side effects related to high drug plasma levels. CONCLUSION: We investigated frequencies of mutations of the following drug metabolizing enzyme genes; CP2D6, CYP2C19 and CYP2B6 in the Shona and the San. Although clear relationships between CYP2D6 genotype and thioridazine and fluphenazine concentrations were observed, these did not reach statistical significance due to the limited sample.size

Mechanisms of drug-drug interaction between rifampicin and fusidic acid

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