Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis

نویسندگان

  • Derek J. Sloan
  • Andrew D. McCallum
  • Alessandro Schipani
  • Deirdre Egan
  • Henry C. Mwandumba
  • Steve A. Ward
  • David Waterhouse
  • Gertrude Banda
  • Theresa J. Allain
  • Andrew Owen
  • Saye H. Khoo
  • Geraint R. Davies
چکیده

Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0-∞ of rifampin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients.

Evaluation of sources of pharmacokinetic variation can facilitate optimization of tuberculosis treatment regimens by identification of avoidable sources of variation and of risk factors for low or high drug concentrations in patients. Our objective was to describe the pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in a cohort of tuberculosis patients established on first-...

متن کامل

Prevalence of Antibiotic Resistance to Isonicotinylhydrazide and Rifampicin in Culture Positive Pulmonary Tuberculosis Patients from 2014 to 2016 in Zahedan City, Iran

Background: One third of the world’s population is infected with TB, and the disease is known as the second deadly global infection, even more severe than measles. The disease kills about 2 million people a year. Approximately 8 million people in the world are affected by advanced tuberculosis (TB). Objective: The current study aimed to determine the freq...

متن کامل

A STUDY OF MYCOBACTERIUM TUBERCULOSIS DRUG RESISTANCE IN PULMONARY TUBERCULOSIS

Tuberculosis remains a major public health problem in both developing and developed countries. Drug-resistant tuberculosis is an increasing health problem and serious challenge to tuberculosis (TB) control programs. Information about the susceptibility pattern of Mycobacterium tuberculosis isolates against anti-tuberculosis drugs is an important aspect to TB control. The objectives of the s...

متن کامل

Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption.

This article describes the population pharmacokinetics of rifampin in South African pulmonary tuberculosis patients. Three datasets containing 2,913 rifampin plasma concentration-time data points, collected from 261 South African pulmonary tuberculosis patients aged 18 to 72 years and weighing 28.5 to 85.5 kg and receiving regular daily treatment that included administration of rifampin (450 to...

متن کامل

Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability.

BACKGROUND It is believed that nonadherence is the proximate cause of multidrug-resistant tuberculosis (MDR-tuberculosis) emergence. The level of nonadherence associated with emergence of MDR-tuberculosis is unknown. Performance of a randomized controlled trial in which some patients are randomized to nonadherence would be unethical; therefore, other study designs should be utilized. METHODS ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:

دوره 61  شماره 

صفحات  -

تاریخ انتشار 2017