Jim Kling

September 07, 2014

MUNICH — When first-line tuberculosis (TB) drugs are taken with food, there is a reduction in maximum plasma concentration and bioavailability of the drug than when taken on an empty stomach, according to the results of a new pharmacokinetic study.

"In the first days of treatment, the number of bacteria is fairly high, and so any mistake in the drug's exposure can lead to resistance," Antonia Saktiawati, MD, who is also a PhD candidate at the University of Groningen, the Netherlands, told Medscape Medical News.

The study features a novel technique to measure blood concentrations of drugs that could have wide applications.

Dr. Saktiawati presented the study results here at the European Respiratory Society (ERS) International Congress 2014.

In the randomized crossover trial, the researchers studied 20 participants (8 of whom were women) who received the standard combination of isoniazid, rifampisin, pyrazinamide, and ethambutol (EMB). On day 1, all drugs were administered intravenously with the exception of PZA, which was administered orally. On days 2 and 3, the drugs were given as a fixed combination while the patients were fasting or after they had eaten a meal high in carbohydrates.

The researchers used liquid chromatography–tandem mass spectrometry to calculate pharmacokinetic curves, including maximum plasma concentration, time to maximum plasma concentration, area under the curve, and overall bioavailability.

When the drugs were taken after a meal, maximum plasma concentration values were significantly lower than when the drugs were taken after a fast.

Table. Concentration of Drugs Before and After Fasting

Concentration (mg/L) Isoniazid Rifampisin Pyrazinamide Ethambutol
Intravenous 6.6 ± 2.9 12.6 ± 2.9 - 5.5 ± 1.8
Fasting 4.7 ± 1.4 11.5 ± 2.8 45.9 ± 9.3 3.1 ± 1.4
Fed 2.7 ± 1.4 8.7 ± 2.5 40.7 ± 7.8 2.5 ± 0.8

 

The investigators report that bioavailability and the area under the curve also significantly decreased when the drugs were taken with food.

"For now, we cannot conclude whether our finding of lower drug exposure when drugs were taken after meals will have a clinical impact. That needs to be determined," said Dr. Saktiawati. "If it does have a clinical impact, then [dosing while fasting] could increase the drug's exposure to the TB bacilli and deter resistance."

For those who can only tolerate the drugs on a full stomach, a possible solution would be to increase drug doses to account for lower uptake, but Dr. Saktiawati cautioned that such an approach would need to be well studied for safety.

A Demonstration of Technology

The project serves as a demonstration of the technology, according to G. B. Migliori, MD, secretary-general of the European Respiratory Society and director of the World Health Organization's Collaborating Center for TB and Lung Diseases.

The technique involves placing a drop of blood onto a strip of paper and allowing it dry before subjecting it to analysis. This allows samples to be collected all over the world and sent cheaply through the mail, with no biological hazards to worry about, said Dr. Migliori.

"It has many advantages because it allows you not only to investigate the role of food [in TB dosing], but you can see if the level of a drug is the correct one," Dr. Migliori told Medscape Medical News. "If it is too high, you lower the dose; if it is too low, you raise the dose."

Other applications could include testing drug levels in immunocompromised patients, such as those with HIV who often have inflammation of the intestine that can reduce absorption of oral drugs.

"We don't have very good data on the absorption of drugs when you have these conditions," said Dr. Migliori. This technique would allow researchers to gain a much better understanding of drug dosing in these and other settings.

Dr. Saktiawati is developing a network of colleagues around the world who could conduct analyses as part of a collaborative group.

"It's the germ of a potential future global system," said Dr. Migliori.

Dr. Saktiawati and Dr. Migliori report no relevant financial relationships.

European Respiratory Society (ERS) International Congress 2014: Abstract 1897. Presented September 8, 2014.

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