Gene Variants in Some CF Children May Improve Effects of Ciprofloxacin
Variants found to impact rate of absorption of antibacterial agent
In children with cystic fibrosis (CF), certain genetic variants were found to be associated with the rate of absorption of the antibacterial agent ciprofloxacin — used to prevent bacterial infections, mainly those caused by Pseudomonas aeruginosa — according to a new study.
Researchers believe that these new data will contribute to the establishment of a more accurate therapeutic protocol for ciprofloxacin use in children with CF.
“We found a significant relationship between [a genetic variant of the GCLC gene] and high ciprofloxacin levels 7.5 hours post-dose. The elevated concentrations of ciprofloxacin contribute to an increase in its therapeutic efficacy,” Olga Butranova, PhD, the study’s senior author and an associate professor of the department of general clinical pharmacology at Peoples’ Friendship University of Russia, also known as RUDN University, said in a press release.
The study, “Gene Polymorphism of Biotransformation Enzymes and Ciprofloxacin Pharmacokinetics in Pediatric Patients with Cystic Fibrosis,” was published in the journal Biomedicines.
In patients with CF, the excessive production of viscous mucous affects the functioning of respiratory and digestive organs. To prevent bacterial infections in the respiratory tract, several medications can be used, including ciprofloxacin.
It is often used to treat infections caused by Pseudomonas aeruginosa, commonly called P. aeruginosa, a major contributor to lung disease in people with CF.
Studying ciprofloxacin use in children
Ciprofloxacin is approved for children with CF, ages 5–17. “But in real clinical practice, this drug is prescribed to patients under five,” said Sergey Zyryanov, MD, PhD, head of the department of general clinical pharmacology at RUDN University and first author of the study.
“Despite the fact that the indications for [ciprofloxacin] use are expanding, and the age threshold is decreasing, there is still little information” on how the therapy works in the body, Zyryanov said.
Notably, information on ciprofloxacin’s pharmacokinetics — the process of absorption, distribution, metabolism, and excretion of a therapeutic compound — is limited for pediatric patients, Zyryanov said, making it “difficult to develop a clear therapeutic algorithm for children.”
Now, this team of scientists in Russia investigated the relationship between ciprofloxacin pharmacokinetics in pediatric CF patients and genetic variants in genes related to the therapy’s biotransformation, or its metabolism within the body.
Their study analyzed data from 33 hospitalized patients with CF, enrolled from 2016 to 2021. The patients were ages 2–18, with eight of them younger than 5.
All received Cyprobay (ciprofloxacin). A blood sample was collected before taking the medicine and every 1.5 hours afterward to determine ciprofloxacin blood concentration.
Researchers found that the CYP2C9 gene — which contains instructions for the production of an enzyme involved in the metabolism of medications and certain compounds — is associated with ciprofloxacin pharmacokinetics.
Patients with a genetic variant of this gene called the CA variant have higher levels of ciprofloxacin exposure — meaning that the medication persists for longer periods in the blood — versus those with the AA variant, according to researchers.
The team found that, for those with the AA variant, “an insufficient clinical effect is possible when using [ciprofloxacin].”
Similar results were obtained for a genetic variant of the CYP2D6 gene, an enzyme also related to the metabolism of medications, as well as for a variant of the GSTP1 gene, an enzyme that plays an important role in detoxification.
Moreover, the team also found a significant correlation between one variant of the GCLC gene — called 7/7 genotype — and higher ciprofloxacin concentrations in the blood, at 7.5 hours after treatment. This finding indicates that, for patients with this genetic variant, the medication may be more effective than it is for others, because it persists longer in the body.
Overall, the researchers concluded that “[genetic variants] of biotransformation enzymes may affect ciprofloxacin pharmacokinetics in children.”
Based on the data obtained, the team suggested that the presence of “slow” genetic variants — those associated with slower drug metabolism — “contributes to the creation of therapeutic concentrations of [ciprofloxacin] in the blood of children with CF, which may contribute to a more favorable course of the disease.”
Concerning age, the data available suggest that the total clearance of ciprofloxacin from the bloodstream decreases with age. That means that younger children seem to metabolize the therapy faster than older patients and may potentially require the use of higher doses to achieve a similar therapeutic efficacy.