Preventing long-term effects after drug holidays in Cancer Patients

Computer modelling suggests that drug combinations could protect from long-term drug level reductions in certain patients after a break from anti-cancer drug tamoxifen.

— By Conn Hastings

Researchers in Germany have used computer modelling techniques to estimate how a break from taking cancer medication affects the amount of drug in patients’ blood. They found that even a short break of two weeks could result in an extended reduction in drug blood levels, potentially reducing the effectiveness of the treatment. However, the scientists also propose a solution: a specific drug and dose combination that could help to rapidly get drug levels back to where they should be.

Taking medication consistently is important, in order to maintain appropriate levels in the blood, and achieve the expected therapeutic benefit. However, this is difficult for patients that need to take drugs for very long periods or with drugs that have unpleasant side-effects. Tamoxifen is a drug used to treat certain types of breast cancer, as it can prevent the growth of cancer cells. Approved as a long-term therapy, it can be taken for as long as 10 years. In general, tamoxifen is well tolerated by patients and is an effective breast cancer treatment.

Tamoxifen is converted into several active drug molecules by an enzyme in the liver called CYP2D6. One of the most important active forms of tamoxifen is called endoxifen. Depending on the genetic background of the patient, they can have types of CYP2D6 that are more or less effective at converting tamoxifen to endoxifen.

Patients with less active CYP2D6 variants are called poor metabolizers, those with intermediate variants are called intermediate metabolizers and those with the most active variants are called extensive metabolizers. Extensive metabolizers are associated with a better therapeutic benefit from a given tamoxifen dosage, compared with intermediate or poor metabolizers.

If a patient goes on a “drug holiday” and stops taking their drugs for an extended period, it is important to find out how fast their blood drug levels can fall and the best way to rapidly get the levels back to where they should be.

Normally, these effects are studied in healthy volunteers. However, given that tamoxifen can sometimes have unpleasant side-effects, giving it to healthy volunteers is an ethical concern. Patient adherence to a drug regimen is also difficult to assess accurately. In a study recently published in Frontiers in Pharmacology, researchers at Bayer and the University of Muenster in Germany, instead used mathematical simulations to estimate the effects of drug holidays from tamoxifen in 24,000 virtual breast cancer patients with different CYP2D6 activity levels.

Strikingly, according to the model, even short drug holidays of two weeks caused drastic deceases in blood levels of the active metabolite endoxifen. After the holiday, it took over 100 days using standard doses of tamoxifen to bring endoxifen back to pre-holiday levels in extensive metabolizers.

However, administering a specific dose of both tamoxifen and endoxifen together dramatically reduced the time it took to reach pre-holiday levels of endoxifen in the blood. This specific drug combination and dose brought the endoxifen levels back to the required concentration in as little as 5 or 7 days, which is up to 116 and 54 days faster than resuming their pre-holiday treatment, for extensive or intermediate metabolizers, respectively.

“These results show that for different genotypes and different drug combinations, the impact of drug holidays is very different,” says corresponding author, Dr. Michael Block, Senior Scientist at Clinical Pharmacometrics at Bayer’s Pharmaceutical Division. “A possible next step could be to start similar assessments for other compounds, which display genotype-dependent behavior in the body”.

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