Pharmacokinetics of Many Anticancer Drugs Differ Among Sexes

A team of researchers recently found notable pharmacokinetic (PK) differences between males and females in at least 14 anticancer drugs. This includes commonly prescribed medications, such as 5-fluorouracil, doxorubicin, paclitaxel, regorafenib, atezolizumab and temozolomide. In those medications, female patients had a slower drug clearance (CL), which may alter the efficacy and toxicity of these therapies.

Background

Many cancer drugs have a narrow therapeutic window, so slight alterations in dosage can have a profound impact on side effects and a patient’s response to the medication. A patient's sex can influence the way the body metabolizes a drug, yet there are no regulatory guidelines to account for these differences. Additionally, the extent of these differences is unknown.

To address this conundrum, the European Society for Medical Oncology (ESMO) invited Cleveland Clinic Cancer Institute Chair Alex A. Adjei, MD, PhD, to join a task force studying the differences between the sexes in cancer treatment and outcome, including differences in oncology medication effects.. The global task force is gathering information that can be used to inform future drug development. A medical oncologist and a pharmacologist by training, Dr. Adjei and his colleagues began studying the absorption, distribution and extraction rate of oncology medications as well as the drug activity and adverse events between males and females.

“Biologically, it makes sense that people with different hormones might handle medications differently,” says Dr. Adjei. “In some drugs, the blood levels are different in men and women but when we develop drugs, we don't differentiate. This research is a call to action to consciously consider these differences.”

Study design

Researchers reviewed a large body of literature, including more than 100 published abstracts and European Medicines Agency/Food & Drug Administration (EMA/FDA) documents for 99 anticancer therapies. The median size of study cohorts was 445 patients.

Using the National Institutes of Health study quality assessment tool, the task force investigators studied PK parameters, including:
• CL or apparent CL
• Area under the time-concentration curve
• Active metabolites, where applicable

Study results

The retrospective analysis uncovered appreciable PK differences, representing
>+20% in clearance in women for 14 medications and potential PK differences in eight additional medications. Female patients experience higher rates of adverse events for several of these medications.

Key findings include:

• Increased toxicity in females with colorectal cancer receiving 5-FU-based chemotherapy in the adjuvant and metastatic setting
• Marked differences in efficacy between males and females receiving capecitabine after resection of biliary cancer
• Suboptimal exposure in men to the approved dose of rituximab in the R-CHOP regimen
• Females with resected intermediate- or high-risk primary gastrointestinal stromal tumors experiencing a greater benefit from adjuvant imatinib

The study authors noted that higher drug exposure does not necessarily correlate with a better response. For example, higher drug levels of 5-FU did not increase efficacy in females with metastatic colorectal cancer.

Additionally, the researchers highlighted the importance of evaluating the PK profile of medications used for supportive care. Notably, there are higher rates of nausea and vomiting among women receiving 5-FU (which shows a sex-specific difference in PK) as well as cisplatin and gemcitabine (which do not). The researchers postulated that these differences may be due to the effect that sex hormones have on how certain medications are processed in the body.

Next steps

Although the FDA has recognized a need for dose optimization with Project Optimus, it has yet to evaluate sex-specific dosing strategies. The task force shared its findings with the EMA and FDA to demonstrate that recognizing PK differences could serve as a way to further personalize cancer treatment.

“The FDA already recognizes sex differentiation in preclinical studies,” says Dr. Adjei. “We hope that this publication will add to the body of evidence that helps move toward adjusting guidance based on how drugs are handled in men and women.”