Investigators may have uncovered notable pharmacokinetic differences between male and female patients in at least 14 anticancer drugs, according to a recent study published by Delahousse et al in ESMO Open.
Background
Many cancer drugs have a narrow therapeutic window. As a result, slight alterations in dosage can have a profound impact on side effects and a patient’s response to the drug. A patient's sex can influence the way the body metabolizes a drug; however, there are no regulatory guidelines to account for these differences—the extent of which is currently unknown.
“Biologically, it makes sense that [patients] with different hormones might handle medications differently,” suggested co–study author Alex A. Adjei, MD, PhD, Chair of the Cleveland Clinic Cancer Institute. “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,” he stressed.
Study Methods and Results
In the study, a global task force of investigators used the data from over 100 published abstracts and European Medicines Agency/U.S. Food & Drug Administration (EMA/FDA) documents for 99 anticancer therapies to examine sex-based differences in cancer treatments, outcomes, and adverse effects. They also assessed drug activity as well as the absorption, distribution, and extraction rate of cancer drugs between male and female patients. The median size of a study cohort was 445 patients.
Using the National Institutes of Health study quality assessment tool, the investigators analyzed pharmacokinetic parameters, including clearance or apparent clearance, area under the time-concentration curve, and active metabolites, where applicable.
The investigators discovered appreciable pharmacokinetic differences, representing ≥ 20% in clearance among female patients for 14 drugs and potential pharmacokinetic differences in eight additional drugs. For instance, in commonly prescribed drugs such as 5-fluorouracil, doxorubicin, paclitaxel, regorafenib, atezolizumab, and temozolomide, female patients had a slower drug clearance, potentially altering the efficacy and toxicity of these therapies. Female patients demonstrated higher rates of adverse events for several of these drugs.
The investigators observed increased toxicity in female patients with colorectal cancer receiving 5-fluorouracil–based chemotherapy in the adjuvant and metastatic settings and marked differences in efficacy between male and female patients receiving capecitabine following the resection of cholangiocarcinoma. Further, they noted that male patients experienced suboptimal exposure to the approved dose of rituximab in the R-CHOP regimen and female patients with resected intermediate- or high-risk primary gastrointestinal stromal tumors experienced a greater benefit from adjuvant imatinib.
Higher drug exposure did not necessarily correlate with an improved response. For example, higher drug levels of 5-fluorouracil did not increase efficacy in female patients with metastatic colorectal cancer.
Additionally, the investigators highlighted the significance of evaluating the pharmacokinetic profile of cancer drugs used for supportive care. Notably, there were higher rates of nausea and vomiting among female patients receiving 5-fluorouracil—which showed a sex-specific difference in pharmacokinetics—as well as cisplatin and gemcitabine, which did not.
Conclusions
The investigators postulated that these differences may be caused by sex hormones’ effects on how the body processes certain cancer drugs. They hope their findings could be used to inform future drug development.
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 pharmacokinetic differences could serve as a way to further personalize cancer treatment.
“The FDA already recognizes sex differentiation in preclinical studies,” underscored 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 [male] and [female patients],” he concluded.
Disclosure: For full disclosures of the study authors, visit esmoopen.com.
