Volume 10 Number 1 2026
Sex and Gender Differences in Drug Response as an Underused Variable in Precision Medicine
Oluwafemi Shittu Bakare 1*, Okoye Oluwabukola 1,Hacer Haltas 2 , Subasini Uthirapathy 2
Integrative Biomedical Research 10 (1) 1-8 https://doi.org/10.25163/biomedical.10110916
Submitted: 23 July 2026 Revised: 10 September 2026 Accepted: 18 September 2026 Published: 20 September 2026
Modern pharmacotherapy still relies, more often than clinicians acknowledge, on a male-default template inherited from decades of trial design rather than biological rationale. Growing pharmacovigilance and mechanistic evidence indicates that sex (biological) and gender (sociocultural) influence drug response through distinct, sometimes opposing, pathways—and that conflating the two carries real clinical consequences. This review addresses a deceptively simple question: how much of the disparity in drug efficacy and adverse drug events (ADEs) between men and women stems from biology versus the social context shaping how symptoms are noticed, reported, and treated? We performed a narrative synthesis of peer-reviewed literature, primarily 2022–2026, drawing on pharmacovigilance datasets, individual patient data meta-analyses, cohort studies, and mechanistic pharmacology research across oncology, psychiatry, nephrology, rheumatology, and substance-use epidemiology. Females consistently reported higher rates of non-serious, subjective adverse events, but this gap narrowed—and reversed for fatal outcomes—once severity was accounted for, a pattern consistent with the "Gender Hypothesis" of differential reporting. Biological mechanisms proved equally important: cytochrome P450 variation, body composition, and hormonal status altered clearance and toxicity across chemotherapeutics, antipsychotics, and immunomodulators, while premenopausal estrogen exposure appeared to blunt antimanic drug-placebo separation. Clinical risk calculators for acute kidney injury applied sex inconsistently or omitted it entirely, despite converging evidence of hormonally mediated renal protection. Sex and gender function as separable, interacting determinants of drug response, and neither substitutes for the other in clinical reasoning. Embedding sex-stratified analysis and SAGER-compliant reporting into trial design and pharmacovigilance infrastructure is not merely an equity concern—it is a prerequisite for pharmacological precision.
Keywords: sex differences; gender differences; pharmacokinetics; pharmacovigilance; precision medicine; adverse drug events; sex-stratified research
Arreola, S. G., Neilands, T. B., Dilworth, S. E., & Carrico, A. W. (2008). Forced sex and drug use in men who have sex with men: Evaluating the role of childhood sexual abuse. Journal of Urban Health, 85(4), 585–596. https://doi.org/10.1007/s11524-008-9296-1
Baimonte, L., Enea, M., Vaccaro, M., Ragonese, P., & Salemi, G. (2025). Sex differences in multiple sclerosis treatment with disease modifying drugs: A step towards gender neurology. Multiple Sclerosis and Related Disorders, 105, 106869.
Baraibar, I., Ros, J., Saoudi, N., Salvà, F., García, A., Castells, M. R., Tabernero, J., & Élez, E. (2023). Sex and gender perspectives in colorectal cancer. ESMO Open, 8(2), 101157.
Basu, R. K., Kaddourah, A., Terrell, T., & Wheeler, D. S. (2014). Assessment of pediatric acute kidney injury risk using clinical score systems. Kidney International, 85(3), 659–667. https://doi.org/10.1038/ki.2013.339
Brown, J. R., Cochran, R. P., & MacKenzie, T. A. (2008). Risk prediction planning for acute kidney injury after cardiac and vascular procedures. American Heart Journal, 156(2), 320–328. https://doi.org/10.1016/j.ahj.2008.04.010
Chatzichristos, G., & Papadopoulou, E. E. (2026). Substance-facilitated sexual violence in Greece: CGT analytic movement from empirical material to conceptual categories. SSM - Qualitative Research in Health, 9, 100739.
Dattolo, P., Vignozzi, L., & Tsalouchos, A. (2026). Gender medicine in nephrology: From biological mechanisms to clinical inequities. Kidney and Dialysis, 6(1), 221–234.
De Angelis, F., Vacca, V., Tofanicchio, J., Strimpakos, G., Giacovazzo, G., Pavone, F., Coccurello, R., & Marinelli, S. (2022). Sex differences in neuropathy: The paradigmatic case of Metformin. International Journal of Molecular Sciences, 23(23), 14503.
Gharaibeh, K. A., & Jaber, B. L. (2017). Predictors of acute kidney injury following total joint arthroplasty: A retrospective cohort study. Journal of Bone and Joint Surgery, 99(11), 910–918. https://doi.org/10.2106/JBJS.16.00931
Ginaldi, L., & De Martinis, M. (2022). Sex and gender aspects for patient stratification in allergy prevention and treatment. Biomedicines, 10, 328.
Gualtierotti, R. (2025). Bridging the gap: Time to integrate sex and gender differences into research and clinical practice for improved health outcomes. European Journal of Internal Medicine, 134, 9–16.
Gustave Roussy Cohort. (2018–2023). Sex-based differences in toxicity outcomes among patients receiving antibody-drug conjugates for advanced non-small-cell lung cancer [Cohort study]. Gustave Roussy Institute.
Kraševec, N. (2022). The multifaceted role of mating type of the fungus and sex of the host in studies of fungal infections in humans. Journal of Fungi, 8, 461.
Latkin, C. A., Dayton, L., Bhaktaram, A., Davey-Rothwell, M. A., Bonneau, H., Yi, G. T., & Falade-Nwulia, O. (2026). Out of sight: Sex differences in public and semi-public drug use settings among people who use opioids in Baltimore, Maryland. International Journal of Environmental Research and Public Health, 23(4), 534. https://doi.org/10.3390/ijerph23040534
Lee, K. M. N., Rushovich, T., Gompers, A., Boulicault, M., Worthington, S., Lockhart, J. W., & Richardson, S. S. (2023). A Gender Hypothesis of sex disparities in adverse drug events. Social Science & Medicine, 339, Article 116385. https://doi.org/10.1016/j.socscimed.2023.116385
Lucena, M. I., Rieder, M. J., Waitt, C., & Medhi, B. (2025). Sex/gender differences in clinical pharmacology: A perspective from the IUPHAR World Smart Medication Day 2025. Pharmacological Research, 219, 107889.
Lumor, L., Vignet, A., Passignat, C., Felten, V., Simon, C., Zaffino, M., Grosjean, G., Giambérini, L., & Minguez, L. (2026). Hormonal influences on sertraline metabolism in bivalves. Environmental Research, 289, 123422.
Marcu, L. G. (2022). Gender and sex-related differences in normal tissue effects induced by platinum compounds. Pharmaceuticals, 15(2), 255.
McMahon, G. M., Zeng, X., & Waikar, S. S. (2013). A clinical risk formulation score for kidney replacement therapy or mortality in patients with rhabdomyolysis. JAMA Internal Medicine, 173(19), 1821–1828. https://doi.org/10.1001/jamainternmed.2013.9788
Mehran, R., Aymong, E. D., & Nikolsky, E. (2004). A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: Development and initial validation. Journal of the American College of Cardiology, 44(7), 1393–1399. https://doi.org/10.1016/j.jacc.2004.06.068
Mehta, R. L., Kellum, J. A., & Shah, S. V. (2006). Acute Kidney Injury Network: Report of an initiative to improve outcomes in acute kidney injury. Circulation, 113(15), 1810–1819. https://doi.org/10.1161/CIRCULATIONAHA.106.181019
Morgan, R., Kalbarczyk, A., Decker, M., Elnakib, S., Igusa, T., Luo, A., & MAGE Consortium. (2024). Gender-responsive monitoring and evaluation for health systems. Health Policy and Planning, 39(9), 1000–1005.
Nash, D. M., & Markle-Reid, M. (2019). Nonsteroidal anti-inflammatory drug use and risk of acute kidney injury in older adults. Nephrology Dialysis Transplantation, 34(7), 1201–1209. https://doi.org/10.1093/ndt/gfy231
Ong, E. J., Naidu, K. N. C., Tee, M., Tan, R. K. J., & Howard, N. (2026). Substance use behaviours among sexual and gender minorities with a history of adverse childhood experiences: A systematic review and narrative synthesis. Comprehensive Psychiatry, 146, Article 152669. https://doi.org/10.1016/j.comppsych.2026.152669
Rakshith, H. T., Lohita, S., Rebello, A. P., Goudanavar, P. S., & Naveen, N. R. (2023). Sex differences in drug effects and/or toxicity in oncology. Current Research in Pharmacology and Drug Discovery, 4, 100152.
Reback, C. J., Fletcher, J. B., & Shoptaw, S. (2017). Childhood sexual abuse and current drug use among transgender women of color. AIDS and Behavior, 21(11), 3221–3230. https://doi.org/10.1007/s10461-017-1845-y
Ruggieri, A., & Anticoli, S. (2025). Sex and gender differences in response to vaccines: Unveiling the biological and societal factors shaping immunity. Vaccine: X, 24, 100637.
Schilt-Solberg, M. A., Blair, L. M., & Kurzer, J. A. M. J. (2025). Intersectionality in substance use disorders: Examining gender, race/ethnicity, and sexual orientation in the 2021–2022 National Survey on Drug Use and Health. Addictive Behaviors Reports, 21, Article 100587. https://doi.org/10.1016/j.abrep.2025.100587
Shankar, M., & Shah, S. (2025). Sex and gender disparities in kidney transplantation. Advances in Kidney Disease and Health, 31, 18–31.
Soldin, O. P., & Mattison, D. R. (2009). Sex differences in pharmacokinetics and pharmacodynamics. Clinical Pharmacokinetics, 48(3), 143–157.
Soranno, D. E., Awdishu, L., Bagshaw, S. M., Basile, D., Bell, S., Bihorac, A., Bonventre, J., Brendolan, A., Granado, R. C.-D., & Collister, D. (2025). The role of sex and gender in acute kidney injury: Consensus statements from the 33rd Acute Disease Quality Initiative. Kidney International, 107(3), 606–616. https://doi.org/10.1016/j.kint.2025.01.008
Storosum, B. W. C., Cohen, S. E., Mattila, T. K., Roes, K. C. B., Welten, C., van den Brink, W., de Haan, L., Denys, D., & Zantvoord, J. B. (2025). Gender differences in the response to antipsychotics or mood stabilizers in patients with acute mania: An individual patient data meta-analysis of placebo-controlled studies. Journal of Psychiatric Research, 181, 358–364. https://doi.org/10.1016/j.jpsychires.2024.11.014
Storosum, B. W. C., Mattila, T., Wohlfarth, T. D., Gispen-de Wied, C. C., Roes, K. C. B., van den Brink, W., de Haan, L., Denys, D., & Zantvoord, J. B. (2026). Impact of gender and age on the effect and safety of antipsychotic medications in early-onset schizophrenia. Journal of the American Academy of Child & Adolescent Psychiatry, 65(3), 345–355.
Swaich, A., Rufus-Sedgemore, K., Choi, J., DeBeck, K., Boyd, J., Milloy, M.-J., Kerr, T., & Hayashi, K. (2026). Gender differences in the association between housing status and violence among people who report exposure to benzodiazepines. International Journal of Drug Policy, 153, Article 105324. https://doi.org/10.1016/j.drugpo.2026.105324
Thakar, C. V., Arrigain, S., & Worley, S. (2005). A clinical score to predict acute renal failure after cardiac surgery. Journal of the American Society of Nephrology, 16(1), 162–168. https://doi.org/10.1681/ASN.2004040294
Tran, A., & Eder, L. (2026). Sex-related differences in psoriatic arthritis (PsA) treatment outcomes. Best Practice & Research Clinical Rheumatology, 40(1), 102132.
Tsai, T. T., Patel, U. D., & Chang, T. I. (2014). Validating acute kidney injury risk metrics across international interventional registries. Journal of the American Heart Association, 3(4), e000912. https://doi.org/10.1161/JAHA.114.000912
Ventura, M. T., Giuliano, A. F. M., Boni, E., Brussino, L., Buquicchio, R., Conte, M., Costantino, M. T., Crivellaro, M. A., Losa, F., & SIAAIC. (2025). Gender and allergy: Mechanisms, clinical phenotypes, and therapeutic response—A position paper from the Società Italiana di Allergologia, Asma ed Immunologia Clinica (SIAAIC). International Journal of Molecular Sciences, 26(18), 9605.
Vona, R., Cittadini, C., Ortona, E., & Matarrese, P. (2025). Sex disparity in cancer: Role of autophagy and estrogen receptors. Cells, 14(4), 273.
Wang, L., Zhang, Y., & Miller, M. (2017). Childhood trauma and adult alcohol misuse among gay and bisexual men. Journal of Homosexuality, 64(8), 1012–1025. https://doi.org/10.1080/00918369.2016.1242332
Woo, Y. J., & Seneviratne, M. (2021). Derivation and clinical verification of postoperative major adverse kidney event (MAKE) models in abdominal emergency surgeries. Kidney360, 2(3), 415–424. https://doi.org/10.34067/KID.0005232020
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