Integrating Pharmacokinetic, Pharmacogenomic, and Clinical Risk Data to Individualise Hormonal Contraception and Minimise Thrombotic Risk: A Translational Framework.

Integrating Pharmacokinetic, Pharmacogenomic, and Clinical Risk Data to Individualise Hormonal Contraception and Minimise Thrombotic Risk: A Translational Framework. | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 3 March 2026 V1 Latest version Share on Integrating Pharmacokinetic, Pharmacogenomic, and Clinical Risk Data to Individualise Hormonal Contraception and Minimise Thrombotic Risk: A Translational Framework. Author : Benedict Ibifuro Green 0009-0000-3837-9464 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.177251408.89256802/v1 177 views 65 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Individualizing hormonal contraception requires integrating clinical risk with drug exposure determinants. We performed a comprehensive narrative evidence synthesis combining epidemiology, mechanistic coagulation studies, physiologically‑based pharmacokinetic (PBPK) modelling, drug–drug interaction (DDI) literature and pharmacogenetic reports to clarify how pharmacokinetic and genetic factors alter contraceptive hormone exposure and influence thrombotic risk. Epidemiologic data confirm increased venous thromboembolism (VTE) risk with combined oestrogen–progestin methods and minimal baseline risk with progestin‑only or non‑hormonal methods; inherited thrombophilias amplify absolute risk. PBPK studies and clinical DDI reports demonstrate that strong CYP3A4 inducers (e.g., rifampicin, certain antiepileptics) substantially reduce systemic steroid exposure – effects variably mitigated by route (intrauterine and depot methods less affected than oral or transdermal). Pharmacogenetic evidence, though limited, indicates clinically meaningful variability in exposure for steroid substrates of CYP3A isoforms and transporters (notably variant CYP3A5 expression influencing implant exposure in some populations). Synthesizing these domains, we propose a translational framework to: (1) quantify exposure-modifying DDIs using PBPK-informed heuristics, (2) prioritize routes/methods least impacted by metabolism or adherence concerns, and (3) target thrombophilia/genotype testing where results would change management. We discuss gaps limiting quantitative risk prediction (heterogeneous genotype data, sparse prospective outcome studies) and propose research priorities, including prospective PBPK–epidemiology linkages and pharmacogenetic validation. This synthesis aims to equip clinicians and clinical pharmacologists with a practical, mechanistically grounded approach to safer, personalized contraceptive selection. Introduction: Hormonal contraception remains essential to reproductive health worldwide. However, exogenous oestrogens and some progestins increase venous (and, less commonly, arterial) thrombotic risk. Venous thromboembolism (VTE) incidence in combined oral contraceptive (COC) users is 6–12 per 10,000 woman‑years compared with 2–4 in non‑users, translating to thousands of preventable events annually through optimised method selection and risk stratification (1–4). Clinicians must weigh contraceptive benefits against individualised thrombotic risk that arises from baseline patient factors, inherited thrombophilias, and concomitant medications that alter steroid exposure or independently elevate thrombotic risk. Recent comprehensive guidance, meta‑analyses and physiologically based pharmacokinetic (PBPK) modelling approaches allow more nuanced, evidence‑based counselling and method selection. (1–4) Despite availability of evidence-based guidelines, contraceptive selection often fails to integrate pharmacokinetic and pharmacogenetic factors that modify both efficacy and safety. Clinicians lack practical tools to quantify exposure changes under drug-drug interaction scenarios or to identify patients who would benefit from genotype-guided method selection. Physiologically based pharmacokinetic modelling has matured to enable in silico prediction of contraceptive exposure under interacting drug regimens, increasingly accepted by regulatory agencies for labelling decisions when prospective outcome trials are impractical. This review integrates guideline statements, systematic reviews, mechanistic biomarker studies, pharmacokinetic/pharmacogenetic data and cost‑effectiveness analyses to inform practical clinical decision‑making and to identify research priorities. Scope and methods: We synthesized current national and international guidelines (1,2), systematic reviews and meta-analyses (3,4), key mechanistic and pharmacokinetic/pharmacogenetic studies, and health economic evaluations to provide an evidence-based, clinician-focused framework. We searched PubMed, Embase, and Cochrane Library (inception to December 2024) using terms: (hormonal contraception OR combined oral contraceptive OR progestin) AND (venous thromboembolism OR thrombosis OR thrombophilia) AND (pharmacokinetics OR drug interaction OR CYP3A4 OR pharmacogenetics). Priority was given to high-impact guideline documents and systematic reviews for baseline recommendations (1,2,3,4), then to prospective cohorts for risk quantification (5,6), mechanistic biomarker studies (11,12,13), physiologically based pharmacokinetic (PBPK) model evidence (17,18,19,20), clinical pharmacology studies of drug-drug and gene-drug interactions (14,15,16,21,22,23,24,25), health economic evaluations (7,26), and translational research (30). Evidence quality was assessed using established criteria for systematic reviews, prospective studies, and PBPK model validation. The aim is a translational synthesis rather than a formal systematic review, integrating epidemiologic, mechanistic, pharmacokinetic, and pharmacogenetic domains into a practical clinical framework. Epidemiology and magnitude of risk: Combined oral contraceptives increase VTE risk relative to non‑use; effect size varies by oestrogen dose and progestin type. Meta‑analytic evidence quantifies multiplicative risk when COCs are combined with inherited thrombophilias (notably Factor V Leiden [FVL] and prothrombin G20210A mutation), significantly elevating absolute VTE incidence in carriers compared with non‑carriers on COCs (4). National medical eligibility criteria summarize absolute risk thresholds and contraindications, assisting safe prescribing across populations (2). Age ≥35 years, obesity (BMI ≥30 kg/m²), smoking and prior personal or strong family VTE history further increase absolute risk and modify counselling (5,6,7). Table 1 presents quantitative estimates of absolute VTE risk across contraceptive methods and thrombophilia status. Table 1. Absolute venous thromboembolism risk estimates (events per 10,000 woman‑years) Non‑user, baseline (reproductive age) 2–4 COC (low‑dose EE + levonorgestrel) 5-7 COC EE + desogestrel / gestodene / drospirenone) 9-12 COC + Factor V Leiden heterozygote 25-35 COC + FVL homozygote or compound thrombophilia <50 Progestin‑only pill / LNG‑IUD / copper IUD 2–3 (near baseline) Etonogestrel implant ~2–3 (near baseline) EE, ethinylestradiol; LNG, levonorgestrel; IUD, intrauterine device. Data synthesized from refs 3,4,5,6. Arterial thrombotic events (myocardial infarction, ischemic stroke) are also elevated by COCs, especially in women who smoke, are aged aura; the same eligibility framework applies (2,8). Pathophysiology and biomarkers linking hormones to thrombosis: Oestrogen components of COCs induce a prothrombotic shift: increased hepatic synthesis of procoagulant factors (II, VII, VIII, X, fibrinogen), reduced natural anticoagulants (protein S, antithrombin), acquired activated protein C (APC) resistance independent of Factor V Leiden, and altered fibrinolysis. These changes are dose‑ and formulation‑dependent. Progestins exert variable effects: androgenic progestins (levonorgestrel, norethindrone) may partially offset estrogenic lipid changes, whereas newer progestins (desogestrel, gestodene, drospirenone) appear metabolically neutral or favourable but have been associated with higher VTE risk in some observational studies – likely reflecting differential oestrogen metabolism, SHBG induction, or residual confounding (3). Observational biomarker studies demonstrate elevated thrombin generation, endogenous thrombin potential (ETP), and APC resistance ratios in COC users and in carriers of specific mutations (protein S K196E, FVL) on low‑dose COCs, mechanistically linking formulation and genotype to thrombotic phenotype (11,12,13). Progestin‑only methods (desogestrel‑only pill, levonorgestrel IUD, etonogestrel implant, depot medroxyprogesterone acetate) lack oestrogen and produce minimal or no prothrombotic biomarker changes, explaining their near‑baseline VTE risk (3,14). Contraceptive formulation, route and comparative safety: VTE risk varies substantially across methods. Oestrogen‑containing formulations – particularly those with higher ethinylestradiol doses (≥50 µg) and third‑ or fourth‑generation progestins – confer greater risk than low‑dose levonorgestrel‑containing COCs. Progestin‑only methods (oral pills, subdermal implants, levonorgestrel‑releasing intrauterine systems) and non‑hormonal copper IUDs show VTE incidence near baseline (Table 1). Long‑acting reversible contraceptives (LARCs – implants and IUDs) offer additional advantages: superior typical‑use efficacy, elimination of daily adherence burden, and avoidance of hepatic first‑pass metabolism that may reduce susceptibility to certain drug‑drug interactions (3,16,15,14). National medical eligibility frameworks (US MEC, WHO MEC) provide method‑specific recommendations stratified by clinical characteristics, designating combined hormonal methods as category 3 (risks usually outweigh benefits) or 4 (unacceptable health risk) for women with personal VTE history, known high‑risk thrombophilia, or multiple risk factors, while supporting progestin‑only and non‑hormonal options as category 1 or 2 (2,8). Inherited thrombophilia, family history and targeted screening: Inherited thrombophilias - notably Factor V Leiden (FVL; prevalence \sout(2–3%)) markedly increase VTE risk. When combined with COCs, risk amplifies multiplicatively: absolute VTE incidence in FVL heterozygotes on COCs reaches 25–35 per 10,000 woman‑years, and in homozygotes or compound heterozygotes exceeds 50 per 10,000 woman‑years, shifting clinical recommendations away from oestrogen‑containing methods (4,5,6). A targeted, history‑based approach to thrombophilia testing is supported by cohort and counselling impact studies (6,7,11,13,26). Test when: • Personal history of unprovoked or oestrogen‑associated VTE • Strong family history (first‑degree relative with VTE at age <50 years or recurrent/unprovoked VTE) and patient is considering oestrogen‑containing contraception • Unusual VTE presentation (cerebral, mesenteric, or recurrent thrombosis) Do not routinely screen asymptomatic women with no personal or family history; universal pre‑prescription thrombophilia testing lacks cost‑effectiveness except in selected high‑prevalence or high‑pretest‑probability contexts (6,7). Economic evaluations confirm that routine screening generates substantial costs with minimal health gains, whereas risk‑prediction tools incorporating clinical factors (age, BMI, smoking, family history) can improve targeting of testing and counselling (26,27). Drug‑drug interactions, pharmacogenetics and exposure‑driven contraceptive failure Contraceptive steroid exposure – and thus efficacy – can be significantly altered by drug‑drug interactions (DDIs) and genetic variation in metabolizing enzymes and transporters. CYP3A4 induction (by rifampin, some antiepileptics [carbamazepine, phenytoin, topiramate], certain antiretrovirals [efavirenz, nevirapine], and herbal products [St John’s wort]) reduces systemic exposure to ethinylestradiol and progestins, increasing contraceptive failure risk. Real‑world adverse‑event analyses link CYP3A4 inducers to higher reported unintended pregnancies, with route‑specific vulnerability: oral formulations are most susceptible; implants show intermediate risk (exposure reductions documented but variable clinical impact); intrauterine methods are least affected (14,16,24). Clinical actionability of pharmacogenetic testing: Current evidence supports genotype-guided contraceptive selection in specific scenarios: CYP2B6 and CYP3A5 testing before etonogestrel implant plus efavirenz/nevirapine co-administration, where variant alleles predict subtherapeutic exposure and documented contraceptive failures (15,21). Pharmacogenetic interactions also occur with vaginally administered hormonal contraceptives and antiretrovirals, though systemic exposure profiles differ from oral routes (22). Routine genotyping before contraceptive initiation in the absence of interacting drugs is not currently supported by evidence and is not cost-effective. PBPK and semimechanistic pharmacokinetic models have quantified levonorgestrel and norgestimate exposure changes under DDI scenarios, defined minimum effective exposure thresholds, and enabled exposure‑bracketing approaches that predict contraceptive efficacy without large outcome trials—an increasingly accepted regulatory and clinical tool (17,18,18,20). For example, model‑based meta‑analysis identified levonorgestrel AUC and trough thresholds required for ovulation suppression, allowing prediction of failure risk when interacting drugs reduce exposure below these margins (17). Pharmacogenetic variation modifies baseline metabolism and can alter DDI magnitude. Studies in women using etonogestrel implants with efavirenz or nevirapine demonstrate that CYP2B6 and CYP3A5 genotypes influence the degree of etonogestrel exposure reduction, with some genotype combinations producing subtherapeutic concentrations and documented contraceptive failures (15,21). Vaginally administered hormonal contraceptives also show pharmacogenetic interactions with antiretrovirals, though systemic exposure and interaction profiles differ from oral routes (22). Genetic variation in ethinylestradiol first‑pass metabolism and sex hormone‑binding globulin (SHBG) may further modulate individual VTE risk, though clinical translation remains investigational (27). Phase II enzyme interactions are emerging: inhibition of sulfotransferase SULT1E1 by investigational drugs has been shown to increase ethinylestradiol exposure, illustrating non‑CYP mechanisms relevant to contraceptive safety and efficacy (25). Laboratory assessment and diagnostic strategy When thrombophilia testing is indicated, select assays suited to the clinical question and interpret results in the context of current contraceptive use and timing relative to acute thrombotic events. • Activated protein C (APC) resistance assays (APTT‑based or dilute Russell viper venom time [RVVT]‑based) screen for Factor V Leiden; sensitivity and specificity differ by method, and current COC use can produce acquired APC resistance, confounding interpretation (13). • Endogenous thrombin potential (ETP)‑based APC resistance tests have been validated for research and regulatory investigation of contraceptive‑associated prothrombotic effects and offer standardized quantification of coagulation activation (11). • Genetic testing for FVL (F5 R506Q), prothrombin G20210A (F2 G20210A), and—when clinically indicated—antithrombin, protein C and protein S deficiencies should be performed only when results will influence contraceptive choice or anticoagulation decisions . Testing during acute thrombosis or on anticoagulation may yield false results; defer or interpret cautiously (4,12,13). Clinicians should collaborate with haematology or specialized thrombosis services for complex cases, including women with prior VTE, multiple thrombophilias, or antiphospholipid syndrome. Integrated clinical decision framework Evidence demonstrates that individualised contraceptive selection reduces thrombotic morbidity. The following structured approach operationalizes current evidence: Step 1: Assess baseline thrombotic risk • Personal history of VTE (provoked or unprovoked) • Strong family history (first‑degree relative, age <50 y or recurrent VTE) • Known inherited thrombophilia • Age ≥35 years • BMI ≥30 kg/m² • Current smoking • Immobility, recent surgery, active cancer • Comorbidities: hypertension, diabetes, migraine with aura • Apply national medical eligibility criteria (US MEC, WHO MEC) for method categorization (2,6,5,8) Step 2: Assess drug‑drug interaction risk • Current or planned use of strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin, topiramate, efavirenz, nevirapine, St John’s wort) • Antiretroviral therapy (assess specific agent interaction profiles and consider pharmacogenetic testing if implant is preferred; 15,21,22) • Other interacting medications (review product labelling and interaction databases) Step 3: Select contraceptive method High thrombotic risk (personal VTE history, known high‑risk thrombophilia [FVL homozygote, compound thrombophilia, antithrombin/protein C/S deficiency], or multiple strong risk factors): • Use progestin‑only methods (LNG‑IUD, copper IUD, etonogestrel implant, desogestrel‑only pill, DMPA) or non‑hormonal methods (copper IUD, barrier) • Avoid all oestrogen‑containing methods (COCs, patch, ring) • Counsel on absolute risk (Table 1), VTE signs/symptoms, and when to seek care Moderate thrombotic risk (single risk factor: age 35–39, BMI 30–34.9, controlled hypertension, family history without known thrombophilia): • Recommend progestin‑only or non‑hormonal LARC as first‑line • If patient prefers combined hormonal method and accepts risk, use lowest‑dose ethinylestradiol (≤30 µg) with levonorgestrel; avoid higher‑risk progestins • Counsel on absolute vs relative risk, shared decision‑making Low thrombotic risk (no risk factors): • All methods medically eligible; counsel on comparative safety, efficacy, non‑contraceptive benefits, and patient preference • Prefer low‑dose levonorgestrel‑containing COCs over third‑/fourth‑generation progestins when combined hormonal methods are chosen • LARC methods offer superior typical‑use efficacy and should be discussed as first‑line options Significant drug‑drug interaction risk (strong CYP3A4 inducers, interacting ARVs): • Recommend LARC methods least susceptible to interactions: LNG‑IUD or copper IUD (14,16) • If etonogestrel implant is preferred, review pharmacokinetic/pharmacogenetic data for the specific interacting drug; consider genotyping (CYP2B6, CYP3A5) if available and implant + efavirenz/nevirapine combination is planned (15,21) • Avoid oral‑only methods when strong inducers are used long‑term • Counsel on barrier backup or alternative methods; document interaction and plan in medical record Step 4: Thrombophilia testing (when indicated) • Test only when results will change management: • Personal VTE history (to guide duration of anticoagulation and contraceptive choice) • Strong family history and patient considering oestrogen‑containing method • Use validated assays; interpret in clinical context (timing, current contraceptive use, anticoagulation status) • Do not perform routine screening in asymptomatic women without personal or family history (6,7). Step 5: Shared decision‑making and informed consent • Discuss absolute risk (number needed to harm), not just relative risk • Use decision aids or risk calculators where available (26) • Acknowledge trade‑offs: efficacy, bleeding patterns, non‑contraceptive benefits (acne control, dysmenorrhea reduction, endometriosis management), convenience • Respect patient preferences and values; some may accept higher VTE risk for cycle control or other benefits; others prioritize lowest possible risk • Document discussion and decision. • Example: For a 28-year-old with BMI 32 kg/m² and no other risk factors considering COC, absolute VTE risk increases from 3/10,000 to ~7-9/10,000 woman-years (Table 1), an additional 4-6 events per 10,000 women per year, or number needed to harm ~1,700-2,500 per year. Compare this to typical-use pregnancy risk with barrier methods (15%) versus COC (<1%), framing the trade-off numerically. Step 6: Monitoring and follow‑up: • Educate on VTE warning signs (leg pain/swelling, chest pain, dyspnoea, neurologic symptoms) • Reassess risk annually and when clinical status changes (new comorbidity, medication change, surgery planned) • For women on anticoagulation seeking contraception, collaborate with haematology to balance bleeding risk (heavy menstrual bleeding on anticoagulants) with thrombotic risk; progestin‑only methods (especially LNG‑IUD) often reduce menstrual blood loss and are preferred (28) Special populations and practical considerations: • Adolescents: Rising prevalence of obesity and sedentary lifestyles increases baseline VTE risk in adolescents. Clinicians should assess BMI, activity level, and family history; counsel on LARC methods (LNG‑IUD, implant) as first‑line when risk factors are present. Behavioural interventions (physical activity, screen‑time reduction) complement contraceptive counselling. Shared decision‑making that incorporates adolescent preferences and addresses misconceptions about LARC is essential (29). • People on antiretroviral or anti‑tuberculosis therapy: Drug and genotype interactions with implants and depot methods necessitate use of pharmacokinetic/pharmacogenetic data to guide method choice. Where evidence indicates significant exposure loss (e.g., etonogestrel implant + efavirenz), favour LARC with demonstrated retained efficacy (LNG‑IUD, copper IUD) or combined non‑hormonal options. If hormonal LARC is chosen despite interaction risk, document rationale, provide barrier backup counselling, and monitor closely. Vaginally administered hormonal methods show different PK and interaction profiles; data remain limited (15,21,22). • Anticoagulated patients: Women on anticoagulation for prior VTE or other indications face dual challenges: elevated baseline thrombotic risk (contraindicating oestrogen) and increased menstrual bleeding on anticoagulants. Progestin‑only methods—particularly LNG‑IUD—reduce menstrual blood loss and are preferred. Collaborate with haematology to individualize anticoagulation intensity, contraceptive choice, and bleeding management. Avoid oestrogen‑containing methods; counsel on copper IUD (effective but may increase bleeding) vs hormonal IUD trade‑offs (28). • Perimenopausal and older reproductive‑age women: Age ≥35 years, especially combined with smoking or other risk factors, elevates VTE and arterial thrombotic risk. Apply strict eligibility criteria; combined hormonal methods are contraindicated in smokers ≥35 years. Progestin‑only and non‑hormonal methods are preferred. Transition planning to menopause and discussion of menopausal hormone therapy (distinct risk profile) should be integrated into contraceptive counselling (2,8). Screening, cost‑effectiveness and health‑systems implications: Economic evaluations consistently demonstrate that routine thrombophilia screening before COC prescription is not cost‑effective in unselected populations. Costs of universal testing (laboratory, follow‑up, counselling) outweigh health gains, given the low prevalence of high‑risk thrombophilias and availability of safer contraceptive alternatives. Targeted testing in women with elevated pretest probability (personal/family VTE history) improves cost‑effectiveness and aligns testing with clinical decision points (7). Incorporating clinical risk‑prediction tools (that integrate age, BMI, smoking, family history) into electronic health records and contraceptive counselling workflows can improve risk stratification, reduce unnecessary testing, and guide method selection without added cost. Population‑level adoption of LARC‑first counselling frameworks in higher‑risk groups may reduce VTE incidence and healthcare costs (26,7). Research gaps and future directions: Key priorities to advance individualized contraceptive safety include: 1. Prospective outcome studies linking modelled exposure reductions to contraceptive failure across formulations, routes and interacting drug regimens - bridging the gap between PK data and real‑world effectiveness. 2. Large, genotype‑stratified cohort studies quantifying absolute VTE risk in carriers of FVL, prothrombin G20210A, and rarer thrombophilias on modern low‑dose formulations and progestin‑only methods; current data derive largely from European cohorts and older, higher‑dose COCs. 3. Standardized, multi‑ancestry pharmacogenetic studies of contraceptive metabolism and response, with sufficient power to detect clinically actionable gene–drug and gene–gene interactions beyond CYP3A and CYP2B6. 4. Biomarker validation studies to refine laboratory risk stratification: prospective evaluation of ETP‑based APC resistance, thrombin generation assays, and other prothrombotic markers as predictors of clinical VTE in contraceptive users. 5. Pragmatic trials of targeted thrombophilia screening strategies incorporating clinical risk scores, family history algorithms, and cost and patient‑cantered outcomes, to define optimal testing thresholds and workflows. 6. Continued refinement of PBPK models and exposure‑bracketing frameworks to predict contraceptive efficacy and safety under DDI and genetic variation scenarios, supporting regulatory decisions and clinical guideline development when direct outcome RCTs are impractical (17,18,19,20). 7. Implementation science research on contraceptive decision aids, shared decision‑making tools, and point‑of‑care risk calculators – evaluating uptake, usability, and impact on method selection and patient satisfaction (22). 8. Long‑term safety and effectiveness data for ultra‑low‑dose oestrogen formulations, oestriol‑containing COCs, and novel progestin‑only methods in diverse populations and high‑risk groups. Regulatory agencies (FDA, EMA) increasingly accept PBPK and exposure‑response modelling to assess generic contraceptive products and DDI labelling, validating the translational use of PK data when clinical outcome trials are not feasible (20). This paradigm supports evidence‑based guideline development and individualized prescribing (20). Limitations This narrative synthesis has limitations. First, as a non-systematic review, our search strategy may not have captured all relevant studies; however, we prioritised high-quality systematic reviews (3,4) and guidelines (1,2,8) that themselves employed systematic methods. Second, heterogeneity in study populations (age, ethnicity, contraceptive formulations, outcome definitions) limits quantitative synthesis. Third, PBPK model predictions (17,18,19,20), while increasingly validated and accepted by regulatory agencies (20), represent in silico estimates that require clinical confirmation; we highlighted where prospective outcome data are lacking. Fourth, pharmacogenetic evidence derives predominantly from African populations using efavirenz-based ART with implants (15,21); generalizability to other populations, drugs, and contraceptive methods requires further study. Finally, this review reflects evidence available through December 2024; the fields of PBPK modelling and pharmacogenomics are rapidly evolving. Conclusion: Safe, effective contraceptive care requires individualised assessment of thrombotic risk, informed method selection, and attention to drug‑drug and gene‑drug interactions that can reduce efficacy or increase harm. Use targeted, history‑based thrombophilia testing when results will change management; prefer progestin‑only or non‑hormonal LARC methods in high‑risk scenarios; apply mechanistic biomarker and PBPK modelling data to guide decisions when empirical outcome data are limited. Shared decision‑making that incorporates absolute risk estimates, patient preferences, and trade‑offs across contraceptive attributes optimises outcomes. Ongoing research to connect exposure changes with clinical outcomes, refine risk‑prediction tools, and evaluate implementation strategies will further enable safer, personalised contraceptive care for diverse populations. Acknowledgement: Dr Nathalie Smilovici Dr Aidan Baker Conflict of interest statement : The author(s) do not declare any conflict of interest Funding: this review was unfunded and totally on author(s) own time. References: 1. Skeith L, Bates SM. Estrogen, progestin, and beyond: thrombotic risk and contraceptive choices. 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Authors Affiliations Benedict Ibifuro Green 0009-0000-3837-9464 [email protected] Tameside and Glossop Integrated Care NHS Foundation Trust View all articles by this author Metrics & Citations Metrics Article Usage 177 views 65 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Benedict Ibifuro Green. Integrating Pharmacokinetic, Pharmacogenomic, and Clinical Risk Data to Individualise Hormonal Contraception and Minimise Thrombotic Risk: A Translational Framework.. Authorea . 03 March 2026. DOI: https://doi.org/10.22541/au.177251408.89256802/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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