The effectiveness of the barrier method and oral contraceptive pills depends on correct and consistent use and inconsistent use remains a significant cause of unintended pregnancy. Alternative contraceptive products are desired to improve user compliance and give better health outcomes. Such products can utilise drugs already used in oral pills, reformulating them to mean they do not need to be taken daily. To support the development of these products it would be useful to further explore their pharmacokinetics, the way the body absorbs, distributes, and gets rid of the drug, as this affects both how well they work and the rate of side effects.
This study aims to assess the use of real-world data to look at the safety of hormonal contraceptives (both short and long acting) and the rate of any unintended pregnancies. This is to explore if the data can be used to inform pharmacokinetic modelling and ultimately support rapid drug development and review of new long-acting formulations of contraceptive products. This would enable possible development of further long-acting contraceptive formulations which would benefit women, in terms of improving compliance of contraceptives and hence reduce unintended pregnancies.
The study will include women aged 13 – 55 years, who are prescribed a contraceptive of interest (initial focus will be on levonorgestrel) in the time-period 01/08/1996 to 31/07/2021. The study will first describe the data available in the CPRD, including the rate of side effects and unintended pregnancies, and then use the data to validate and refine pharmacokinetic models.
It is estimated that about 34% of pregnancies are unplanned. The factors associated with unintended pregnancy are attributed to sexual activity without the use of contraception, while failure of contraception used consistently is uncommon, inconsistent use of contraception remains a significant cause of unintended pregnancies.
The overall aim of the study is to assess the use of real-world data for establishing the effectiveness and safety of hormonal contraceptives and its value in informing a pharmacokinetic-pharmacodynamic (PKPD) model to assess the feasibility of an exposure-based bracketing approach to support rapid drug development and review of long-acting contraceptive formulations. This would enable possible development of further long acting contraceptive formulations which would benefit women, by improving compliance of contraceptives and hence reduce unintended pregnancies.
The study population will include all women, aged 13 – 55 years at the time of prescription, registered in a CPRD contributing practice with acceptable data receiving at least one prescription for a contraceptive of interest in England between 01/08/1996 and 31/07/2021.
This is a descriptive study using a retrospective cohort design. The primary exposure is hormonal contraceptive use, focussing on levonorgestrel in the first instance. The primary outcomes are pregnancy and adverse events potentially related to hormonal contraceptive use. Rates for these outcomes will be calculated and stratified by other covariates.
Mathematical models to describe the change in the contraceptive concentration in the body over time after dosing via different formulations (the drug pharmacokinetics) will be developed from previously published work. Individual patient level data from this study will then be used to verify if these models correctly describe actual observations and scenarios, then verified models are planned to be used to predict drug exposure and effects in various other scenarios both for drug development applications and in clinical practice.
The outcomes to be measured are:
- Pregnancy occurring while using a hormonal contraceptive
• With a secondary outcome to look at the type of pregnancy outcome – where that information is available and is feasible e.g. full-term pregnancy, pre-term pregnancy, post-term, ectopic, stillbirth, spontaneous or induced abortion.
- Possible adverse events linked to hormonal contraceptive use, including
• Nausea and vomiting
• Lower abdominal pain
• Headache
• Dizziness
• Depressed mood
• Anxiety and nervousness
• Acne
• Hirsutism
• Hair loss
• Vaginitis
• Thromboembolic disorders
• Pulmonary embolism
• Stroke
• Myocardial Infarction
• Hypersensitivity Reactions and Injection/implant site reactions (for relevant formulations)
Further details, including feasibility, of the outcomes are listed in the Exposures, Outcomes and Covariates section.
Preeti Datta-Nemdharry - Chief Investigator - MHRA
Sophie Scanlon - Corresponding Applicant - MHRA
Andrew Butler - Collaborator - MHRA
Andrew Owen - Collaborator - University of Liverpool
Daniela Bozadzhieva - Collaborator - MHRA
Henry Pertinez - Collaborator - University of Liverpool
Katherine Donegan - Collaborator - MHRA
Susan Cole - Collaborator - MHRA
Andrew Butler - Collaborator - MHRA
Eman El-Khateeb - Collaborator - University of Liverpool
HES Admitted Patient Care;CPRD Aurum Pregnancy Register