Currently available combined oral contraception

Kimble, Thomas; Thurman, Andrea Ries; Schwartz, Jill L.

doi:10.1586/eog.11.48

“…Because HIV‐1 infection requires lifelong therapy, 1 GSK3640254 is expected to be coadministered with common medications, including combined oral contraceptives 10 . Combined oral contraceptives contain synthetic oestrogenic and progestin hormones, including ethinyl oestradiol and levonorgestrel, respectively, that inhibit ovulation by suppressing the release of follicle‐stimulating hormone (FSH) and luteinizing hormone (LH) 11 . Because decreased ethinyl oestradiol and levonorgestrel concentrations may reduce the efficacy of combined oral contraceptives, it is critical to characterize potential drug interactions when these medications are given in combination with novel or emerging therapies such as GSK3640254.…”

Section: Introductionmentioning

confidence: 99%

Lack of pharmacokinetic interaction between the HIV‐1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women

Dumitrescu

¹

,

Greene

²

,

Joshi³

et al. 2021

Brit J Clinical Pharma

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Aims: GSK3640254 is a next-generation maturation inhibitor likely to be coadministered with combined oral contraceptives in HIV-positive women.Methods: This phase I, open-label, 1-way study assessed pharmacokinetic and pharmacodynamic interactions of GSK3640254 200 mg and ethinyl oestradiol 0.03 mg/ levonorgestrel 0.15 mg once daily in healthy female participants who received ethinyl oestradiol/levonorgestrel for 10 days with a moderate-fat meal after which GSK3640254 was added from Days 11 to 21. Primary endpoints were area under the plasma concentration-time curve to the end of the dosing interval (AUC 0-t ), maximum observed concentration (C max ) and plasma concentration at the end of the dosing interval (C τ ) for ethinyl oestradiol and levonorgestrel. Serum follicle-stimulating hormone, luteinizing hormone and progesterone concentrations were determined.Adverse events were monitored.Results: Among 23 enrolled participants, 17 completed the study. Geometric least squares mean ratios (with vs. without GSK3640254) of AUC 0-t , C max and C τ were 0.974, 0.970 and 1.050 for ethinyl oestradiol and 1.069, 1.032 and 1.083 for levonorgestrel, respectively. Three participants had elevated progesterone levels, which occurred before GSK3640254 administration in 2 participants. No participants had elevated follicle-stimulating hormone or luteinizing hormone values. Fourteen participants (61%) reported adverse events. Four participants reported asymptomatic elevated transaminase levels meeting liver-stopping criteria; of these, 3 events occurred before GSK3640254 administration and led to study withdrawal. Conclusion:Ethinyl oestradiol/levonorgestrel plus GSK3640254 coadministration did not affect steady-state pharmacokinetics or pharmacodynamics of ethinyl oestradiol Employee of GlaxoSmithKline Teodora Pene Dumitrescu, Jianfeng Xu or PPD Theresa T. Pham at the time of the study.The authors confirm that the Principal Investigator for this paper is Theresa T. Pham and that she had direct clinical responsibility for participants.

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“…In oral steroid contraceptives composed of both exogenous estrogen and progesterone, progesterone induces anovulation by preventing the midcycle rise in LH secretion [ 41 , 42 ]. This is due to progesterone’s suppression of follicular development and gonadotropin secretion [ 43 ].…”

Section: Methodsmentioning

confidence: 99%

Toward an optimal contraception dosing strategy

Gavina

¹

,

Reyes

²

,

Olufsen

³

et al. 2023

PLoS Comput Biol

4

0

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Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to attain this state to achieve contraception. However, large doses are associated with adverse effects such as increased risk for thrombosis and myocardial infarction. This study utilizes optimal control theory on a modified menstrual cycle model to determine the minimum total exogenous estrogen/progesterone dose, and timing of administration to induce anovulation. The mathematical model correctly predicts the mean daily levels of pituitary hormones LH and FSH, and ovarian hormones E2, P4, and Inh throughout a normal menstrual cycle and reflects the reduction in these hormone levels caused by exogenous estrogen and/or progesterone. Results show that it is possible to reduce the total dose by 92% in estrogen monotherapy, 43% in progesterone monotherapy, and that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. Finally, we show that by combining estrogen and progesterone the dose can be lowered even more. These results may give clinicians insights into optimal formulations and schedule of therapy that can suppress ovulation.

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“…In oral steroid contraceptives composed of both exogenous estrogen and progesterone, progesterone induces anovulation by preventing the midcycle rise in LH secretion [34, 35]. This is due to progesterone’s suppression of follicular development and gonadotropin secretion [36].…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, the lack of follicle growth results in an inadequate amount of estradiol inhibiting the LH surge [3]. The estrogen component suppresses FSH secretion blocking folliculogenesis, stabilizing the endometrium, which minimize bleeding [35, 37].…”

Section: Methodsmentioning

confidence: 99%

Toward an optimal contraception dosing strategy

Gavina

¹

,

Reyes

²

,

Olufsen

³

et al. 2022

Preprint

1

0

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Anovulation refers to a menstrual cycle characterized by the absence of ovulation. Exogenous hormones such as synthetic progesterone and estrogen have been used to attain this state to achieve contraception. However, large doses are associated with adverse effects such as increased risk for thrombosis and myocardial infarction. This study utilizes optimal control theory on a modified menstrual cycle model to determine the minimum total exogenous estrogen/progesterone dose, and timing of administration to induce anovulation. The mathematical model correctly predicts the mean daily levels of pituitary hormones LH and FSH, and ovarian hormones E2, P4, and Inh throughout a normal menstrual cycle and reflects the reduction in these hormone levels caused by exogenous estrogen and/or progesterone. Results show that it is possible to reduce the total dose by 92% in estrogen monotherapy, 43% in progesterone monotherapy, and that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. Finally, we show that by combining estrogen and progesterone the dose can be lowered even more. These results may give clinicians insights into optimal formulations and schedule of therapy that can suppress ovulation.AUTHOR SUMMARYHormonal contraceptives composed of exogenous estrogen and/or progesterone are commonly administered artificial means of birth control. Despite many benefits, adverse side effects associated with high doses such as thrombosis and myocardial infarction, cause hesitation to usage. Our study presents an improved mathematical model for hormonal control of the menstrual cycle and applies optimal control theory to minimize total exogenous estrogen and/or progesterone dose, and determine timing of administration that lead to contraception. We observe a reduction in dosage of about 92% in estrogen monotherapy and 43% in progesterone monotherapy. Our simulations show that it is most effective to deliver the estrogen contraceptive in the mid follicular phase. In addition, we illustrate that combination therapy significantly lower doses further. Our findings may give clinicians insights into optimal dosing scheme for contraception.

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Currently available combined oral contraception

Cited by 6 publications

References 74 publications

Lack of pharmacokinetic interaction between the HIV‐1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women

Lack of pharmacokinetic interaction between the HIV‐1 maturation inhibitor GSK3640254 and combination oral contraceptives in healthy women

Toward an optimal contraception dosing strategy

Toward an optimal contraception dosing strategy

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