In vivo release of levonorgestrel from Sino-implant (II) — an innovative comparison of explant data

Callahan, Rebecca L.; Taylor, Douglas; Jenkins, David W.; Owen, Derek H.; Cheng, Linan; Cancel, Aïda; Dorflinger, Laneta J.; Steiner, Markus J.

doi:10.1016/j.contraception.2015.06.028

Cited by 5 publications

(10 citation statements)

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“…The target sample size of 51 explant sets per group was estimated to provide approximately 80% power to detect differences in LNG release profiles between the device groups at the .05 significance level. Power was estimated by simulating 2000 sets of data generated under a nonlinear model previously used to describe Jadelle® release rates [ 13 ] and available sparse Sino Implant (II) data [ 12 ]. A single device was randomly chosen for months with more than one available; for months with no data, the device removed closest in time was chosen.…”

Section: Methodsmentioning

confidence: 99%

“…Due to the small number of removals done at study clinics, explants were available for only 10 women in the China study. Removed explants from both studies were washed according to a cleaning protocol developed by the University of North Carolina Infectious Diseases Research Laboratory [ 12 ]. Explants were then shipped to Shanghai Dahua Pharmaceutical Co. (China) for LNG content testing using a validated high-performance liquid chromatography method for lot release testing that was approved by WHO as part of the Sino-implant (II) prequalification process 1 .…”

Section: Methodsmentioning

confidence: 99%

“…Prior to conducting the DR trial, four of the authors (M.S., D.T., D.J., L.D.) estimated and compared LNG release rates using sparse Sino-implant (II) data and historical reports for Jadelle® and concluded that the devices may have similar clinical performance through 3 years [ 12 ]. That exploratory analysis was limited because duration of implant use was not precisely known and there were no subject-level Jadelle® data available to the authors.…”

Section: Introductionmentioning

confidence: 99%

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Levonorgestrel release rates measured through analysis of two-rod contraceptive explants

et al. 2020

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Objective The objective was to characterize and compare in vivo rates of levonorgestrel (LNG) release from Sino-implant (II) and Jadelle® contraceptive implants. Study design We sampled 48 Sino-implant (II) and 49 Jadelle® explant sets for residual LNG content from participants treated for up to 51 months in a randomized contraceptive efficacy trial in the Dominican Republic (DR). Additional Sino-implant (II) explants were obtained from 8 women who became pregnant in the DR trial and 10 who contributed 3 to 5 years of use in a cohort study in China. Baseline LNG loads were estimated from five unused implant sets per device type. Release profiles were estimated using mixture models that captured initial burst fractions and compared with efficacy and pharmacokinetics data from the DR trial. Results Estimated baseline LNG loads for Sino-implant (II) and Jadelle® were 142.8 mg and 150.5 mg, respectively (vs. the labeled 150 mg). There was an initial burst release of drug (5.6% and 7.9%, respectively) followed by an exponential decrease in LNG content evident for each device. Release rates were significantly lower for Sino-implant (II) throughout the treatment period, with estimated rates after 3 years of 24.2 mcg/day and 29.0 mcg/day for Sino-implant (II) and Jadelle®, respectively. The estimated Sino-implant (II) rate after 3 years was similar to the predicted rate after 5 years (23.6 mcg/day) for Jadelle® (rate ratio: 1.03; 95% confidence interval: 0.92–1.13). Conclusions Sino-implant (II) LNG release rates were significantly lower than Jadelle® with Sino-implant (II) rates through year 3 comparable to Jadelle® rates through year 5. These results reinforce the 3-year duration of action for which Sino-implant (II) was prequalified by the World Health Organization. Implications This analysis confirms the WHO prequalification of Sino-implant (II) for 3 years of use and supports different durations of action for Jadelle® and Sino-implant (II). It provides additional evidence that this approach can complement efficacy trials in determining duration of action of hormonal contraceptives in general.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Levonorgestrel release rates measured through analysis of two-rod contraceptive explants

et al. 2020

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“…Silicone matrix implants are widely used for contraceptive implants and cost less than US$10 for generic versions of an implant that is effective for 5 years 26 . But the daily doses required for long-acting hormonal contraception, which, after an initial burst phase, typically release doses of active agents of 50 micrograms or less per day, 27 is about 2 orders of magnitude less than the daily amount to be released from the current long-acting nanoemulsion of cabotegravir. Thus, even if some of the new very potent, long-acting ARV candidates prove to be substantially more potent in humans than cabotegravir, it seems only to be realistic currently to imagine a duration of up to 1 year, even with an optimal formulation.…”

Section: Implants That Are Easier To Implement: Biodegradable and Refmentioning

confidence: 99%

Long-Acting HIV Treatment and Prevention: Closer to the Threshold

Barnhart

2017

Glob Health Sci Pract

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Substantial progress has been made toward viable, practical long-acting approaches to deliver HIV treatment and prevention through: (1) continued improvements in long-acting antiretrovirals (ARVs); (2) better innovative delivery systems; and (3) collaboration of willing partners to advance new ARVs. More progress on those 3 fronts is still needed to arrive at the goal of optimized HIV treatment and prevention for all who would benefit—and of finally controlling the HIV epidemic.

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“…This approach has been applied to products for other indications as well. Data on residual drugs extracted from explanted contraceptive implants (Sino-Implant (II) and Jadelle) at various time points have been used to estimate monthly and daily levonorgestrel release rates [ 73 ]. This methodology could potentially be applied to vaginal rings such that predictive models are applied to residual drug levels in removed vaginal rings at various times to evaluate adherence.…”

Section: Cumulative Measuresmentioning

confidence: 99%

Biomarkers and biometric measures of adherence to use of ARV‐based vaginal rings

Stalter

Moench

MacQueen

et al. 2016

Journal of the International AIDS Society

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IntroductionPoor adherence to product use has been observed in recent trials of antiretroviral (ARV)-based oral and vaginal gel HIV prevention products, resulting in an inability to determine product efficacy. The delivery of microbicides through vaginal rings is widely perceived as a way to achieve better adherence but vaginal rings do not eliminate the adherence challenges exhibited in clinical trials. Improved objective measures of adherence are needed as new ARV-based vaginal ring products enter the clinical trial stage.MethodsTo identify technologies that have potential future application for vaginal ring adherence measurement, a comprehensive literature search was conducted that covered a number of biomedical and public health databases, including PubMed, Embase, POPLINE and the Web of Science. Published patents and patent applications were also searched. Technical experts were also consulted to gather more information and help evaluate identified technologies. Approaches were evaluated as to feasibility of development and clinical trial implementation, cost and technical strength.ResultsNumerous approaches were identified through our landscape analysis and classified as either point measures or cumulative measures of vaginal ring adherence. Point measurements are those that give a measure of adherence at a particular point in time. Cumulative measures attempt to measure ring adherence over a period of time.DiscussionApproaches that require modifications to an existing ring product are at a significant disadvantage, as this will likely introduce additional regulatory barriers to the development process and increase manufacturing costs. From the point of view of clinical trial implementation, desirable attributes would be high acceptance by trial participants, and little or no additional time or training requirements on the part of participants or clinic staff. We have identified four promising approaches as being high priority for further development based on the following measurements: intracellular drug levels, drug levels in hair, the accumulation of a vaginal analyte that diffuses into the ring, and the depletion of an intrinsic ring constituent.ConclusionsWhile some approaches show significant promise over others, it is recommended that a strategy of using complementary biometric and behavioural approaches be adopted to best understand participants’ adherence to ARV-based ring products in clinical trials.

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In vivo release of levonorgestrel from Sino-implant (II) — an innovative comparison of explant data

Cited by 5 publications

References 10 publications

Levonorgestrel release rates measured through analysis of two-rod contraceptive explants

Levonorgestrel release rates measured through analysis of two-rod contraceptive explants

Long-Acting HIV Treatment and Prevention: Closer to the Threshold

Biomarkers and biometric measures of adherence to use of ARV‐based vaginal rings

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