Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

Haazen, Wouter

doi:10.4172/2155-6113.1000355

Cited by 6 publications

(5 citation statements)

References 20 publications

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“…It should be noted that for rings releasing very low quantities of drug such that plasma levels are extremely low and highly variable (e.g. the dapivirine-releasing matrix-type vaginal ring [150][151][152][153], any potential correlation may be lost in the noise. For reservoir-type rings, which offer near-constant daily in vitro release rates, plasma concentrations are observed to remain almost constant or to decline slowly with time [30,36,154].…”

Section: Different Levels Of Ivivcmentioning

confidence: 99%

In vitro release testing methods for drug-releasing vaginal rings

Boyd

Variano

Spence

et al. 2019

Journal of Controlled Release

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Drug-releasing vaginal rings are torus-shaped devices, generally fabricated from thermoplastics or silicone elastomers, used to administer pharmaceutical drugs to the human vagina for periods typically ranging from three weeks to twelve months. One of the most important product performance tests for vaginal rings is the in vitro release test. Although it has been fifty years since the a vaginal ring device was first described in the scientific literature, and despite seven drug-releasing vaginal rings having been approved for market, there is no universally accepted method for testing in vitro drug release, and only one non-compendial shaking incubator method (for the estradiol-releasing ring Estring ®) is described in the US Food and Drug Administration's Dissolution Methods Database. Here, for the first time, we critically review the diverse range of test methods that have been described in the scientific literature for testing in vitro release of drugreleasing vaginal rings. Issues around in vitro-in vivo correlation and modelling of in vitro release data are also discussed.

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Section: Different Levels Of Ivivcmentioning

confidence: 99%

In vitro release testing methods for drug-releasing vaginal rings

Boyd

Variano

Spence

et al. 2019

Journal of Controlled Release

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“…Since the concept of these 'topical virucides' was first proposed back in 1990 (Stein, 1990), almost three decades of extensive research effort have elapsed and a handful of lead candidate products having reached late stage clinical testing. Currently the most developmentally advanced vaginal microbicide product is a vaginal ring device containing the experimental antiretroviral agent dapivirine (DPV; formerly known as TMC-120) dispersed in a silicone elastomer matrix-type ring and intended for continuous use over 28 days (Malcolm et al, 2005;McCoy et al, 2017;Nel et al, 2016aNel et al, , 2016bNel et al, , 2014aNel et al, , 2014bNel et al, , 2009Romano et al, 2009). In 2016, the results of two pivotal Phase III clinical studies were reported demonstrating that the DPV ring significantly reduced the risk of HIV-1 infection in women and was well-tolerated (Baeten et al, 2016;Nel et al, 2016b).…”

Section: Introductionmentioning

confidence: 99%

Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers

Bashi

McCoy

Murphy

et al. 2019

International Journal of Pharmaceutics

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With a dapivirine-releasing vaginal ring having successfully completed late-stage clinical testing for HIV prevention and currently undergoing regulatory review, there is now growing interest in next-generation multipurpose prevention technologies that seek to combine antiretroviral and contraceptive drugs within a single product. Here, we focus on ongoing efforts to develop a silicone elastomer vaginal ring releasing both dapivirine and levonorgestrel. Specifically, we evaluate various strategies aimed at both better understanding and reducing the tendency of levonorgestrel to bind with the elastomer, including: (i) formulation and post-manufacturing strategies aimed at reducing the extent of levonorgestrel reaction with addition-cure silicone elastomers; (ii) evaluation of a simple silicone system to model the complex elastomer; (iii) use of model compounds representing the enone and ethinyl moieties of levonorgestrel to probe the mode of addition of levonorgestrel to addition-cure silicone elastomers; and (iv) solution and solid-state 13 C-NMR analysis to probe the structural features of the levonorgestrel-silicone system. The results demonstrate that both the enone and ethinyl groups within levonorgestrel undergo hydrosilylation reaction with hydrosiloxane groups in the silicone elastomer leading to binding. The results also highlight potential strategies for further optimising the dapivirine+levonorgestrel silicone vaginal ring formulation to ensure that the levonorgestrel is available for release.

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“…Since there is no significant difference in SVF+Tween solubility between the polymorphs (Table 6), possible explanations include differences in silicone elastomer solubility between the two forms of DPV, or differences in drug distribution at the surface of the ring devices. Given that much greater variability in drug concentrations are observed in vaginal ring pharmacokinetic studies, 28,30,[53][54][55] it is highly unlikely that these relatively small differences in in vitro release over early timepoints would be clinically significant.…”

Section: In Vitro Releasementioning

confidence: 99%

“…[7][8][9][10][11][12] A wide range of formulation strategies have been reported for vaginal administration of DPV, [13][14][15][16][17][18] the most advanced and the most promising of which are silicone elastomer vaginal rings. [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] Two Phase III efficacy studies -The Ring Study (IPM027) and APSIRE (MTN-020) -involving more than 4,500 women volunteers across southern and eastern Africa have recently been completed, designed to support licensure of a monthly matrix-type silicone elastomer vaginal ring containing 25 mg micronized DPV intended for 28-day continuous use (DPV Ring-004). The studies showed approximately 30% reduced incidence of HIV infection in women compared to a placebo, the first time two studies have confirmed statistically significant efficacy for a HIV microbicide.…”

Section: Introductionmentioning

confidence: 99%

Packing Polymorphism of Dapivirine and Its Impact on the Performance of a Dapivirine-Releasing Silicone Elastomer Vaginal Ring

McCoy

Murphy

Boyd

et al. 2017

Journal of Pharmaceutical Sciences

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A silicone elastomer vaginal ring providing sustained release over 28 days of the anti-retroviral microbicide dapivirine has recently completed phase III clinical testing and showed moderate protection against HIV acquisition. In support of the product licensure program, we report the impact of dapivirine packing polymorphism on the thermal and solubility characteristics of dapivirine and on the in vitro performance of the 25 mg dapivirine ring product. This is the first time that polymorphism has been reported for a drug-releasing vaginal ring product. Thermal, particle size, powder X-ray diffraction, and thermodynamic solubility analyses of dapivirine polymorphic forms I and IV, both of which are persistent at room temperature and with form I being the thermodynamically stable form, were conducted for both micronized and non-micronized materials. No significant differences in solubility between DPV forms I and IV were observed in media commonly used for in vitro release testing. Matrix-type silicone elastomer vaginal rings were manufactured and the impact of dapivirine polymorphism on key in vitro parameters (compression and tensile behavior; content assay; in vitro release; residual content assay) was investigated. The data demonstrate that dapivirine packing polymorphism has no significant impact on in vitro performance of the 25 mg dapivirine vaginal ring.

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Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

Cited by 6 publications

References 20 publications

In vitro release testing methods for drug-releasing vaginal rings

In vitro release testing methods for drug-releasing vaginal rings

Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers

Packing Polymorphism of Dapivirine and Its Impact on the Performance of a Dapivirine-Releasing Silicone Elastomer Vaginal Ring

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