A phase I study to assess safety, pharmacokinetics, and pharmacodynamics of a vaginal insert containing tenofovir alafenamide and elvitegravir

Abstract

BackgroundNew multi-purpose prevention technology (MPT) products are needed to prevent human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV2). In this study, we evaluated a fast-dissolve insert that may be used vaginally or rectally for prevention of infection.ObjectiveTo describe the safety, acceptability, multi-compartment pharmacokinetics (PK), and in vitro modeled pharmacodynamics (PD) after a single vaginal dose of an insert containing tenofovir alafenamide (TAF) and elvitegravir (EVG) in healthy women.MethodsThis was a Phase I, open-label, study. Women (n=16) applied one TAF (20mg)/EVG (16mg) vaginal insert and were randomized (1:1) to sample collection time groups for up to 7 days post dosing. Safety was assessed by treatment-emergent adverse events (TEAEs). EVG, TAF and tenofovir (TFV) concentrations were measured in plasma, vaginal fluid and tissue, and TFV-diphosphate (TFV-DP) concentration in vaginal tissue. PD was modeled in vitro by quantifying the change in inhibitory activity of vaginal fluid and vaginal tissue against HIV and HSV2 from baseline to after treatment. Acceptability data was collected by a quantitative survey at baseline and post treatment.ResultsThe TAF/EVG insert was safe, with all TEAEs graded as mild, and acceptable to participants. Systemic plasma exposure was low, consistent with topical delivery, while high mucosal levels were detected, with median TFV vaginal fluid concentrations exceeding 200,000 ng/mL and 1,000 ng/mL for up to 24 hours and 7 days post dosing, respectively. All participants had vaginal tissue EVG concentrations of > 1 ng/mg at 4 and 24 hours post dosing. The majority had tissue TFV-DP concentrations exceeding 1000 fmol/mg by 24 – 72 hours post dosing. Vaginal fluid inhibition of HIV-1 and HSV-2 in vitro significantly increased from baseline and was similarly high at 4 and 24 hours post dosing. Consistent with high tissue TFV-DP concentrations, p24 HIV antigen production from ectocervical tissues infected ex vivo with HIV-1 significantly decreased from baseline at 4 hours post dosing. HSV-2 production from tissue also decreased post treatment.ConclusionsA single dose of TAF/EVG inserts met PK benchmarks, with PK data supporting an extended window of high mucosal protection. PD modeling supports mucosal protection against both HIV-1 and HSV-2. The inserts were safe and highly acceptable.Clinical trial registrationClinicalTrials.gov, identifier NCT03762772.

Formulation Development of Topical Inserts Containing Doxycycline and Doxycycline Combined with Tenofovir Alafenamide and Elvitegravir for the Prevention of Sexually Transmitted Infections

“…Furthermore, in previous studies in NHPs and women, TAF/EVG inserts with a very similar composition to the ones reported in this paper rapidly disintegrated in the vagina, achieving high concentrations of TAF and EVG at the first timepoint of sample collection, 2 and 4 h, respectively, after insertion [21,46]. Future research should explore the dissolution behaviors of DOX and TED inserts under physiologically relevant and clinical conditions.…”

“…In a previous CONRAD Phase I clinical study of tenofovir and emtricitabine vaginal inserts, although insert dissolution proceeded at a slower-than-expected rate, drug release commenced as soon as the inserts were imbibed in fluid (manuscript in preparation). Furthermore, in previous studies in NHPs and women, TAF/EVG inserts with a very similar composition to the ones reported in this paper rapidly disintegrated in the vagina, achieving high concentrations of TAF and EVG at the first timepoint of sample collection, 2 and 4 h, respectively, after insertion [21,46]. Future research should explore the dissolution behaviors of DOX and TED inserts under physiologically relevant and clinical conditions.…”

Formulation Development of Topical Inserts Containing Doxycycline and Doxycycline Combined with Tenofovir Alafenamide and Elvitegravir for the Prevention of Sexually Transmitted Infections

“…Furthermore, in previous studies in NHPs and women, TAF/EVG inserts with a very similar composition to the ones reported in this paper rapidly disintegrated in the vagina, achieving high concentrations of TAF and EVG at the first timepoint of sample collection, 2 and 4 h, respectively, after insertion [21,46]. Future research should explore the dissolution behaviors of DOX and TED inserts under physiologically relevant and clinical conditions.…”

“…In a previous CONRAD Phase I clinical study of tenofovir and emtricitabine vaginal inserts, although insert dissolution proceeded at a slower-than-expected rate, drug release commenced as soon as the inserts were imbibed in fluid (manuscript in preparation). Furthermore, in previous studies in NHPs and women, TAF/EVG inserts with a very similar composition to the ones reported in this paper rapidly disintegrated in the vagina, achieving high concentrations of TAF and EVG at the first timepoint of sample collection, 2 and 4 h, respectively, after insertion [21,46]. Future research should explore the dissolution behaviors of DOX and TED inserts under physiologically relevant and clinical conditions.…”

Preclinical Pharmacokinetics of a Triple-Combination Intravaginal Ring for HIV Prevention

“…Reformulation of the TDF-FTC-EVG/EVG(Na) pod-IVR to eliminate one of the NRTI agents simply would entail omitting the corresponding drug pods and would have no impact on the release characteristics of the remaining drugs. Doncel and colleagues at CONRAD are developing an on-demand, fast-dissolving insert delivering TAF and EVG for vaginal and rectal HIV-1 PrEP and post-exposure prophylaxis (PEP), and these efforts have proceeded to clinical trials [69,70,71,72]. A TDF-EVG(Na) IVR would constitute a logical complement to this promising product.…”

Innovations in monoclonal antibody-based multipurpose prevention technology (MPT) for the prevention of sexually transmitted infections and unintended pregnancy

“…There is already a precedent for using hydrogels and dissolvable polymer matrices to prevent HSV-2 and HIV transmission through the delivery of small-molecule antiviral drugs such as tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) and elvitegravir (EVG) to the vagina or rectum ( 82 – 85 ). The first human clinical trial to topically deliver mAbs to the vagina was the MABGEL trial which delivered three HIV mAbs, 2F5, 4E10, and 2G12 in 2.5 ml of gel.…”

Formulation Development of Topical Inserts Containing Doxycycline and Doxycycline Combined with Tenofovir Alafenamide and Elvitegravir for the Prevention of Sexually Transmitted Infections

“…Furthermore, in previous studies in NHPs and women, TAF/EVG inserts with a very similar composition to the ones reported in this paper rapidly disintegrated in the vagina, achieving high concentrations of TAF and EVG at the first timepoint of sample collection, 2 and 4 h, respectively, after insertion [21,46]. Future research should explore the dissolution behaviors of DOX and TED inserts under physiologically relevant and clinical conditions.…”

“…In a previous CONRAD Phase I clinical study of tenofovir and emtricitabine vaginal inserts, although insert dissolution proceeded at a slower-than-expected rate, drug release commenced as soon as the inserts were imbibed in fluid (manuscript in preparation). Furthermore, in previous studies in NHPs and women, TAF/EVG inserts with a very similar composition to the ones reported in this paper rapidly disintegrated in the vagina, achieving high concentrations of TAF and EVG at the first timepoint of sample collection, 2 and 4 h, respectively, after insertion [21,46]. Future research should explore the dissolution behaviors of DOX and TED inserts under physiologically relevant and clinical conditions.…”

Preclinical Pharmacokinetics of a Triple-Combination Intravaginal Ring for HIV Prevention

“…Reformulation of the TDF-FTC-EVG/EVG(Na) pod-IVR to eliminate one of the NRTI agents simply would entail omitting the corresponding drug pods and would have no impact on the release characteristics of the remaining drugs. Doncel and colleagues at CONRAD are developing an on-demand, fast-dissolving insert delivering TAF and EVG for vaginal and rectal HIV-1 PrEP and post-exposure prophylaxis (PEP), and these efforts have proceeded to clinical trials [69,70,71,72]. A TDF-EVG(Na) IVR would constitute a logical complement to this promising product.…”

Innovations in monoclonal antibody-based multipurpose prevention technology (MPT) for the prevention of sexually transmitted infections and unintended pregnancy

“…There is already a precedent for using hydrogels and dissolvable polymer matrices to prevent HSV-2 and HIV transmission through the delivery of small-molecule antiviral drugs such as tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) and elvitegravir (EVG) to the vagina or rectum ( 82 – 85 ). The first human clinical trial to topically deliver mAbs to the vagina was the MABGEL trial which delivered three HIV mAbs, 2F5, 4E10, and 2G12 in 2.5 ml of gel.…”

Formulation Development of Topical Inserts Containing Doxycycline and Doxycycline Combined with Tenofovir Alafenamide and Elvitegravir for the Prevention of Sexually Transmitted Infections

“…Furthermore, in previous studies in NHPs and women, TAF/EVG inserts with a very similar composition to the ones reported in this paper rapidly disintegrated in the vagina, achieving high concentrations of TAF and EVG at the first timepoint of sample collection, 2 and 4 h, respectively, after insertion [21,46]. Future research should explore the dissolution behaviors of DOX and TED inserts under physiologically relevant and clinical conditions.…”

“…In a previous CONRAD Phase I clinical study of tenofovir and emtricitabine vaginal inserts, although insert dissolution proceeded at a slower-than-expected rate, drug release commenced as soon as the inserts were imbibed in fluid (manuscript in preparation). Furthermore, in previous studies in NHPs and women, TAF/EVG inserts with a very similar composition to the ones reported in this paper rapidly disintegrated in the vagina, achieving high concentrations of TAF and EVG at the first timepoint of sample collection, 2 and 4 h, respectively, after insertion [21,46]. Future research should explore the dissolution behaviors of DOX and TED inserts under physiologically relevant and clinical conditions.…”

Preclinical Pharmacokinetics of a Triple-Combination Intravaginal Ring for HIV Prevention

“…Reformulation of the TDF-FTC-EVG/EVG(Na) pod-IVR to eliminate one of the NRTI agents simply would entail omitting the corresponding drug pods and would have no impact on the release characteristics of the remaining drugs. Doncel and colleagues at CONRAD are developing an on-demand, fast-dissolving insert delivering TAF and EVG for vaginal and rectal HIV-1 PrEP and post-exposure prophylaxis (PEP), and these efforts have proceeded to clinical trials [69,70,71,72]. A TDF-EVG(Na) IVR would constitute a logical complement to this promising product.…”

Innovations in monoclonal antibody-based multipurpose prevention technology (MPT) for the prevention of sexually transmitted infections and unintended pregnancy

“…There is already a precedent for using hydrogels and dissolvable polymer matrices to prevent HSV-2 and HIV transmission through the delivery of small-molecule antiviral drugs such as tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF) and elvitegravir (EVG) to the vagina or rectum ( 82 – 85 ). The first human clinical trial to topically deliver mAbs to the vagina was the MABGEL trial which delivered three HIV mAbs, 2F5, 4E10, and 2G12 in 2.5 ml of gel.…”